the asymmetric synthesis of polyfunctional pyrrolidine
TRANSCRIPT
University of Wollongong Theses Collection
University of Wollongong Theses Collection
University of Wollongong Year
The asymmetric synthesis of
polyfunctional pyrrolidine alkaloids and
their analogues
Karl B. LindsayUniversity of Wollongong
Lindsay, Karl B, The asymmetric synthesis of polyfunctional pyrrolidine alkaloids andtheir analogues, PhD thesis, Department of Chemistry, University of Wollongong, 2003.http://ro.uow.edu.au/theses/167
This paper is posted at Research Online.
http://ro.uow.edu.au/theses/167
i
The Asymmetric Synthesis of Polyfunctional
Pyrrolidine Alkaloids and Their Analogues
A thesis submitted in fulfillment of the
requirements for the award of the degree DOCTOR OF PHILOSOPHY
from
UNIVERSITY OF WOLLONGONG
by
Karl B Lindsay, BSc (Hons) University of Wollongong Department of Chemistry
Wollongong, Australia October 2003
ii
Declaration I, Karl Lindsay hereby confirm that all material in this thesis is my own work, conducted in
the chemistry department at the University of Wollongong. This material has not been
submitted for qualifications at any other academic institution.
Date
K. B. Lindsay
iii
Publications Arising from this Thesis Lindsay, K. B.; Pyne, S. G. Asymmetric synthesis of (-)-swainsonine, (+)-1,2-di-epi-
swainsonine, and (+)-1,2,8-tri-epi-swainsonine J. Org. Chem 2002, 67, 7774-7780.
Lindsay, K. B.; Tang, M.; Pyne, S. G. Diastereoselective synthesis of polyfunctional
pyrrolidines via vinyl epoxide aminolysis/ring-closing metathesis: synthesis of chiral 2,5-
dihydropyrroles and (1R,2S,7R,7aR)-1,2,7-trihydroxypyrrolizidine Synlett 2002, 731-734.
Davis, A. S; Gates, N. J; Lindsay, K. B; Tang, M; Pyne, S. G. A new strategy for the
diastereoselective synthesis of polyfunctional pyrrolidines Synlett 2004, 49-52.
iv
Table of Contents
Title page. i
Declaration. ii
Publications Arising from this Thesis. iii
Table of Contents. iv-vii
List of Schemes, Figures and Tables. viii-xi
List of Abbreviations. xii-xv
Abstract. xvi
Acknowledgements. xvii
Chapter 1 : General Introduction. 1
1.1 Stemona Alkaloids. 1
1.1.1 Introduction to Stemona Alkaloids. 1
1.1.2 Synthesis of Stemona Alkaloids. 3
1.2 Indolizidine Alkaloids. 17
1.2.1 Introduction to Indolizidine Alkaloids. 17
1.2.2 Synthesis - Chiral Pool Methods. 19
1.2.3 Synthesis - Asymmetric Methods. 28
1.3 Proposed Synthetic Approach. 35
Chapter 2 : Synthesis of Vinyl Epoxides. 41 2.1 Chloroallyboration. 41
2.2 Nicolaou's Six Step Approach. 42
2.2.1 Alkyne Homologation. 44
2.2.2 Reduction of Propargylic alcohols. 45
2.2.3 Epoxidation of Allylic Alcohols. 47
2.2.4 Oxidation of Epoxy Alcohols to Aldehydes. 49
2.2.5 Wittig Olefination. 50
v
Chapter 3 : Aminolysis and Early Model Studies. 52
3.1 Aminolysis with Allylamine. 52
3.2 Synthesis of the (+)-Croomine CD Ring System. 53
3.3 Synthesis of 1-Substituted Allyl Amines. 56
Chapter 4 : Indolizidine Alkaloids. 61
4.1 (-)-Swainsonine. 61
4.1.1 Aminolysis and Metathesis. 61
4.1.2 Cyclisation and Dihydroxylation. 61
4.1.3 Failed Alternatives. 65
4.2 Synthesis of (+)-1,2 Di-epi-swainsonine. 66
4.3 Synthesis of (+)-1,2,8 Tri-epi-swainsonine. 69
4.4 (-)-Swainsonine Revisited . 70
4.5 Synthesis of a Polyhydoxylated Pyrrolo[1,2-a]azepine. 73
4.6 An Oxazolidinone Based Approach to (-)-Swainsonine. 75
4.6.1 Oxazolidinone Synthesis. 75
4.6.2 Dihydroxylation. 77
4.6.3 (-)-Swainsonine Perfected. 79
Chapter 5 : Stemona Alkaloids Revisited. 81
5.1 Aminolysis with Hindered Amines. 81
5.2 Early Protection Problems. 83
5.3 An Attempted Organolithium Approach. 84
5.4 Protecting Group Studies. 86
5.5 Further Aminolysis Studies. 89
5.6 Oxazolidinones as Protecting Groups for Metathesis. 91
5.7 Elaboration Towards (+)-Croomine. 94
Chapter 6 : Conclusions and Future Directions. 103
6.1 Conclusions. 103
vi
6.2 Future Directions. 106
Chapter 7 Experimental. 108
7.1 General Experimental. 108
7.2 General Experimental Methods. 110
7.2.1 General Method for Silylation of Primary Alcohols. 110
7.2.2 General Method for PMB Protection of Primary Alcohols. 112
7.2.3 General Method for Homologation of Alkynes to Propargylic
Alcohols. 114
7.2.4 General Method for Lindlar Hydrogenation of Propagylic Alcohols. 117
7.2.5 General Method for REDAL Reduction of Propargylic Alcohols. 119
7.2.6 General Method for m-CPBA Epoxidation of Allylic Alcohols. 120
7.2.7 General Method for Sharpless Asymmetric Epoxidation of Allylic
Alcohols. 121
7.2.8 General Methods for Oxidation of Alcohols to Aldehydes. 124
7.2.9 General Method for Wittig Olefination. 127
7.2.10 General Methods for Aminolysis of Vinyl Epoxides. 130
7.2.11 General Method for N-Boc Protection of Amines. 134
7.2.12 General Method for Ring Closing Metathesis. 137
7.2.13 General Method for Hydrogenation of 2,5-Dihydropyrroles. 142
7.2.14 General Method for Secondary Alcohol Silylation. 144
7.2.15 General Method for cis-Dihydroxylation with OsO4. 150
7.2.16 General Method for Alcohol Benzylation. 153
7.2.17 General Method for TFA Deprotection of N-Boc and
N-Boc/O-PMB derivatives. 160
7.2.18 General Method for Appel Cyclisation of Amino Alcohols. 163
7.2.19 General Method for Debenzylation of Benzyl Ethers via
Hydrogenation. 167
7.3 Miscellaneous Experimental Methods. 171
7.3.1 Experimental for Chapter 2. 171
7.3.2 Experimental for Chapter 3. 172
vii
7.3.3 Experimental for Chapter 4. 175
7.3.4 Experimental for Chapter 5. 185
Chapter 8 : References. 214
viii
List of Schemes, Figures and Tables Figure 1.1: The 1-aza-bicyclic ring system. 1
Figure 1.2: Picture of Stemona root. 2
Figure 1.3: Stemona alkaloids and the pyrrolo[1,2-a]azepine core. 2
Scheme 1.1: Willaims' synthesis of (+)-croomine. 4
Scheme 1.2: Morimoto's N-acyliminium approach to pyrrolidinyllactones. 5
Scheme 1.3: Wipf's synthesis of the (-)-tuberostemonine tricyclic core. 5
Scheme 1.4: Rigby's synthesis of the (-)-tubersotemonine tricyclic core. 6
Scheme 1.5: Kende's synthesis of (±)-isostemofoline. 7
Scheme 1.6: Jacobi's synthesis of (-)-stemoamide. 8
Scheme 1.7: Jung's synthesis of the (-)-stenine tricyclic core. 9
Scheme 1.8: Aube's synthesis of (±)-stenine. 10
Scheme 1.9: Hinman's synthesis of the BCD ring system of (+)-croomine. 11
Scheme 1.10: Kende's synthesis of (±)-stemonamide and (±)-isostemonamide. 12
Scheme 1.11: Williams' synthesis of (-)-stemospironine. 13
Scheme 1.12: Gurjar's synthesis of (-)-stemoamide. 14
Scheme 1.13: Wipf's synthesis of (-)-tuberostemonine. 16
Scheme 1.14: Booker-Milburn's synthesis of the neotuberostemonine tetracyclic
core. 17
Figure 1.4: Examples of indolizidine alkaloids. 18
Scheme 1.15: Mootoo's synthesis of (-)-swainsonine. 19
Scheme 1.16: Mootoo's synthesis of (+)-castanospermine. 20
Scheme 1.17: Singh's synthesis of (+)- and (-)-lentiginose. 21
Scheme 1.18: Perez's synthesis of a (-)-swainsonine analogue. 22
Scheme 1.19: Carmona's synthesis of tetrahydroxyindolizidines. 23
Scheme 1.20: Pearson's synthesis of 6- and 7-substituted (-)-swainsonine
analogues. 24
Scheme 1.21: Pearson's synthesis of 3-benzyloxymethyl (-)-swainsonine
analogues. 25
Scheme 1.22: Pearson's improved synthesis of (-)-swainsonine. 25
ix
Scheme 1.23: Polt's synthesis of (-)-8-epi and (+)-1,2-diepi-swainsonine. 26
Scheme 1.24: Pilli's synthesis of (+)-lentiginose. 27
Scheme 1.25: Paolucci's synthesis of di- and tetra-hydroxy indolizidines. 28
Scheme 1.26: Blechert's synthesis of (-)-swainsonine. 29
Scheme 1.27: Katsuki's synthesis of (-)-swainsonine. 30
Scheme 1.28: Carretero's synthesis of (-)-swainsonine. 31
Scheme 1.29: Genisson's synthesis of (-)-lentiginose. 32
Scheme 1.30: Somfai's synthesis of (+)-castanospermine. 33
Scheme 1.31: Trost's synthesis of (-)-swainsonine. 34
Scheme 1.32: A general retro-synthetic analysis of 1-aza-bicyclic systems. 36
Scheme 1.33: Ring closing metathesis of protected diallylamines. 37
Scheme 1.34: Beaks synthesis of bicyclic lactams via ring closing metathesis. 37
Scheme 1.35: Hanessians trimethylstannyl radical carbocyclisation. 38
Scheme 1.36: Summary of Somfai's divergent approach to β-amino alcohols. 40
Scheme 2.1: Vinyl epoxides via chloroallylboration. 42
Scheme 2.2: Flexible synthesis of vinyl epoxides from alkynes. 43
Table 2.1: Summary of alkyne homologation results. 44
Table 2.2: Summary of propargyl alcohol reduction results. 45
Figure 2.1: Partial 1H NMR spectra of 212c and 212d showing the difference
between the E and Z alkene protons. 46
Table 2.3: Summary of epoxidation results. 47
Scheme 2.3: Synthesis of a Mosher ester. 49
Figure 2.2 Diagram showing the Sharpless nmenonic for epoxidation of
allylic alcohols. 49
Table 2.4: Summary of results for the oxidation of epoxy alcohols to
aldehydes. 49
Table 2.5: Summary of results for Wittig olefination. 51
Scheme 3.1: Aminolysis of vinyl epoxides with allyl amine catalysed with
p-TsOH.H2O. 53
Scheme 3.2: N-Boc protection and ring closing metathesis. 53
Scheme 3.3: Possible mechanisms of vinyl epoxide aminolysis. 55
x
Scheme 3.4: Synthesis of CD ring system of (+)-croomine. 55
Scheme 3.5: Failed aminolysis of a vinyl epoxide with ammonia. 57
Scheme 3.6: Retro-synthetic analysis of (+)-croomine. 57
Scheme 3.7: Synthesis of the amine fragment via deallyation. 58
Scheme 3.8: Mechanism for the formation of an unexpected product from
deallyation. 59
Scheme 4.1: Aminolysis and ring closing metathesis. 61
Scheme 4.2: Synthesis of (-)-swainsonine - the first approach. 62
Figure 4.1: Diagram showing the preferred face of attack in the
dihydroxylation of dehydroindolizidines. 64
Scheme 4.3: Failed protecting group alternatives. 65
Scheme 4.4: Pivaloyl ester as a protecting group for the secondary alcohol. 66
Scheme 4.5: Synthesis of (+)-1,2-di-epi-swainsonine. 67
Scheme 4.6: Synthesis of (+)-1,2,8-tri-epi-swainsonine. 70
Scheme 4.7: Synthesis of a benzylated dehydroindolizidine. 71
Scheme 4.8: Dihydroxylations of the O-benzyl dehydroindolizidine. 71
Scheme 4.9: Completion of the total synthesis of (-)-swainsonine. 73
Scheme 4.10: Synthesis of a polyhydroxylated pyrrolo[1,2-a]azepine. 74
Figure 4.2: Diagram showing the preferred face of attack in the
dihydroxylation of 5,7a-dihydro-1H,3H-
pyrrolo[1,2-c]oxazol-3-one. 75
Scheme 4.11: Synthesis of an oxazolidinone. 77
Scheme 4.12: Dihydroxylation of oxazolidinones. 78
Table 4.1: Summary of dihydroxylation results for the dihydroxylation
of a 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one. 78
Figure 4.3: Diagram showing the matched and mismatched arrangements
with the AD-mix α and β. 79
Scheme 4.13: A second total synthesis of (-)-swainsonine. 80
Scheme 5.1: Aminolysis of a vinyl epoxide with ammonia. 81
Scheme 5.2: Aminolysis of vinyl epoxides with a substituted allylamine. 82
Table 5.1: Summary of results for the aminolysis of a vinyl epoxide with
xi
a substituted amine. 82
Scheme 5.3: Protection and RCM of a hindered amino alcohol. 83
Scheme 5.4: An attempted organolithium approach. 84
Scheme 5.5: Model system of the organolithium approach. 85
Scheme 5.6: Proposed mechanism for the formation of the model system
product. 86
Scheme 5.7: Summary of protecting group explorations. 87
Scheme 5.8: Further protecting group explorations. 87
Scheme 5.9: Still further protecting group explorations. 88
Scheme 5.10: Aminolysis studies. 89
Scheme 5.11: Model study featuring the use of a Cbz carbamate protecting
group. 90
Scheme 5.12: Oxazolidinone metathesis examples. 92
Scheme 5.13: Exploration of the oxazolidinone protecting group. 93
Scheme 5.14: TBS protection in the presence of free amines. 94
Scheme 5.15: The oxazolidinone protecting group in practise. 95
Scheme 5.16: Mechanism for the formation of an aziridine by-product. 96
Scheme 5.17: Manipulations in the oxazolidinone series. 97
Scheme 5.18: Synthesis of the BC ring system of (+)-croomine. 99
Scheme 5.19: Mechanism of Appel cyclisation reaction. 99
Scheme 5.20: Attempted conclusion of (+)-croomine synthesis. 100
Scheme 5.21: Possible mechanism for the formation of a hemiaminal during
oxidation of a hydroxy-azepine. 101
Figure 6.1: Diagram illustrating the flexibility of the methods developed in
this thesis. 103
Scheme 6.1 Summary of the syntheses of (-)-swainsonine and
(+)-1,2-di-epi-swiansonine. 104
Scheme 6.2 Summary of the synthesis of (+)-1,2,8-tri-epi-swainsonine and
the CD ring system of croomine. 104
Scheme 6.3 Summary of the synthesis of pyrrolo[1,2-c]azepines. 105
xii
List of Abbreviations [α]D specific rotation
Ac acetyl
Ac2O acetic anhydride
AIBN azobis(isobutyronitrile)
Aloc allyloxycarbonyl
Ar aromatic
ax axial
BAIB bis-acetoxy iodobenzene
BBN 9-borabicyclo[3.3.1]nonane
Bn benzyl
Boc tert-butyloxycarbonyl
br broad
Bu butyl
Bz benzoyl
CAN ceric(IV) ammonium nitrate
Cbz benzyloxylcarbonyl
CSA camphor sulfonic acid
Cy cyclohexyl
d doublet
δ chemical shift
DABCO 1,4-diazabicyclo[2.2.2]octane
DBB 4,4'-di(tert-butyl)biphenyl
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DEB diethylbenzene
DEPT distortionless enhanced proton spin transfer
DHQ dihydroquinine
xiii
DHQD dihydroquinidine
DIAD diisopropylazadicarboxylate
DIBAL-H diisobutylaluminium hydride dIcp diisopinocampheyl
DIEA diisopropylethylamine
DIPT diisopropyl tartarate DMAP N,N-dimethyl-4-aminopyridine
DMF N,N-dimethylformamide
DMPU 1,3-di-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
DMS dimethyl sulfide
DMSO dimethyl sulfoxide
Et ethyl
eq equatorial
Fmoc florenylmethyloxycarbonyl
FVT flash vacuum thermolysis
Grubbs' cat. benzylidene bis(tricyclohexylphosphine)dichlororuthenium
HMDS hexamethyldisilylamine
HMPA hexamethylphosphoramide
Hz hertz
i iso
IDCP iodonium dicollidine perchorate
LDA lithium diisopropylamide
LiOTf lithium trifluromethanesulfonate
m multiplet
m meta
m-CPBA meta-chloroperoxybenzoic acid
M molar
Me methyl
MEM β-methoxyethoxymethyl
MOM methoxymethyl
m.p. melting point
xiv
Ms mesyl, methanesulfonyl
MS mass spectrometry
M.S. molecular sieves
MTPA Mosher's acid, α-methoxy-α-trifluromethylphenylacetic acid
NDMBA N,N-dimethylbarbituric acid
NMO N-methylmorpholine-N-oxide
Ns Nosyl
o ortho
p pentuplet
p para
PCC pyridinium chlorochromate
pet. sp. petroleum spirit bp 40-60 oC
Piv pivaloyl
Ph phenyl
PHAL phthazine
PMB para-methoxybenzyl
ppm parts per million
PPTS pyridininium 4-toluenesulfonate
Pr propyl
p-Ts tosyl, para-toulenesulfonyl
Pyr pyridine
q quartet
REDAL sodium bis-(2-methoxyethoxy) aluminium hydride
Rf relative mobility
RT room temperature
s singlet
t triplet
t tert
TBAF tetra-n-butylammonium fluoride
TBS tert-butyldimethylsilyl
TBDPS tert-butyldiphenylsilyl
xv
TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxyl
Tf triflyl, trifluromethanesulfonyl
TFA trifluroacetic acid
THF tetrahydrofuran
TIPS triisopropylsilyl
tlc thin layer chomatography
TMEDA tetramethylenediamine
TMS trimethylsilyl
TPAP tetrapropylammoniumperruthenate
xvi
Abstract
The aim of this project was to develop a flexible asymmetric synthesis of 1-aza-
[2+n.3.0] bicyclic ring systems (n=1,2,3). This was accomplished by the aminolysis of
chiral vinyl epoxides followed by ring closing metathesis of the resulting dienes to give a
2,5-dihydropyrroles. These 2,5-dihydropyrroles were very versatile and could readily be
converted to the desired 1-azabicyclic ring structures. Further elaboration to natural
products was also possible.
To this end the synthesis of the indolizidine alkaloid (-)-swainsonine has been
developed via two distinct approaches. Furthermore, the (+)-1,2-di-epi- and (+)-1,2,8-tri-
epi-swainsonine analogues were prepared using similar methods. The first example of a
trihydroxy-pyrrolo[1,2-a]azepine was also prepared.
Our efforts to apply the same synthetic approach to the Stemona alkaloids led to the
successful synthesis of a pyrrolo-butyrolactone model system. Attempts to elaborate the
same methods to the total synthesis of (+)-croomine, were restricted by the extremly
hindered nature of the amino-diene core. Nevertheless the BC ring system of (+)-croomine
was constructed, and the synthesis proceeded as far as the triol 334 which was, in principle,
only three synthetic steps from (+)-croomine. Regrettably transformation of this advanced
intermediate into (+)-croomine could not be achieved in the time available.
xvii
Acknowledgements I am extremely grateful to have benefited form the support, supervision, guidance
and patience of Prof. Stephen Pyne, without whom this project would never have been
concieved. The other members of the Pyne research Group (past and present) have been an
excellent source of both knowledge and entertainment over the past four years, which I am
also grateful for. I thank the University of Wollongong for financial support in the form of
a UPA scholarship. I am thankful for the vast body of support provided by the staff of the
University of Wollongong Chemistry Department, including the NMR support staff,
administration staff, computer support staff and the mass spectroscopy group. Thank you
to Dr Reg Smith at Phytex for the kind provision of an authentic sample of (-)-swainsonine.
Finally thank you to Colette Godfrey, whose love and support have played an essential role
in maintaining my sanity over the course of this project.
1
Chapter 1: Introduction
This thesis is concerned with developing a general method of preparing 1-aza-
[2+n.3.0]-bicyclic ring systems (Figure 1.1). The application of such a method to the total
synthesis of natural products containing these ring systems might then be investigated.
Poly-functionalized 1-aza-[2+n.3.0]-bicyclic rings are a key feature of the pyrrolizidine
(n=1), indolizidine (n=2) and Stemona (n=3) alkaloids, and efficient flexible methods are
required for the total synthesis of these compounds and their analogues. The Stemona and
indolizidine alkaloids are of particular relevance to the work reported herein, therefore a
brief introduction to these alkaloids, and recent synthetic efforts towards them follows.
N)n(
n=1, pyrolizidine alkaloidsn=2, indolizidine alkaloidsn=3, Stemona alkaloids
Figure 1.1 The 1-aza-[2+n.3.0]-bicyclic ring system.
1.1 Stemona Alkaloids 1.1.1 Introduction to Stemona Alkaloids
The Stemona alkaloids are a unique class of chemical compounds, isolated from the
roots of the Stemonaceae family of plants (Figure 1.2). Members of this family, such as S.
tuberosa, S. parviflora and S. japonica, have long been used in traditional Chinese and
Japanese medicines to treat respiratory diseases (e.g. tuberculosis, bronchitis and pertussis),
and also as antihelmintics in animals. For example, the water extracts obtained from the
roots of some Stemonaceae species were widely used in China against human and cattle
parasites, agricultural pests and as domestic insecticides.1
This biological activity has prompted numerous phytochemical studies within the
Stemonaceae species.2 To date more than 40 alkaloids in this class have been isolated from
this species and their structures elucidated. The Stemona alkaloids have attracted a great
deal of recent attention due to the wide range of biological activities they exhibit. (-)-
Tuberostemonine was the first Stemona alkaloid to be tested for biological activity. It was
2
found to inhibit excitatory transmission at the crayfish neuromuscular junction, which is
considered a model for mammalian nervous systems.3 Several other alkaloids in the
Stemona group possess potent insecticidal activity.1
Figure 1.2 Picture of the Roots and Leaves from Stemona tuberosa.
NH
O
OCH3
H
HCH3
O
NCH3
O
OCH3
CH3O
NO
OO
CH3H
H
H
O NH
CH3OH
OO
O
N OO
H H
H
O
CH3
CH3
H
N
(-)-stenine stemonamine (-)-stemoamide
tuberostemospironineparvistemoline pyrrolo[1,2-a]azepine Figure 1.3 Stemona alkaloids from the five major groups, and the pyrrolo[1,2-a]azepine
core.
The vast majority of Stemona alkaloids possess a pyrrolo[1,2-a]azepine (1-
azabicyclo[5.3.0]-decane) ring system as a core unit (Figure 1.3). In addition γ-
3
butyrolactone moieties are extremely common, present as appended, trans-, cis- and spiro-
fused systems. Further structural classification is possible, with the alkaloids (-)-stenine,
(-)-stemoamide, tuberostemospironine, stemonamine and parvistemoline defining the 5
major groups.2 A sixth, miscellaneous group, contains those Stemona alkaloids which
result from cleavage of the basic pyrrolo[1,2-a]azepine nucleus.
1.1.2 Synthesis of Stemona Alkaloids The varied biological activities and synthetically challenging polycyclic structures
of the Stemona alkaloids have prompted numerous synthetic studies.2 The first total
synthesis of a Stemona alkaloid was reported by Williams et al. in 1989, and was concerned
with the preparation of (+)-croomine (Scheme 1.1).4 Methyl-(S)-2-methyl-3-
hydroxypropionate was transformed into the acetylene 1 in 4 steps using standard methods.
Homologation of the alkyne transformed it into ester 2, then a copper-catalysed conjugate
addition of the Grignard reagent BnO(CH2)4MgBr to the alkyne ester, and finally reduction
of the ester with DIBAL-H gave the allylic alcohol 3. Sharpless asymmetric epoxidation,
followed by Swern oxidation of the resulting epoxy alcohol yielded the aldehyde, which
was converted to vinyl epoxide 4 by Wittig olefination. Reduction with LiBH4, followed
by hydrogenation of the resulting product mixture using rhodium on alumina, gave the
saturated alcohol. This was protected as a benzoate ester, before treatment with lithium
azide in DMPU affording the azido compound 5. Reaction with BF3.OEt2 yielded the
saturated dioxepine, then saponification and Swern oxidation gave an unstable aldehyde,
which was subjected to Wittig olefination with the ylide 6 giving compound 7. Acid
hydrolysis of the acetal, followed by saponification gave a triol, which was oxidized using
Jones' reagent to form the lactone ring, giving 8 after methylation of the terminal carboxylic
acid with diazomethane. Removal of the benzyl ether and subsequent oxidation gave the
azido aldehyde, which was treated with PPh3 to form an aza-ylide. Subsequent
intramolecular Wittig condensation gave a seven membered imine, which was reduced with
NaBH4 to give the azepine 9. The final cyclisations of the C and D rings of (+)-croomine
were achieved in a single iodoamination step, by treating 9 with iodine.
This synthesis, together with three total syntheses of (-)-stenine,5-8 four total
syntheses of (-)-stemoamide,9-13 and one additional total synthesis of (+)-croomine,14,15 are
4
comprehensively covered in a recent review.2 Since the publication of this review no less
than eight total syntheses of Stemona alkaloids have been reported, in addition to several
simpler model structures.
MEMO
R
MEMO
OH
BnOMEMO
OBn
OH
COOMe
MEMO
OHN3
BnO
BzO
OO
N3
OBn
BzO
O N3
OBn
O
COOMe
NH
OO
COOMe
HO
N
O
O
O H
H
CH3
H
CH3Ph3P
OBz
croomine
1 R=H2 R=COOMe
a
b,c d-f g-j
k-n o-r s-u
v
A
B
CD
3 4
5
6
7 8
9
Scheme 1.1 Reagents: (a) n-BuLi, THF, -78 oC to 0 oC; then , ClCO2Me, -78 oC, (63 %); (b) BnO(CH2)4MgBr, Me2S.CuBr, TMEDA, Et2O, -78 oC (95%); (c) DIBAL-H, CH2Cl2, -78 oC (98 %); Ti(i-PrO)4 (cat.), D-DIPT (cat.), t-BuOOH, MS 4Å, CH2Cl2, -50 oC (83 %); (e) (COCl)2, DMSO, CH2Cl2, Et3N, -78 oC to 0 oC; (f) Ph3P=CHCOMe, 0 oC to RT (89 %, 2 steps); (g) LiBH4, Et2O, MeOH, 0 oC (81 %); (h) 5 % Rh/Al2O3, H2, THF (62 %); (i) BzCl, Et3N, CH2Cl2, 0 oC to RT (97 %); (j) LiN3, DMPU, 110 oC (94 %); (k) BF3.Et2O, CH2Cl2, 0 oC (81 %); (l) LiOH, THF, aq. MeOH (97 %); (m) (COCl)2, DMSO, CH2Cl2, Et3N, -78 oC to 0 oC (91 %); (n) 6, THF, -10 oC (70-81 %); (o) aq. HBF4, MeOH (72 %); (p) LiOH, THF, MeOH, H2O, 22 oC (86 %); (q) Jones' reagent, THF, 0 oC; (r) CH2Cl2, Et2O (78 % 2 steps); (s) BCl3, CH2Cl2, -78 oC to 0 oC; then MeOH, -78 oC (77 %); (t) (COCl)2, DMSO, CH2Cl2, Et3N, -78 oC to 0 oC (92 %); (u) Ph3P, THF, 22 oC; then NaBH4, MeOH (90 %); (v) I2, CH2Cl2, Et2O, 22 oC (25 %).
In 1993 Morimoto et al. formulated an N-acyliminium ion approach (Scheme 1.2)
to the formation of pyrrolidinyllactone system 12 commonly found in the Stemona
alkaloids.16 To catalyse the reaction between pyrrolidine 10 and furan 11 various Lewis
5
acids, solvents and temperatures were used to optimize the yield and diastereoselctivity.
The best results were obtained using TMSOTf in diethyl ether at -78 oC, which gave the
desired lactone 12 in good yield as a 9:1 mixture of syn:anti isomers.
NCbz
OMe
O OTMS ONCbz
OHH
+ Lewis Acid
Solvent
1210 11 Scheme 1.2 Reagents TMSOTf, Et2O -78 oC (97 %, 9:1).
Wipf et al. reported an approach to the tricyclic core of (-)-tuberostemonine
(Scheme 1.3).17 N-Aloc-tyramine 13 was converted to its dienone via reaction with
iodobenzene diacetate in methanol, then treatment with NaHCO3 in DMSO afforded the
cyclisation product 14. Compound 14 was converted to the dienolate and alkylated with
iodide 15, which afforded compound 16. Luche reduction of the enone 16 gave the allylic
alcohol, which was protected as a benzyl ether prior to desilylation and N-Aloc cleavage to
give 17. Selective hydrogenation of the exocyclic alkene was followed by Mitsonobu
cyclisation to give the azepine ring, and finally Birch reduction of the benzyl ether afforded
alcohol 18.
OH
NH
Aloc
NOAlocH
OMe
NH
OMe
OHI OTBS
NH Aloc
OTBSO
OMe
NHH
OH
OMe
BnO
a,b c d-g
h-j
13 14
15
16
17 18 Scheme 1.3 Reagents (a) PhI(OAc)2, MeOH (35 %); (b) NaHCO3, DMSO 40 oC (80 %); (c) LiHMDS, THF, then 15 -20 oC (59 %); (d) NaBH4, CeCl3, MeOH/THF, RT, (91 %); (e) BnBr, n-Bu4NI, NaH, THF, RT (83 %); (f) TBAF, THF, RT (94 %); (g) (PPh3)4Pd(0), Bu3SnH, AcOH, CH2Cl2 (88 %); (h) H2, Pd/C, MeOH (98 %); (i) PPh3, DIAD, CH2Cl2, 0 oC to RT (59 %); (j) Na, NH3, THF (86 %).
6
The same tricyclic core was also the focus of a study by Rigby et al. (Scheme 1.4).18
The first of their approaches began with a [1+4] cycloaddition between 1-
isocyanatocyclohexene 19 and the oxadiazoline 20 which gave the hydroindole 21.
Compound 21 was N-alkyalted with 1,4-dibromobutane in the presense of NaH, before a
radical cyclisation with Ph3SnH and AIBN in benzene afforded the azepine ring with good
diastereoselectivity. Subsequent reduction with LiAlH4, and treatment with acid afforded
tricyclic compound 22. Their second approach involved a [1+4] cycloaddition between 19
and cyclohexylisocyanide, to give hydroindole 23. N-alkylation with 1,4-diiodobutane,
was followed by anionic azepine cyclisation (via the metalloenamine) to provide 24. Mild
hydrolysis gave an enol, which was then oxidized with m-CPBA giving the tricyclic target
25.
NCO
NN
O
OMeMeO
NH
O
OMeMeO
NH H
H
O
NCO NH
O
NHCy
NO
NHCy
NO
O
H
+ a-c d-g
h i,j k,l
19
19
20 2122
23 24 25 Scheme 1.4 Reagents (a) xylenes, reflux; (b) amberlite IR 120; (c) MeLi (71 % 3 steps); (d) NaH, DMF, Br2(CH2)4 (77 %); (e) Ph3SnH, AIBN, PhH slow addition (85 %); (f) LiAlH4, THF, reflux; (g) TFA, RT (68 % 2 steps); (h) Cy-N=C, CH3CN, RT (83 %); (i) NaH, DMF, then I2(CH2)4 0 oC to RT (56 %); (j) EtMgBr, diglyme, 120 oC (70 %); (j) (COOH)2, THF/H2O (60 %); (l) m-CPBA, CHCl3, -15 oC (93 %).
In 1999 Kende et al. reported a total synthesis of (±)-isostemofoline (Scheme 1.5).19
1,2-Hexanediol 26 was transformed into the pyrrole 27 via selective secondary alcohol
oxidation to the ketone, primary hydroxyl protection (MOM ether), condensation of the
ketone with hydrazone 28, reductive elimination with Na2S2O4 and finally N-Boc
protection. A [4+3] cycloaddition with 29 gave the bicyclic adduct 30, which was
converted to nortropinone 31 via silyl deprotection, exospecific hydrogenation and
nucleophilic decarbomethoxylation. Condensation of 31 with furfural, and O-alkylation
7
with allyl iodide followed by stereoselective Claisen rearrangement gave 32. Oxidative
cleavage of the terminal alkene, selective reduction with Zn(BH4)2 and then TIPS
protection yielded the protected enone which underwent conjugate addition methyl lithium
to give 33. Desilylation and tosylation, was followed by ozonolysis to convert the furan
into the corresponding acid. Reduction to the aldehyde 34 was accomplished via a mixed
anhydride in three steps, and this was reacted with the lithium anion 35 to form the alcohol
36. Dess-Martin oxidation gave the ketone, which was treated with TFA and then base to
effect triple cyclisation. Finally, dehydration with triflic anhydride gave (±)-
isostemofoline.
N
OMOM
Boc
N
OMOMTBSO
MeOOCBocOH
OH
N
O
MOMO
Boc
O
N
O
MOMO
BocO
N
O
MOMO
OTIPS
Boc
N
O
MOMO
OTs
Boc
O
O
N
O
MOMO
OTsO
OMe
OH
Boc
O
N
O
O
MeOH
OTBS
N2
COOMeNN
O
OLiO
OMe
a-e fg-i
j-l m-pq-v
w x-z
(+)-isostemofoline
2627
28 2930
31
32 33
34
35 36
Scheme 1.5 Reagents (a) 13 % aqueous NaOCl, HOAc (65 %); (b) MOMCl, iPr2NEt, CH2Cl2, 0 oC to RT (93 %); (c) 28, KOEt (80 %); (d) Na2S2O4, EtOH, H2O, 90 oC (35 %); (e) Boc2O, DMAP, CH3CN (72 %); (f) rhodium octanoate dimer, 29, pentane, reflux (90 %); (g) TBAF, THF (65 %); (h) H2, 5 % Pd/C, MeOH (90 %); (i) H2O, DMSO, 150 oC (90 %); (j) furfural, NaOH, MeOH, H2O, reflux (90 %); (k) LiHMDS, 1.1 equiv DMPU, THF, 0 oC, then CH2=CHCH2I, RT (91 %); (l) PhCH3, reflux (86 %); (m) K2OsO4.H2O, NaIO4, Et2O, H2O, RT; (n) Zn(BH4)2, THF -10 oC (52 % 2 steps); (o) TIPSCl, imidazole, DMF (93 %); (p) 2.2 equiv MeLi, 1.1 equiv DMPU, Et2O, -40 oC (85 %); (q) TBAF, THF (90 %); (r) p-TsCl, pyridine, CHCl3 (90 %); (s) O3, CH2Cl2 then Me2S (65 %); (t) i-BuOCOCl, N-methylmorpholine, THF, 0 oC; (u) NaBH4, MeOH; (v) Dess-Martin periodinane, CH2Cl2 (30 % 3 steps); (w) 35, THF, -78 oC (56 %); (x) Dess-Martin periodinane, CH2Cl2 (61 %); (y) CF3COOH, then sat. aq. NaHCO3 (67 %); (z) Tf2O, CH2Cl2 (12 %).
8
In 2000 Jacobi and Lee reported their total synthesis of (-)-stemoamide.20 This was
achieved by replication of their earlier synthesis of (±)-stemoamide12 making use of
optically active starting materials (Scheme 1.6). Beginning with the chiral acid 37,
methylation and subsequent ester reduction gave alcohol 38, which was then protected as
its acetal 39 with ethyl vinyl ether. N-alkylation with compound 40 in the prescence of
NaH gave compound 41, before deprotection of the alcohol with p-TsOH afforded 42. Two
methods were used to convert the hydroxymethylene group of 42 into the required propynyl
group and both were low yielding. The better of the two methods began with Swern
oxidation to give the aldehyde 43 then reaction with (MeO)2P(O)CHN2 in the presence of
base gave the alkyne. Methylation with LDA and methyl iodide gave a low yield of the
desired methylated adduct 44 together with an unwanted bis-methylated product.
Thermolysis of 44 yielded the butenolide, which was then reduced with NaBH4/NiCl2 to
give (-)-stemoamide in good yield.
NO
OO
CH3H
H
HO
N
N
O
MeOH
O
N
N
O
MeOH
RO
NH
ORO
HNH
OH
HOOC
O
N
N
O
MeOH
O
N
OMeO Cl
stemoamide
38 R=H39 R=CH(OEt)CH3
41 R=CH(OEt)CH3
42 R=H
a,b
c
d
e
f
g,h / i,j k,l
37
40
43 44 Scheme 1.6 Reagents: (a) SOCl2/MeOH, (90 %); (b) NaBH4, MeOH (92 %); (c) CH2=CHOEt, H+ (93 %); (d) NaH, 40 (67 %); (e) p-TsOH, MeOH (83 %); (f) (COCl)2, DMSO, CH2Cl2, NEt3 -78 oC to RT; (g) CBr4, (Me2N)3P, THF -30 oC (38 % 2 steps); (h) n-BuLi, then MeI (23 %); (i) (MeO)2P(O)CHN2, t-BuOK, THF -78 oC (65 % 2 steps); (j) LDA, THF then MeI, (Me2N)3P -78 oC (32 %); (k) DEB ∆ (52 %); (l) NaBH4, NiCl2 (73 %).
9
Jung et al. have reported an approach to the tricyclic core of (-)-stenine, by applying
Diels-Alder methodology (Scheme 1.7).21 Stille coupling of 45 with 46 gave diene 47.
The alcohol function of 47 was oxidised with Jones' reagent to the corresponding acid,
which was methylated via reaction with diazomethane. The resulting methyl ester was
reacted with dimethyl lithium methylphosphonate, and the resulting β-keto-phosphonate
coupled with aldehyde 48 under Horner-Wadsworth-Emmons conditions to give triene 49
in excellent yield for the four steps. Diels-Alder cyclisation in refluxing benzene gave the
two diastereoisomeric adducts of 50 in 40 % and 19 % yield. The major diastereoisomer
was treated with hydroxylamine hydrochloride in pyridine to give a separable 10:1 mixture
of oximes. A Beckmann rearrangement of the major oxime with p-TsCl gave the 7-
membered lactam 51. Finally PMB deprotection with DDQ and cyclisation of the alcohol
via its mesylate gave the BCD ring skeleton 52 of (-)-stenine.
I
OTBDPS
SnBu3
OH
OTBDPS
OH
TBDPSO
O
OPMB
O
OPMB
H
H
TBDPSO
NO
TBDPSO
H
H
H
O OMPM
NH O
TBDPSO
H
H
H
OPMB
+ a b-e
g,h
f
i, j
4546 47
48
49
50 51 52
Scheme 1.7 Reagents (a) Pd(CH3CN)2Cl2, i-Pr2NEt, THF, DMF (62 %); (b) Jones ox.; (c) CH2N2, Et2O (80 % 2 steps); (d) LiCH2P(O)(OMe)2; (e) 48, i-Pr2NEt, LiCl, CH3CN (79 % 2 steps); (f) PhCl, reflux (59 %, de 40:19); (g) NH2OH.HCl, pyridine (93 %, 10:1); (h) p-TsCl, pyridine (89 %); (i) DDQ (89 %); (j) MsCl, Et3N, pyridine (70 %).
Aube et al. used a very similar Diels-Alder approach in their formal total synthesis
of (±)-stenine (Scheme 1.8)22. A Julia coupling between aldehyde 53 and sulfone 54 gave
the diene 55. Silyl deprotection and Swern oxidation gave the aldehyde, which was reacted
with dimethyl lithium methylphosphonate. The resulting β-hydroxyphosphonate was
oxidized with TPAP/NMO to the oxophosphonate, which was then subjected to a Horner-
10
Wadsworth-Emmons coupling with 3-azidopropanal giving the triene 56. Treatment of 56
with MeAlCl2 initiated a Diels-Alder cycloaddition, followed by an intramolecular Schmidt
reaction, in a cascade fashion, giving 3 tricyclic lactams, including the desired isomer 57 in
43 % yield. Debenzylation of 57 by Birch reduction, followed by oxidation and
iodolactonization gave butyrolactone 58. Keck allylation followed by methylation of the
lactone then gave 59. This lactone had previously been transformed by Chen and Hart in 4
steps to give (±)-stenine.8
O
TBSO
SO2
NN N
NPh
BnO
TBSO
BnO
O
BnO
N3
N
O
BnOH
HHN
O
O
CH3O
H
H HN
O
OI
O
H
H H NH
O
OCH3
H
HCH3
+
stenine
a b-f g
h-j k,l m-p
53 54
55
56
57 58 59 Scheme 1.8 Reagents (a) LiHMDS, THF, -78 oC (90 %); (b) PPTS, EtOH; (c) (COCl)2, DMSO, NEt3; (d) LiCH2P(O)(OMe)2, -78 oC; (e) TPAP, NMO, 4Å M.S.; (f) Ba(OH)2.8H2O, N3(CH2)2CHO (55 %, 5 steps); (g) MeAlCl2, CH2Cl2, reflux, 48 h (43 %); (h) Na, NH3; (i) CrO3, H2SO4; (j) I2, NaHCO3 (80 %, 3 steps); (k) allyltributylstannane, AIBN, benzene; (l) LiHMDS, MeI (72 % 2 steps); (m) OsO4 (cat.), NaIO4, THF, H2O, RT (84 %); (n) HSCH2CH2SH, SiO2-SOCl2, CH2Cl2, RT (100 %); (o) (p-MeOC6H4PS2)2, CH2Cl2, RT (100 %); (p) W-2 Raney-Ni, EtOH, reflux (80 %).
Heathcock and Hinman recently applied an aza-Cope rearrangement strategy to the
BCD ring system of (+)-croomine (Scheme 1.9).23 The starting enone 60 was prepared in 6
steps using standard methods.23 Stork reductive allylation gave the trans isomer, which
was converted to its oxime before Beckmann rearrangement gave the lactam 61.
Conversion of 61 to the O-methylhemiaminal 62 was accomplished by reaction with H2SO4
in methanol, then the aza-Cope rearrangement was conducted giving 63. The authors
attempted a number of conditions, of which they report that TiCl4 followed by LiEt3BH to
11
be the most efficient. Dihydroxylation of the double bond with osmium tetraoxide and
cleavage of the resulting diol with sodium periodate gave the corresponding aldehyde,
which was condensed with ethyl(triphenylphosphoranylidine) acetate to give the
unsaturated ester 64. Photochemical deconjugation, preceeded dihydroxylation of the
alkene. The resulting diol underwent ring closure to the lactone when treated with p-TsOH.
It should be noted that the stereochemistry at C11 is opposite that of the Stemona alkaloid
(+)-croomine, due to the intrinsic facial selectivity of the cis-dihydroxylation step.
Reaction with methanesulfonyl chloride and triethylamine then afforded the butenolide 65.
Reduction of the butenolide double bond with NaBH4 and NiCl2 was followed by α-
methylation with LDA and methyl iodide, gave 66 and completed the model synthesis.
ON
O O
HH
ON
O O
HH
N
O
HH COOEtN
O
HH
N
O
OMe
O
O
NH
O
O
O
O
a-c d
e f-h
i-l m,n
60
6162
63 64
65 66
62
64
Scheme 1.9 Reagents (a) Li, NH3, then allyl iodide (63 %); (b) HONH2, pyridine, H2O, ∆ (83 %); (c) p-TsCl, pyridine, RT (92 %); (d) cat. H2SO4, MeOH, RT (77 %); (e) TiCl4, CH2Cl2, -78 oC to 0 oC, then LiEt3BH (62 %); (f) OsO4, NMO; (g) NaIO4, THF; (h) Ph3P=CHCOOEt (82 % 3 steps); (i) hν, i-Pr2NH, CH2Cl2; (j) OsO4, NMO; (k) p-TsOH, PhH, reflux; (l) CH3SO2Cl, Et3N (62 % 4 steps); (m) NiCl2, NaBH4 (89 %); (n) LDA, THF, CH3I (74 %).
Kende et al. recently reported an approach to the total synthesis of (±)-stemonamide
and (±)-isostemonamide (Scheme 1.10).24,25 This synthesis exploited the N-acyliminium
approach established by Morimoto et al.16 in order to establish the lactone moiety. To this
end the silyloxyfuran 67 was reacted with the N-acyliminium ion generated from 68 by
12
reaction with BF3.OEt2 to give 69 as a 1:2 mixture of diastereoisomers. Swern oxidation of
69 gave the corresponding aldehydes, which were cyclised via deprotonation with DBU,
then a second Swern oxidation afforded a mixture of 70 and 71 in 70 % yield for the 3
steps. The isomers 70 and 71 were separated, then each was taken separately to the
appropriate alkaloid using identical methods. Compound 71 was treated with TBSOTf and
collidine to give the silyl enol ether, which was reacted with Pd(OAc)2 to give enone 72.
Copper catalysed conjugate addition of the Grignard reagent PMBO(CH2)4MgBr with 72
gave 73 as a 6.4:1 mixture of diastereoisomers. Treatment of this mixture with potassium
hydride then dimethylmethyleneammonium trifluroacetate gave the methylene ketone 74.
Removal of the sterically hindering PMB protecting groups via CAN oxidation, then
allowed for isomerization of the exocyclic double bond into the ring using RhCl3 to give
75. Cyclisation of the azepine ring was accomplished by converting 75 into its mesylate
before treatment with NaH to give stemotinine. Isostemotinine was prepared from 70 in an
analogous manner.
O
NPMB
O
OTMSO
OMeN O
PMBOH
O OMe
O
ON
O
O O
PMB
OMe
ON
O
O O
PMB
OMe
O
N
O
OMeOO
NH
O
O
OH
MeO
O
N
O
O
OPMBPMB
MeO
ON
O
O O
PMB
OMe
O
N
O
O
OPMBPMB
MeO
O
N
O
OMeO
stemotinine
isostemotinine
a b,c,b
d,e
f g h,ij,k
+
67
68
69
70
71 72
73 74 75
d-k
Scheme 1.10 Reagents (a) BF3.OEt2, CH2Cl2, RT, 40 min (82 %); (b) (COCl)2, DMSO, NEt3, CH2Cl2; (c) DBU, CH2Cl2, RT, 18 h (70 % 3 steps); (d) TBSOTf, collidine, PhCH3, 0 oC to RT, 7 h (80 %); (e) Pd(OAc)2, O2, DMSO, 80 oC, 1 to 2 d (93 %); (f) PMBO(CH2)4MgBr, CuBr.Me2S, TMSCl, HMPA, THF, -78 oC (74 %); (g) KH, THF then Me2N+=CH2.CF3COO-, RT, 18 h (67 %); (h) CAN, CH3CN-H2O (3:1), RT (80 %); (i)
13
RhCl3.xH2O, EtOH-H2O (10:1), reflux (66 %); (j) MsCl, DMAP, pyridine, CH2Cl2, 0 oC, 1 h (71 %); (k) NaH, THF, RT, 30 h (46 %).
Williams et al. have also reported a total synthesis of (-)-stemospironine (Scheme
1.11).26 The method used in this synthesis was very similar to their earlier synthesis of (+)-
croomine, understandably so, as these two compounds only differ in that stemospironine
contains an additional methoxy group. The latter stages of the synthesis are as described
above (Scheme 1.1) and the only difference lies in the synthesis of the key allylic alcohol
80. (Scheme 1.11) Asymmetric reduction of alkyne 76 with (R)-Alpine borane gave the
alcohol which was protected as its TBDPS ether. Deprotonation of the alkyne, then
reaction with iso-propyl chloroformate gave the homologated alkyne 77. Copper catalysed
Grignard coupling with 78 gave a good yield of the alkene 79. Desilylation followed by
methylation installed the key methoxy group and DIBAL-H reduction afforded the required
allylic alcohol 80 in good yield.
OBnO
OTBDPS
BnO
COOiPr
MEMO
OH
OBnMeO
COOiPr
OBnTBDPSO
MEMO
MEMO MgBr
a-c d
e-g
76 77
78
7980
Scheme 1.11 Reagents (a) (R)-Alpine borane, THF, -10 oC to RT, (95 %, 88 % ee); (b) TBDPSCl, imidazole, CH2Cl2, RT, (80 %); (c) n-BuLi, ClCOOi-Pr, THF, -78 oC (90 %); (d) CuBr.DMS, THF, 78, -78 oC to RT (70 %); (e) TBAF, THF, RT (90%); (f) NaH, MeI, DMF (85 %); (g) DIBAL-H, CH2Cl2, -78 oC (92 %).
Gurjar et al. have reported a carbohydrate based formal total synthesis of (-)-
stemoamide (Scheme 1.12).27 D-Glucose was readily transformed into the starting bis-
acetal 81 using literature methods.28 Swern oxidation, then a Barbier reductive allylation
gave 82. Hydroboration-oxidation of 82, followed by silylation and mesylation gave the
azido alcohol 83 after reaction of the mesylate with NaN3. Two step oxidation of the
14
alcohol to the acid was followed by methylation to the methyl ester 84. Hydrogenation
with Pd/C/H2 gave the amine which readily underwent cyclisation to give the 2-
pyrrolidinone 85. Compound 85 was N-alkylated with allylbromide, followed by selective
removal of the 5,6-acetonide mesylation and then elimination to yield diene 86. The
azepine ring was formed by ring closing metathesis without complication. Hydrogenation
removed the new double bond giving 87. Treatment of 87 with Amberlyst-15 ion exchange
resin and MeOH gave the methyl glycoside, which was then transformed into its imidazoyl
xanthate derivative. Barton radical deoxygenation (n-Bu3SnH, AIBN) gave the deoxy
product, then treatment with BF3.EtO and m-CPBA in CH2Cl2 gave the lactone 88. Finally,
α-methylation with LDA and MeI in THF afforded (-)-stemoamide.
NO
OO
CH3H
H
HN
OOO
H
H
H
NO
OH
H
H
OO
NO
OH
H
H
OO
OO
NHO
OH
H
OO
H
OO
O
HO
O
H
OHN3
OO
O
HO
O
HOH
OO
O
HO
O
HOH
OO
O
HO
O
H
ON3 MeO
stemoamide
a,b c-f
j k-n o,p
q-t
g-i
u
81 82 83
84 85 86
87 88 Scheme 1.12 Reagents (a) (COCl)2, DMSO, Et3N, -78 oC, 1 h (80 %); (b) CH2=CHCH2Br, Zn, sat. NH4Cl. THF, 30 min (81 %); (c) BH3.(CH3)2S, THF, 0 oC to RT, 1 h, then NaOAc, H2O2, 30 min, 65 %; (d) TBSCl, imidazole, CH2Cl2, RT, 1 h (90 %); (e) MsCl, Et3N, CH2Cl2, 0 oC to RT, 30 min (85 %); (f) NaN3, DMF, 75-85 oC, 32 h, (77 %); (g) (COCl)2, DMSO, Et3N, -78 oC, 1 h (80 %); (h) NaClO2, DMSO, NaH2PO4, H2O, 0 oC-RT, 1h (95 %); (i) CH2N2, 50 % KOH (aq), Et2O, -20 oC, 5 min (94 %); (j) Pd/C, H2, MeOH, RT, 6 h, (87 %); (k) CH2=CHCH2Br, 50 % KOH (aq), benzene, n-Bu4NI, RT, 2 h (74 %); (l) 0.8 % H2SO4 (aq), MeOH, RT, 8 h (84 %); (m) MsCl, Et3N, CH2Cl2, 0 oC, 10 min (70 %); (n)
15
NaI, ethyl methyl ketone, reflux, 4 h (66 %) (o) Grubbs' cat., CH2Cl2, reflux, 12 h, (83 %); (p) Pd/C, H2, MeOH, RT, 6 h (85 %); (q) Amberlyst-15, MeOH, reflux, 3 h (70 %); (r) Im-CS-Im, PhCH3, reflux, 6 h; (s) n-Bu3SnH, AIBN, PhCH3, reflux, 12 h (45 % 2 steps); (t) m-CPBA, BF3.OEt2, CH2Cl2, 0 oC to RT, 12 h (30 %); (u) LDA, THF, CH3I (74 %).
Wipf et al. reported the first total synthesis of (-)-tuberostemonine (Scheme 1.13).29
Cbz-L-tyrosine was converted to the starting compound 89 in three steps using standard
methods.8 Palladium catalysed removal of the OBz group, then alcohol silylation, was
followed by carbamate deprotection, N-cinnamylation, desilylation and oxidation of the
resulting alcohol to the corresponding enone. Alkylation with KHMDS/allyl iodide
proceeded with excellent stereoselectivity to give the diene 90. Ring closing metathesis
with Grubbs' second generation catalyst afforded the tricyclic core and a three step removal
of the azepine double bond was followed by Luche reduction of the ketone and TBS
protection to give the silyl ether 91. The methyl ester was converted to its Wienreb amide
and reaction with the bromo-orthoester 92 afforded the corresponding ketone. Reduction
with L-selectride gave the alcohol. p-TsOH catalysed deprotection of the silyl ether and
orthoester hydrolysis proceeded with concomitant lactone cyclisation to give 93. Claisen
rearrangement with N,N-dimethylacetamide-dimethyl-acetal gave 94, which was followed
by a selenolactonization to give 95. Keck allylation, followed by α-methylation of the
lactone was followed by isomerisation of the allyl group using allyltritylamine,
diisopropylethylamine in the presence of Grubbs' second generation catalyst. The
isomerised alkene was then cleaved using ethylene cross metathesis with the ruthenium
catalyst 96 in the presence of acid, and finally hydrogenation of the resulting terminal vinyl
group afforded (-)-tuberostemonine.
16
ONH
H
H
CH3
O
OCH3
H
H
CH3
OO
NPhSe
HH
H
O
O
H
H
CH3
O
ONH
H
H
H
H
CH3
O
O
Me2N
ONH
H
H
H
H
CH3
O
OH
NHH
H
H
TBSO
O
OMeNO
H
H
PhH
COOMe
NH
H
OHCbz
OBz
COOMe
OO
O
Br
NN
RuO
Mes
Mes
ClCl
tuberostemonine
a-g h-m
n-q s
t-x
r
8990
91
92
9394
95
96
91
Scheme 1.13 Reagents (a) Pd2(dba)3CHCl3, NEt3. HCOOH, PBn3, THF, 65 oC (93 %); (b) TBSCl, imidazole, DMAP, CH2Cl2 (97 %); (c) Et3SiH, Pd(OAc)2, NEt3, CH2Cl2, RT (90 %); (d) cinnamyl bromide, K2CO3, PhCH3, 60 oC (96 %); (e) TBAF, THF, RT (96 %); (f) TPAP, NMO, CH2Cl2 (88 %); (g) KHMDS, CH2=CHCH2I, -90 oC (66 %); (h) Grubbs' second gen. cat., CH2Cl2, reflux (92 %); (i) PhSH , NEt3, CH2Cl2 (91 %); (j) (PPh3)3RhCl, H2, EtOH/CH2Cl2, RT; (k) DBU, CH2Cl2, RT (89 % 2 steps); (l) CeCl3.7H2O, NaBH4, THF/MeOH, 0 oC (71 %); (m) TBSCl, imidazole, DMAP, CH2Cl2, RT (79 %); (n) (Me)(OMe)NH.HCl, Me2AlCl, CH2Cl2, RT (94 %); (o) 92, LiDBB (95 %); (p) L-selectride, THF, -78 oC (80 %); (q) p-TsOH, MeOH (70 %); (r) N,N-dimethylacetamide dimethyl acetal, xylenes, 135 oC (78 %); (s) PhSeCl, MeCN/H2O, 0 oC (67 %); (t) AIBN, allyltriphenylstannane (neat) 95 oC (70 %); (u) LDA, HMPA, THF, -78 oC, then MeI (76 % including rec. sm.); (v) Grubbs' second gen. cat., allyltritylamine, DIEA, PhCH3, 110 oC (85 %); (w) p-TsOH, 96, CH2Cl2, reflux, ethylene (81 %); (x) Pd/C, H2, MeOH (97 %).
Booker-Milburn et al. recently reported a rapid approach to the tetracyclic core of
neotuberosteminine (Scheme 1.14).30 The readily available starting diol 97 was converted
via the corresponding bis-mesylate to the dinitrile 98. Hydrolysis to the diacid, then
cyclisation gave the C2 symmetric bis-lactone 99. Grignard alkylation, with concomitant
lactone ring opening gave the acid 100, which was reduced to the alcohol via its mixed
17
anhydride. This alcohol was then coupled to three different maleimide derivatives 101
(R=H, Me, Cl). Photocyclisation to 102 was followed by a Zn/AcOH reduction which gave
the tetracyclic nucleus 103 of neotuberostemonine, potentially a useful intermediate in the
total synthesis of the natural alkaloid.
O
OH
OH
O
CN
CN
O
OO
O
H
H
H
H O
O
H
HCOOH
N
O
O
H
HO
O
RR
N
O
O
O O
H
HH
H
HN
O
O
O O
H
HH
H
H
R R
a b,c / d e
f,g h i
97 98 99 100
101 102 103 Scheme 1.14 Reagents (a) MsCl, Et3N, Et2O, 2 h, then KCN, DMSO, 100 oC, 5 h (75 %); (b) KOH, EtOH, H2O (85 %); (c) p-TsOH, PhCH3, reflux (93 %); (d) H2SO4 (6M), heat, 2 h (45 %); (e) EtMgBr (10 equiv), CuBr.Me2S (10 equiv, THF/Me2S (2:1), -20 oC (89 %); (f) EtOCOCl, Et3N, then NaBH4 (84 %); (g) DIAD, PPh3, THF, -78 oC to RT, 24 h maleimide(R=H, 35 %)/dimethylmaleimide(R=CH3, 31 %)/dichloromaleimide(R=Cl, 63 %); (h) hν, pyrex, MeCN, 30-120 min (R=H 11 %, R=CH3 65 %, R=Cl 60 %); (i) Zn, AcOH, RT, 1.5 h (86 %).
1.2 Indolizidine Alkaloids 1.2.1 Introduction to Indolizidine Alkaloids
Structurally related to the Stemona alkaloids are the indolizidine alkaloids, which
are defined by the 1-aza-bicyclo[4.3.0]octane core that they possess. Polyhydroxylated
members of this family are often potent glycosidase inhibitors, because in their protonated
form they mimic the glycosyl cation intermediate of sugar chain hydrolysis.31 The toxicity
to livestock of the legumes Swainsona canescens and Castanospermum australe led to the
isolation of the toxic principles (-)-swainsonine32 and (+)-castanospermine respectively (fig
1.3).33 (-)-Swainsonine is also present in locoweeds (Astragalus and Oxytropis species)
and ingestion of locoweed is responsible for the disorder 'locoism' in the western United
18
States.34 (-)-Lentiginose was first isolated in 1990 from the leaves of Astragalus
lentiginosus, which also contains (-)-swainsonine.35 Slaframine and (-)-swainsonine are
both present in Rhizoctonia leguminicola.36
N
H
OH
OH
N
H OAc
NH2N
OH
OHHOH
N
OHHOH
OH
OH
(-)-swainsonine (+)-castanospermine (-)-lentiginose slaframine Figure 1.4 Examples of indolizidine alkaloids.
The glycosidase inhibitory activity of indolizidine alkaloids has been extensively
studied,31 and together with other related classes such as the pyrrolizidines, piperidines,
pyrrolidines and nortropanes, they are viewed as potential therapeutics. Glycosidases are
involved in a wide range of important biological processes such as intestinal digestion,
post-translational processing of glycoprotiens and the lysosomal catabolism of
glycoconjugates.31 It follows that the above alkaloids have enormous potential in the
treatment of many diseases such as viral infection, cancer, diabetes and glycosphingolipid
storage diseases.
Not surprisingly, a vast body of research has been conducted regarding the synthesis
of these alkaloids. The indolizidine alkaloids, which are particularly relevant to this
project, have not escaped this attention. Due to its potent biological activity, (-)-
swainsonine has been the focus of extensive synthetic efforts. In addition a number of
analogues have been reported, featuring inversion of configuration, removal, replacement
and selective protection of the hydroxyl groups. All of these modifications resulted in a
decreased α-mannosidase inhibitory activity.37 El Nemr has published a comprehensive
review entitled 'Synthetic Methods for the Stereoisomers of (-)-Swainsonine and its
Analogues',38 covering synthetic efforts in this area prior to the year 2000. Syntheses in
this field have followed two distinct approaches. The chiral pool approach exploits the
polyhydroxylated nature of the products by beginning with carbohydrate, amino acid, or
maleic acid starting materials, which have the advantage of being cheap and
enantiomerically pure. Futhermore they often possess the hydroxyl functionalities in the
desired absolute configuration. However the preexisting chiral centers can limit the
19
flexibility of carbohydrate or amino acid based methods.39 The other approach, involving
non-chiral starting materials, has gained popularity in recent years due to the proliferation
of new asymmetric synthetic methods.
1.2.2 Chiral pool methods Mootoo et al. reported a rapid synthesis of both (-)-swainsonine (Scheme 1.15) and
(+)-castanospermine (Scheme 1.16) via a triple reductive amination strategy, beginning
with the monosaccaharide derivatives 103 and 104 respectively.40 For the synthesis of (-)-
swainsonine, 2,3:5,6-di-O-isopropylidene-mannofuranose 103 was protected as its O-PMB
ether. Removal of the exocyclic isopropylidene and oxidative cleavage of the resulting diol
with NaIO4 gave aldehyde 105. Reaction of 105 with allyltrimethylsilane and BF3.OEt2
gave predominantly the (R)-alcohol, which was benzylated to give compound 106.
Iodocyclisation and tetrahydrofuran ring opening gave the hydroxyalkene. Hydroboration
followed by a Swern oxidation of the diol product gave ketoaldehyde 107. DDQ cleavage
of the PMB followed by triple reductive amination of the resulting bis-hemiacetal with
NaCNBH3 and ammonium formate gave the indolizidine ring system 108. Deprotection
according to literature precedent41 afforded (-)-swainsonine.
O
O O
O O
OHO O
O O
OPMB O
O O
OPMBBnO
N
OO
HBnO
N
OHOH
HOH
O
O O
BnO
OPMB
OMe
O
(-)-swainsonine
a-c d,e
f-i j,k l,m
103105 106
107 108 Scheme 1.15 Reagents (a) PMBCl, NaH, nBu4NI, DMF ; (b) HOAc; (c) NaIO4 (80 % 3 steps); (d) allyltrimethylsilane, BF3.OEt2 (77 %); (e) BnBr, NaH, nBu4NI, DMF (97 %); (f) IDCP, CH2Cl2/MeOH; (g) Zn, 95 % EtOH ∆ (78 % 2 steps); (h) BH3, THF, then Na2O2 (86 %); (i) (COCl)2, DMSO, CH2Cl2, NEt3 (84 %); (j) DDQ, NEt3, CH2Cl2/H2O (79 %); (k) NH4HCO2, NaCNBH3, MeOH (69 %); (l) 10 % Pd/C, MeOH/HCOOH; (m) HCl, THF/H2O (80 % 2 steps).
20
In their related synthesis of (+)-castanospermine, Mootoo et al. began with aldehyde
104 a readily available derivative of D-glucose.42 A Whitesides allylation of 104 gave a 9:1
mixture of epimers, and then benzylation afforded compound 109. Iodoetherfication and
reductive elimination to compound 110, followed by Swern oxidation, ozonolysis and acid
hydrolysis of the resulting keto aldehyde gave 111, which was isolated as its tautomeric
bis-hemiacetal. Triple reductive amination with NaCNBH3 and ammonium formate gave
the indolizidine ring structure 112 and debenzylation via hydrogenation gave (+)-
castanospermine.
OOHC
BnO
BnO OBn
OMe OBnO
BnO OBn
OMe
BnOOH
BnO
BnO OBn
BnO
OMeOMe
OBnO
BnO OBn
BnOCHO
CHO
NH
BnO
BnO
BnO OBn
NH
OH
OH
OH OH
(+)-castanospermine
a,b c,d
e-g h i
104 109 110
111 112 Scheme 1.16 Reagents (a) allyl bromide, Sn, CH3CN/H2O (10:1) ultrasound (75 %); (b) BnBr, NaH, n-Bu4NI, DMF (97 %); (c) IDCP, CH2Cl2/MeOH; (d) Zn, 95 % EtOH ∆ (74 % 2 steps); (e) (COCl)2, DMSO, CH2Cl2, NEt3 (95 %); (f) O3, CH2Cl2, -78 oC, then Ph3P (95 %); (g) THF/9M HCl (81 %); (h) NH4OOCH, NaCNBH3, MeOH (78 %); (i) 10 % Pd/C, MeOH, HCOOH (80 %).
Singh et al. reported a total synthesis of (-)- and (+)-lentiginose from D-mannitol
and L-tartaric acid respectively (Scheme 1.17).35 D-Mannitol is readily transformed into
the starting diol 113. Cleavage of the diol with lead tetraacetate gave an aldehyde, which
was reduced to an alcohol using NaBH4. The alcohol was converted to its tosylate and
reaction with NaN3 afforded the azido group. Removal of the acetonide group with TFA
gave the diol 114. Diol cleavage with lead tetraacetate again gave an aldehyde and
diastereoselective addition of allyltributylstannane gave the homoallylic alcohol 115.
Mesylation of this alcohol, then reduction of the azide with LiAlH4 proceeded with
21
subsequent cyclisation of the pyrrolidine ring, before N-acylation with acryloyl chloride
afforded diene 116. Ring closing metathesis gave the bicyclic compound 117 and finally
reduction with Pd/C/H2 and then LiAlH4 afforded (-)-lentiginose. For the synthesis of (+)-
lentiginose, L-(+)-tartaric acid was transformed into 118 according to literature precedent.43
The primary alcohol was converted to its azide via the tosylate, then desilylation and
oxidation gave an azido aldehyde. Diastereoselective addition of allyltributylstannane gave
the homoallylic alcohol ent-115 which could then be transformed into (+)-lentiginose using
identical methods to those of the enantiomer.
OO
OHOBn
OBn OH
OBn
OBnOH
OH N3 OBn
OBnOH
N3
N
O
OBnBnO
N
O
H
OBn
OBn
N
H
OH
OH
TBDMSOOH
OBn
OBn OBn
OBnOH
N3
(-)-lentiginose
L-(+)-tartaric acid
a,b c d-f
g h
i-kref 43
113 114115
116 117
118 ent-115 Scheme 1.17 Reagents (a) (i) Pb(OAc)4, CH2Cl2, 3 h; (ii) NaBH4, EtOH, 3 h; (iii) p-TsCl, Et3N, CH2Cl2, 12 h; (iv) NaN3, DMF, 80 oC, 8 h (80 % 4 steps); (b) CF3COOH, THF/H2O 4:1, 65 oC, 8 h (97 %); (c) (i) Pb(OAc)4, CH2Cl2, 3 h; (ii) SnCl4, allyltributyl tin, CH2Cl2, -78 oC, 1 h (82 % 2 steps); (d) MsCl, NEt3, CH2Cl2, 6 h (92 %); (e) LiAlH4, THF, reflux, 12 h (68 %); (f) acryloyl chloride, NEt3, CH2Cl2, 12 h (85 %); (g) Grubbs' cat., PhCH3, reflux, 24 h (86 %); (h) (i) Pd/C, H2 (ii) LiAlH4, THF, reflux, 6 h (97 %); (i) (i) p-TsCl, NEt3, CH2Cl2, 12 h; (ii) NaN3, DMF, 80 oC, 12 h (60 %); (j) TBAF, THF, 8 h (95 %); (k) (i) NCS, DMS, CH2Cl2, NEt3, -25 oC, 4 h; (ii) SnCl4, allyltributyltin, CH2Cl2, -78 oC, 1 h (70 %).
Diaz-Perez et al. produced an innovative swainsonine analogue 119 incorporating:
(i) sp2 hybridisation at the anomeric centre; (ii) analogous charge delocalisation; and (iii) a
pseudoanomeric group with the correct orientation to mimic the natural aglycon (Scheme
1.18).37 These features are expected to confer a marked improvement in the α-mannosidase
22
inhibitory activity. Beginning with pyranose 120, which is readily available from D-
mannopyranose, two pathways were reported. The shorter method consisted of azide
reduction to give amine 121, which was converted via a γ-hydroxyisothiocyanate into
cyclic thiocarbamate 122. Acid catalysed removal of the acetonide and methoxy protecting
groups gave 119 in low yield due to the harsh conditions required to hydrolyse the methoxy
group. Reviewing their protecting group strategy, 120 was hydrolysed (TFA/H2O, 100 oC)
and reprotected via treatment with TBSCl/pyridine then acetic anhydride, before an azide
reduction then gave 123. The amine was converted to an isothiocyanate, then removal of
the TBS group with TBAF preceeded rearrangement to the cyclic thiocarbamate 124.
Deacetylation of 124 yielded 119 in 73 % yield. Unfortunately the biological activity of
119 as an α-mannosidase inhibitor was not reported.
O
O O
N3 OMe
OHO
O O
NH2 OMe
OH
NH
OOS
O O
OMe
O
NOH
HOH
OH OH
S
O
OAc OAc
NH2 OAc
TBSO
NH
OOS
OAc OAc
OAc
a b,c
de-g
h,ij
119
120 121 122
123 124 Scheme 1.18 Reagents (a) H2, 10 % Pd/C, MeOH, 3 h; (b) CSCl2, CaCO3, H2O/acetone (40 % 2 steps); (c) NEt3, DMF, 80 oC, 30 min (85 %); (d) TFA/H2O 1:1, 100 oC, 48 h (18 %); (e) TFA/H2O 1:1, 100 oC, 48 h (80 %) (f) TBSCl, pyridine, 45 min, then Ac2O (62 %); (g) H2, 10 % Pd/C, MeOH, 2 h; (h) CSCl2, CaCO3, H2O/CH2Cl2, 0 oC, 10 min (67 % 2 steps); (i) TBAF, THF, then NEt3, dioxane, 45 min (73 %); (j) NaOMe, MeOH (79 %).
Carmona et al. have prepared a host of tetrahydroxy indolizidines, two of which are
shown in Scheme 1.19.44 Beginning with the protected amino hexose 125, side chain
extension with hydrogen methylmalonate gave a 5:4 mixture of alkenes 126 and 127
respectively. Dihydroxylation of the double bond of 126 either with osmium tetraoxide or
Sharpless AD mixes gave the diol 128, then ring closure and deprotection afforded the
23
indolizidine 130 Compound 131 was prepared in a similar manner. Several other isomers
of 130 and 131 were prepared using similar methods.
N
O O
Boc CHON
O O
COOMe
Boc
N
O O
COOMe
Boc
N
O O
OH
OH
COOMeBoc
N
O OOH
OH
OH
Boc
N
O
OH OH
OH
OH
HN
OH
H
OH
OHOH
+a
b
c,d
e-h
i,j
125 126 127
128 129130 131 Scheme 1.19 Reagents (a) HOOCCH2COOMe, pyridine, piperidine, 100 oC (90 %); (b) OsO4, NMO, acetone/H2O (91 %); (c) (i) TFA aq, 2h (ii) NaOMe, MeOH reflux 16 h (iii) Ac2O, pyridine, DMAP (82 %); (d) NaOMe, MeOH (100 %); (e) DIBAL-H, CH2Cl2, -20 oC (60 %); (f) p-methoxybenzoyl chloride, CH2Cl2, NEt3 (85 %); (g) AD-mix-α, t-BuOH/H2O, MeSO2NH2, 0 oC, 24 h (72 %, de 97 %); (h) NaOMe, MeOH (76 %); (i) p-TsCl, pyridine, -15 oC (42 %); (j) (i) TFA aq (ii) NH4OH (94 %).
Pearson and Hembre recently reported two papers,45,46 with the similar theme of
preparing substituted analogues of (-)-swainsonine. The first of these focused on the
preparation of 6- and 7-substituted analogues of (-)-swainsonine (Scheme 1.20).46 The
allylic alcohol 133 had been previously prepared from 132 by the same authors.47 A
Johnson orthoester Claisen rearrangement gave the required esters each as a 1:1 mixture of
diastereoisomers and reaction with HN3 under Mitsunobu conditions gave the azides 134.
Both the ethyl and -(CH2)2OBn analogues were prepared. Epoxidation with m-CPBA
facilitated the separation of the diastereoisomers and azide reduction proceeded with
subsequent lactam ring closure. Finally, lactam reduction afforded the 6-substituted (-)-
swainsonine analogues 135. Preparation of the 7-substituted analogues proceeded in the
same manner. Lactone 132 was reduced to the aldehyde and addition of the Grignard
reagent formed from 1-hexynylide and 4-benzyloxy-1-butynylide gave the propargyl
alcohols. Reduction of the propargyl alcohols via Lindlar hydrogenation to the (Z)-allylic
24
alcohols and silylation of the primary alcohol gave compounds 136. Replicating the same
sequence used for the 6-substituted series yielded the 7-substituted (-)-swainsonine
analogues 137 and 138.
O
OO
O
OO
TBSO OH
OO
N3 O ROMe
NOH
OH HOH
R
OO
TBSO OH R'
OO
N3 O
R'
OMe
O NOH
OH HOH
R'
NOH
OH HOH
R'
ref 47 a,b c-e
f-h
i-k l-n
132133 134
135
136
137
138
R= Et, (CH2)2OBn
R'= n-Bu, (CH2)2OBn
R= Et, (CH2)2OBn
R'= n-Bu, (CH2)2OBn R'= n-Bu, (CH2)2OBn Scheme 1.20 Reagents (a) (i) RC(OMe)3, cat. EtCOOH, toluene, reflux, (ii) TBAF, THF (R=Et 83 %, R=(CH2)2OBn 67 %); (b) HN3, PPh3, EtO2CN=NCO2Et, PhH (R=Et 85 %, R=(CH2)2OBn 66 %); (c) m-CPBA, CH2Cl2 (R=Et 69 %, R=(CH2)2OBn 56 %); (d) (i) H2, PdOH)2/C, MeOH, EtOAc (ii) NaOMe, MeOH, reflux (R=Et 66 %, R=(CH2)2OBn 79 %); (e) (i) BH3.SMe2 (ii) 6N HCl/THF (R=Et 99 %, R=(CH2)2OBn 97 %); (f) DIBAL-H, (g) RC≡CMgBr (2 steps R=n-Bu 84 %, R=(CH2)2OBn 88 %); (h) (i) H2, Pd, BaSO4 (ii) TBSCl, imidazole (R=n-Bu 81 %, R=(CH2)2OBn 70 %); (i) (i) MeC(OMe)3,cat. EtCOOH, PhCH3, reflux (ii) TBAF, THF (R=n-Bu 75 %, R=(CH2)2OBn 70 %); (j) HN3, PPh3, EtO2CN=NCO2Et, PhH (R=n-Bu 77 %, R=(CH2)2OBn 80 %); (k) m-CPBA, CH2Cl2 (R=n-Bu 95 %, R=(CH2)2OBn 75 %); (l) (i) H2, Pd(OH)2/C, MeOH, EtOAc (ii) NaOMe, MeOH, reflux (R=n-Bu 60 %, R=(CH2)2OBn 89 %); (m) BH3.SMe2; (n) 6N HCl/THF (R=n-Bu 99 %, R=(CH2)2OBn 97 %).
The second of Pearsons' papers regarded the preparation of 3-benzyloxymethyl
derivatives of (-)-swainsonine (Scheme 1.21).45 D-ribose had been previously transformed
into 139 by the same group.48 Protection of the secondary alcohol as its MOM ether and
desilylation, was then followed by BH3.SMe2 reduction of the lactam give 140. Selective
O-benzylation (with various substituted benzyl halides) and deprotection then afforded the
(-)-swainsonine analogues 141. The 3-epimer of 141 was also prepared in an analogous
manner, as were the 2-napthyl-CH2-, 4-Ph-PhCH2-, 4-tBu-PhCH2- and 4-Me-PhCH2-
analogues.
25
N
O
O
O
HOH
TBSO
N
O
O
HOMOM
OH
N
OHH
OH
OH
O
Ar
D-ribose ref 48 a-c d-f
139 140 141
12
3
Scheme 1.21 Reagents (a) i-Pr2NEt, CH3OCH2Cl, -10 oC to RT; (b) TBAF, THF, RT; (c) BH3.SMe2, THF, RT (91 % 3 steps); (d) NaH, ArCH2X, n-Bu4NI, THF, RT (70-90 %); (e) 6N HCl, THF, RT; (f) Dowex 1x8-200 (70-100 %, 2 steps).
Pearson et al. have also recently reported a short efficient formal synthesis of (-)-
swainsonine (Scheme 1.22).49 Beginning with D-ribose, acetonide protection and then
reaction with vinyl magnesium bromide gave the triol 142. Oxidative cleavage of the diol
gave the aldehyde, which collapsed to the lactol, then reductive amination with
dibenzylamine gave amino alcohol 143. Johnson orthoester Claisen rearrangement gave
the ester 144 in 43 % yield from D-ribose, and notably the first purification was conducted
at this stage. Sharpless catalytic asymmetric dihydroxylation gave the diol, which readily
collapsed to the lactone 145. Mesylation of the alcohol, was followed by hydrogenation,
which proceeded with concomitant bis-cyclisation to give the known lactam 146. Lactam
reduction and mild acid hydrolysis of the acetonide then afforded (-)-swainsonine.
OHOH
OO
OH
OO
OHBn2N
OO
Bn2N MeOOC
OOO
Bn2N
O
OHN
HOHOH
OHN
HOH
O
O
O
D-ribose
(-)-swainsonine
a,b c,d e
f g,h i,j
142 143144
145 146 Scheme 1.22 Reagents (a) acetone, conc. HCl; (b) CH2=CHMgBr, THF; (c) NaIO4, SiO2, CH2Cl2; (d) Bn2NH, AcOH, NaBH3CN, MeOH; (e) MeC(OMe)3, cat. EtCOOH, PhCH3, reflux (43 % 5 steps); (f) K3Fe(CN)6, K2OsO4.2H2O, K2CO3, MeSO2NH2, (DHQD)2PHAL, H2O, t-BuOH (58 %); (g) MsCl, NEt3, CH2Cl2 (60 %); (h) Pd(OH)2, HCO2NH4, AcOH, MeOH, reflux (80 %); (i) BH3.THF; (j) aq. HCl (96 % 2 steps).
26
Polt and Ravasi have reported a short synthesis of 8-epi- and (+)-1,2-di-epi-
swainsonine (Scheme 1.23).39 Beginning with the protected D-serine compound 147,
reaction with i-Bu5Al2H and then vinyl magnesium bromide gave 148 as a separable 1.7:1
mixture of diastereoisomers, which exist as oxazolidine-imine tautomers. Pivaloyl
protection (of the major isomer of 148) trapped the imine tautomer, then dihydroxylation
gave 149 (dr=10:1). Imine reduction of 149 with NaH3BCN gave the amino diol but
pivaloyl migration was a problem. Reduction of 149 with LiBH4, simultaneously reduced
the imine and removed the pivaloyl ester, then cyclisation of the resulting triol using
PPh3/CCl4/NEt3 gave the pyrrolidine 150 in good yield. Protection of the diol as its
acetonide and desilylation could be accomplished in a single step, then Swern oxidation to
the aldehyde, followed by nucleophilic addition of an allylstannane gave homo-allylic
alcohol 151 (dr >20:1). O-silylation, then hydroboration (9-BBN) with an oxidative
workup afforded the primary alcohol. Cyclisation via the mesylate, then deprotection with
TFA afforded 8-epi-swainsonine, which was isolated as its tris-acetate 152. (+)-1,2-Di-epi-
swainsonine was also prepared in the same manner in 14 steps from the minor isomer of
148.
O
N
TBSO
OMePh
Ph
OH
N
TBSO
Ph
Ph
OPiv
N
TBSO
Ph
Ph
OHOH
N
OH
OH
HTBSO
Ph
Ph N
H
Ph
Ph
OH
O
O
N
OAc OAc
OAc
H
a b,c d,e
f-h i-o
147 148 149
150 151 152
α-OH:β-OH = 1.7:1
Scheme 1.23 Reagents (a) (i) i-Bu5Al2H (ii) H2C=CHMgBr, THF, -78 oC to RT (iii) NaHCO3 aq. (76 %); (b) (CH3)3CCOCl, pyridine, DMAP (92 %); (c) K2OsO4.2H2O, K3Fe(CN)6, t-BuOH, K2CO3, NaHCO3 (70 %); (d) LiBH4, THF, reflux (84 %); (e) PPh3, CCl4, Et3N, DMF (91 %); (f) (CH3)2C(OCH3)2, 1.45 equiv CSA, CH2Cl2, reflux, 72 h (81 %); (g) (COCl)2, DMSO, Et3N, CH2Cl2, -60 oC to RT; (h) CH2=CHCH2SnBu3, BF3.OEt2, CH2Cl2 -78 oC (80 %); (i)TBSOTf, 2,6-lutidine, CH2Cl2, 0 oC (96 %); (j) 9-BBN, THF, RT; (k) H2O2, EtOH, NaOH (73 % 2 steps); (l) MeSO2Cl. NEt3, CH2Cl2; (m) H2, Pd/C, MeOH (n) CF3COOH, H2O (o) Ac2O, DMAP, pyridine (68 %, 4 steps).
27
Pilli et al. have exploited an N-acyliminium ion approach to the indolizidine
skeleton to prepare mono- and di-hydroxylated indolizidines (Scheme 1.24).50 Tartaric acid
was converted to the N-allyl imide 153 according to literature precedent, then regioselective
reduction and acetylation, followed by allylation via an N-acyliminium intermediate gave
compound 154. The authors made a number of attempts to improve the stereoselectivity of
the allylation reaction, by using allylstannane in place of allylsilane, by replacing the O-
acetyl protecting groups with TBS silyl ethers, and by using a plethora of different Lewis
acids. The best diastereoisomeric ratio (4:1) was achieved using allystannane and BF3.OEt2
on the O-silylated derivative. Subsequent ring closing metathesis, separation of the
isomers, hydrogenation, and finally reduction of the lactam moiety gave (+)-lentiginose and
8a-epi-lentiginose.
OH OH
COOHHOOCN
OAcAcO
O O N
OAcAcO
O
NOH
OHH
NOH
OHH
a b,c d-f (+)-lentiginose
8a-epi-lentiginose
tartaric acid
153 154
Scheme 1.24 Reagents (a) (i) AcCl, reflux, (ii) allylamine, CH2Cl2, RT (iii) AcCl, reflux (99 %); (b) (i) NaBH4, EtOH, -23 oC (ii) Ac2O, NEt3, DMAP, CH2Cl2 (76 %); (c) allylsilane, TiCl4, CH2Cl2 (89 %, d.r. 1:1); (d) Grubbs' cat., CH2Cl2, reflux (88 %); (e) H2, PtO2, AcOEt (f) LiAlH4, THF, reflux (60-82 % 2 steps).
Paolucci and Mattoli have prepared di- and tetra-hydroxyindolizidines (Scheme
1.25).51 The authors had previously described the transfomation of D-mannitol into the
starting material 155.52 The N-Boc group of pyrrolizidine 156 was removed with TMSI
and the free nitrogen was alkylated giving the 3-butenoyl derivative, which was treated
with Grubbs' catalyst to effect ring closing metathesis giving 157. Lactam reduction and
deprotection then gave the dihydroxylated derivative 158. Alternatively dihydroxylation of
the double bond in 159 formed after ring closing metathesis gives access to the
tetrahydroxylated derivatives 160, after separation of the 5:1 mixture of isomers, lactam
28
reduction and then deprotection. Other stereoisomers of 158 and 160 were also prepared in
a similar manner.
O
NHBoc
OH
N
OO
Boc
N
O
O
OH
O
NHBoc
OH
N
O
H OBn
OBn
N
OH
OH
H
N
OH
OH
OHH
OH
a,b c-e
f
g-i
155
156157 158
159 160
ref 52
ref 52
Scheme 1.25 Reagents (a) (i) TMSI, acetone; (ii) CH2=CHCH2COCl, NEt3, CH2Cl2 (85 %); (b) Grubbs' cat., benzene, RT to reflux (92 %); (c) H2, Pd/C (90 %); (d) (i) BH3.Me2S, THF, RT to reflux; (ii) EtOH, reflux (80 %); (e) HCl (2 M), 60 oC (76 %); (f) (i) PPh3, PhCOOH, DEAD, THF, RT (75 %); (ii) K2CO3, MeOH, H2O (90 %); (g)OsO4 cat., NMO, acetone, H2O (78 %, d.r. 5:1); (h) (i) BH3.Me2S, THF, RT to reflux; (ii) EtOH, reflux (75-98 %); (i) H2, Pd (black), EtOH, HCl (57-72 %).
1.2.3 Asymmetric Methods Blechert et al. have applied a ruthenium catalysed ring rearrangement approach to
produce an efficient synthesis of (-)-swainsonine (Scheme 1.26).53 The synthesis begins
with the chiral oxazolidinone 161, which was obtained via an asymmetric palladium-
catalysed desymmetrisation reaction. Base hydrolysis of 161 gave the protected amino
alcohol. Base catalysed reaction with allyl bromide gave N-allylation, then O-silylation
gave 162 in good overall yield. Ruthenium catalysed ring rearrangement with Grubbs'
catalyst was thermodynamically controlled, and the reaction proceeded favourably due to
steric relief for the bulky TBS group in 162, giving the more stable pyrrolidine 163 in good
yield. Selective hydroboration (9-BBN) and oxidative workup afforded the terminal
alcohol, and subsequent removal of the N-tosyl group gave the amino alcohol, which the
authors found advantageous to isolate as its N-allylcarbamate. Mesylation of the terminal
alcohol, then carbamate deprotection with Pd(PPh3) proceeded with cyclisation giving the
indolizidine 164. Dihydroxylation with OsO4/NMO gave a ~2:1 mixture of isomers,
however when AD mix-α was used, this ratio improved to 20:1. Desilylation and
29
acetylation gave a mixture of tris-acetates, which were separated, then deacetylation over
basic ion exchange resin gave (-)-swainsonine in good yield.
N
O
O
Ts
OTBS
NTs
N
H OTBS
Ts
N
HTBSO
N
OHH OH
OH
(-)-swainsonine
a-c d e-h
i-j
161 162 163
164 Scheme 1.26 Reagents (a) KOH, MeOH, 70 oC, 1 h (98 %); (b) CH2=CHCH2Br, K2CO3, DMF, RT, 12 h (99 %); (c) TBSOTf, 2,6-lutidine, CH2Cl2 (98 %); (d) 5 mol % Grubbs' cat., CH2=CH2, CH2Cl2, 40 oC, 1 h (98 %); (e) (i) 9-BBN, THF, 0-55 oC, 8 h (ii) NaOH, H2O2, EtOH, reflux, 1 h (83 %); (f) (i) Na/Hg, MeOH, reflux, 2 h (ii) NaOH, CH2=CHCH2COOCl, CH2Cl2, H2O, RT 1 h (89 %); (g) MsCl, NEt3, CH2Cl2, 0 oC, 2 h (98 %); (h) Pd0, NEt3, dimedone, THF, RT 3 h, 60 oC 3 h (95 %); (i) (i) AD-mix-α, CH3SO2NH2, 5 oC, 1 week (ii) TBAF, THF, RT, 24 h (iii) Ac2O, pyridine, DMAP, CH2Cl2, RT, 24 h (68 %); (j) Amberlite IRA-401, MeOH, RT, 2 h (96 %).
Katsuki et al. have also prepared (-)-swainsonine asymmetrically via a chiral
Mn(III)-salen mediated desymmetrisation of a meso-pyrrolidine (Scheme 1.27).54 To this
end 2,5-dihydropyrrole 165 was protected as its N-Boc carbamate, then dihydroxylation
and acetonide protection gave 166. Chiral Mn(III)-salen catalysed oxidative
desymmetrisation with PhIO gave an alcohol in 71 % ee, which was then oxidized to
lactam 167 with PCC. Treatment of the N-Boc lactam with Cl(CH2)4MgBr afforded chloro
ketone 168. Reaction of 168 with TMSOTf and PhSH effected N-deprotection, and the free
amine underwent K2CO3 mediated cyclisation to chloroimine 169. Heating 169 in toluene
effected cyclisation of the 6-membered ring giving a bicyclic iminium salt, which was
treated with base to give the enamine. The enamine was subjected to hydroboration
(BH3.THF) with an oxidative workup to install the final hydroxyl group (dr 9:1). Finally
removal of the acetonide afforded (-)-swainsonine.
30
NH
OO
N
HH
Boc
OO
N
HH
O
Boc
O
O
NH
O
ClH
H
Boc
O
ON Cl
N
OHH OH
OH
(-)-swainsonine
a-c d,e f
g h-k
165 166 167
168 169 Scheme 1.27 Reagents (a) Boc2O, NEt3, DMAP, CH2Cl2, RT, 12 h; (b) K2OsO4.2H2O, K3Fe(CN)6, K2CO3, DABCO, CH3SO2NH2, t-BuOH, H2O, RT, 15 h; (c) (CH3)2C(OMe)2, p-TsOH, DMF, RT, 20 h (75 % 3 steps); (d) Chiral Mn(III)-salen, PhIO, PhCl, -25 oC, 25 h; (e) PCC, CH2Cl2, RT, 8 h (56 % 2 steps); (f) Br(CH2)4Cl, Mg, THF, -78 oC, 1.5 h (71 %); (g) TMSOTf, PhSH, CH2Cl2 0 oC, 1.5 h (83 %); (h) PhCH3, reflux, 16 h; (i) t-BuNH2, KHMDS, PhCH3, 2 h; (j) BH3.THF, THF, RT, 10 h, then NaOAc, H2O2, RT, 12 h (67 % 3 steps); (k) PPTS, MeOH, RT, 65 h (45 %).
Carretero et al. have also recently reported access to (-)-swainsonine via a vinyl
sulfone (Scheme 1.28).55 Beginning with the di-Boc derivative of 5-aminopentanal 170,
reaction with p-tolylsulfinyl phenylsulfonyl methane, and then careful monodeprotection of
the amine gave the racemic alcohol 171. Kinetic resolution with lipase-PS and vinyl
acetate, gave the corresponding O-acetyl derivative, which was isolated, then cleaved and
reprotected as its TIPS ether. Careful N-Boc deprotection with TFA gave compound 172,
then base catalysed cyclisation gave a 19:1 mixture of trans : cis piperidines. N-alkylation
allowed the separation of these isomers, giving 173 in good yield. Deprotonation of 173
provided the sulfonyl carbanion, then intramolecular acylation gave the corresponding α-
sulfonyl ketone which was reduced to a single alcohol 174 using NaBH4. Desulfonation of
174 with Na-Hg then gave the dehydro-indolizidine 175. Dihydroxylation of 175 gave a
4:1 mixture of diastereoisomers of 176 in favour of the di-epi-configuation of (-)-
swainsonine. Interestingly when the TIPS protecting group was removed prior to
dihydroxylation, the authors report a 3:2 ratio of isomers in favour of the (-)-swainsonine
configuation, however they give no explanation of these results, which seemingly
contradict those of other research groups. (c.f. Blechert vide supra53, and Pyne et al. vide
31
infra56). Conversion of these mixtures to the corresponding triacetates facilitated separation
of the isomers, and finally deprotection afforded (-)-swainsonine and (+)-1,2-di-epi-
swainsonine.
N(Boc)2
CHO
NHBocSO2Ph
OH
NH3.OOCCF3
SO2Ph
OTIPS
N
OTIPS
SO2PhCOOEt N
HSO2Ph
OH
OTIPS
N
HOTIPS
N
H OH
OH
OTIPS
N
H OH
OH
OH
N
H OH
OH
OH
+
a,b c-f g,h
i j k
l-n
170 171 172
173 174 175
176 swainsonine 1,2-di-epi-swainsonine
Scheme 1.28 Reagents (a) PhSO2CH2SOTol, piperidine, CH2Cl2, 0 oC (91 %); (b) TFA (1.5 eq), CH2Cl2, RT (94 %); (c) Lipase PS, CH2=CHOAc, PhCH3, RT (46 %); (d) Lipase PS, 0.1 M Na2HPO4, RT (98 %); (e) TIPSCl, imidazole, CH3CN, RT (82 %); (f) TFA, CH2Cl2, RT (100 %); (g) MeOH, NEt3, -78 oC (98 %); (h) BrCH2COOEt, Lil. cat., K2CO3, CH3CN, 80 oC (93 %); (i) (i) LiHMDS, THF, 0 oC, (ii) NaBH4, MeOH, 0 oC (95 %); (j) Na-Hg, Na2HPO4, MeOH, RT (94 %); (k) OsO4, Me3NO, acetone, H2O, RT; (l) HCl 5 M; (m) Ac2O, pyridine, RT; (n) K2CO3, MeOH, RT.
Genisson et al. have recently prepared (-)-lentiginose and its pyrrolizidine congener
(Scheme 1.29).57 Acidic hydrolysis of the known epoxyamine 177,58 followed by N-
alkylation gave the two dienes 178 (n=0,1). Ring closing metathesis proceeded in spite of
the free amine, giving the pyrrolidine/piperidine compounds 179 in good yield. Removal
of the N-benzyl and alkene groups by hydrogenation and then cyclisation gave (-)-
lentiginose (n=1) and its pyrrolizidine analogue (n=0).
32
TBDPSONHBn
O
OH
OH
BnNn
OH
BnNOH
OH
n
OH
NOH
OH
n
a,b c
d,e
177 178
179 lentiginose (n=1)
n=0,1
Scheme 1.29 Reagents (a) 3 M H2SO4, dioxane, reflux (70 %) (b) n=0, allylbromide, NaHCO3, THF, H2O, RT (85 %), n=1, 4-butenyltrifluoromethanesulfonate, proton-sponge, CH2Cl2, RT (67 %); (c) n=0, Grubbs' cat., CH2Cl2, reflux (70 %), n=1, Grubbs' 2nd gen. cat., PhCH3, 70 oC (66 %); (d) H2 (12 bar), Pd/C, MeOH, 12 M HCl cat. (90 %); (e) PPh3, CCl4, NEt3, DMF, RT (68 %).
Somfai et al. have recently reported a total synthesis of (+)-castanospermine and its
close relative (+)-1-deoxynojirimycin (Scheme 1.30).59 Beginning with a regioselective
Sharpless asymmetric dihydroxylation of diene 180, the resulting diol was protected as an
acetonide, prior to reduction of the ester with DIBAL to give the allylic alcohol 181.
Sharpless asymmetric epoxidation gave the epoxy-alcohol, which was protected as a
TBDPS ether. The PMB group was then removed oxidatively using DDQ, and the
resulting alcohol was converted to the azide 182 via the corresponding mesylate.
Staudinger reduction of 182 gave the amine, which underwent cyclisation to the piperidine
183. Acid hysrolysis of 183 gave (+)-1-deoxynojirimycin. Compound 183 was bis-
benzylated in two steps, then TBDPS removal and Swern oxidation gave aldehyde 184.
Sakurai allylation of 184, was followed by dihydroxylation of the new allyl double bond
and oxidative cleavage of the diol gave the homologated aldehyde 185. Finally, reductive
amination with an acidic workup produced (+)-castanospermine.
33
O
OEtOPMB
OO
OHPMBO
OO
ON3 OTBDPS
NH
OO
OTBDPS
OH
NH
OH
OH
OHOH
N
OO OBn
OBnN
OO OBn
OBn
N
OH
OHHOHOH
(+)-1-deoxynojirimycin (+)-castanospermine
a-c d-h i,j
k
l-o p-r
s
180 181 182
183184 185
Scheme 1.30 Reagents (a) AD-mix-α, CH3SO2NH2. t-BuOH, H2O (80 %); (b) 2-methoxypropene, p-TsOH cat., DMF (97 %); (c) DIBAL-H, -78 oC, CH2Cl2 (93 %); (d) (+)-DIPT, Ti(i-PrO)4, t-BuOOH, CH2Cl2, -20 oC (80 %); (e) TBDPSCl, NEt3, DMAP, CH2Cl2 (97 %); (f) DDQ, CH2Cl2, H2O (92 %); (g) MsCl, i-PrEtN, CH2Cl2 (100 %); (h) NaN3, DMF, 70 oC (91 %); (i) Ph3P, THF, H2O (83 %); (j) EtOH, ∆, (100 %); (k) HCl (37 %), MeOH (100 %); (l) KHMDS, BnBr, THF, -78 oC (82 %); (m) BnBr, K2CO3, CH3CN, ∆ (97 %); (n) TBAF, THF, RT (100 %); (o) (COCl)2, DMSO, NEt3, CH2Cl2, -78 oC (93 %); (p) CH2=CHCH2SiMe3, TiCl4, CH2Cl2, -65 oC (71 %); (q) OsO4, NMO, t-BuOH, THF, H2O; (r) NaIO4, NaHCO3, THF, H2O (84 % 2 steps); (s) H2, Pd/C, then TFA (81 %).
Trost et al. have also prepared (-)-swainsonine, starting from the diol 186, which
was readily prepared from anthracene and benzoquinone (Scheme 1.31).190 Reaction of
186 with tosylisocyanate gave the meso-bis-carbamate, then palladium catalysed
desymmetrisation using Trost's chiral diphosphine ligand 196 afforded the oxazolidinone
187 in >99 % ee. Cis-dihydroxylation of the double bond in 187 proceeded from the β-face
then acetonide protection and base hydrolysis of the oxazolidinone yielded the protected
amino alcohol 188. Flash vacuum pyrolysis liberated anthracene, producing the chiral
cyclohexene 189 in 91 % yield. TIPS protection of the alcohol, then ozonolysis followed
by a reductive workup gave the diol 190. A regioselective Mitsonobu cyclisation gave the
34
pyrrolidine 191, which was oxidised to the corresponding aldehyde 192 using Dess-Martin
periodinane. The aldehyde 192 was reacted with vinyl magnesium bromide, then the
resulting allylic alcohol was transformed into the bicyclic carbamate 193 via methyl
carbonate formation and reductive N-deprotection. Unfortunately the authors were unable
to transform 193 into lactam 194 by forming the corresponding palladium-π-allyl
intermediate, followed by decarboxylation and intramolecular amination. The alternative
route involved a Horner-Wadsworth-Emmons olefination, then reduction of the resulting
alkene via catalytic hydrogenation gave 195. Reductive N-deprotection proceeded with
concomitant cyclisation of the lactam gave 194. Borane reduction of the lactam, and finally
acid hydrolysis of the protecting groups then afforded (-)-swainsonine in 17 steps and 13 %
overall yield.
H
H
OH
OH ONTs
H
H
O
H
HOH NHTs
O
O
O
O
NHTsOH
O
O
NHTs
OTIPS
OHOH
TsNO
OOTIPSH
O
N
O
O
OHOTIPS
N
OHH
OH
OHO N
O
O
O
OTIPSH
TsNO
OOTIPSH
EtOOC
TsNO
OOTIPSH
OH
NH
NH
OO
PPh2 Ph2P
a,b c-e f
g,h
(-)-swainsonine
i j
k-m
n-o
p
q,r
186 187 188
189 190191
192
193 194
195196
Scheme 1.31 Reagents (a) Tosyl isocyanate, THF, RT to 60 oC (90 %); (b) [(dba)3Pd2].CHCl3, 196, THF, DMSO (80 %, >99% ee); (c) OsO4, NMO, CH2Cl2, RT, 12 h (95 %); (d) 2,2-dimethoxypropane, p-TsOH.H2O, acetone, RT, 2 h (94 %); (e) K2CO3,
35
MeOH:H2O 9:1, 60 oC, 1.5 h (96 %); (f) FVT 500 oC, 0.05 mmHg (91 %); (g) TIPSOTf, 2,6-lutidine, CH2Cl2, RT, 3 h (95 %); (h) O3, CH2Cl2, -78 oC, 15 min, then Me2S, -78 oC to RT, then NaBH4, MeOH, 0 oC, 1 h (62 %); (i) DIAD, PPh3, THF, 0 oC, 45 min (86 %); (j) Dess-Martin periodinane, NaHCO3, CH2Cl2, RT, 45 min (98 %); (k) H2C=CHMgBr, THF, -78 oC, 10 min (95 %); (l) n-BuLi, methyl chloroformate, THF, -78 oC, 15 min (62 %); (m) 3 % Na(Hg), Na2HPO4, MeOH, RT, 30 min (68 %); (n) Triethyl phosphonoacetate, LiCl, DBU, CH3CN, RT, 2 h (90 %); (o) PtO2, H2 (1 atm), EtOH, RT, 1.5 h (99 %); (p) 3 % Na(Hg), Na2HPO4, MeOH, RT, 3 h (72 %); (q) BH3.Me2S, THF, RT, 2 h, then EtOH (95 %); (r) 6N HCl, THF, RT, 14 h (88 %).
1.3 Proposed Synthetic Approach It was proposed that for this project the structural similarity between the Stemona
and indolizidine sets of alkaloids could be exploited. While there is an abundant number of
total syntheses of these alkaloids, few of these methods (Perez's triple reductive amination
is a notable exception40) are easily applied to alkaloids of other types.
Thus we designed a synthetic strategy that could potentially be adapted to both
Stemona and indolizidine alkaloids, and indeed other 1-aza-[n+2.3.0]-bicyclic ring systems
such as the pyrrolizidines. Central to both classes of alkaloids is the pyrrolidine ring, which
is fused to the second ring at the 1 and 2 positions. Another common feature is an oxygen
substituent on the carbon vicinal to the nitrogen outside of the pyrrolidine ring. Finally the
absolute stereochemistry must be accounted for. By placing our major disconnections
about this common pyrrolidine core, we hoped to introduce a high degree of flexibility into
the synthesis, which could accommodate the varied substituents of the Stemona and
indolizidine alkaloids.
Our proposed general retro-synthetic strategy for preparing 1-aza-[n+2.3.0]-bicyclic
systems is outlined in Scheme 1.32. The key disconnection is the ring closing metathesis of
an appropriate diene in order to form the pyrrolidine ring. If this approach is to be
exploited then an efficient synthesis of β-amino alcohol dienes is required. Many existing
routes to β-amino alcohols rely on amino acid starting materials, which in turn severely
limits the number of accessible derivatives. Alternatively an asymmetric approach may be
taken, which then allows for more flexibility. We had thought that the amino alcohols
might be easily prepared via the aminolysis of an epoxide.
36
OO
N
H
H
O
HCH3
N
HOH
OH OH
OO
N
H
H H
O
CH3
CH3
O
OHNH2
OP
O
RH R'
NBoc
OP
H OHH
NH
OP
H OHH
NH
OP
CH3OH
H
H H
OH
OP
Swainsonineaminolysis
aminolysis
three ringclosures
spirolactoneformation
ring closing metathesis
dihydroxylation
ring closure
R or R' = H
aminolysis
Croomine
A
B
C
D
Scheme 1.32 Retro-synthetic analysis of the 1-azabicyclic systems (+)-croomine and (-)-swainsonine.
Our synthetic approach is flexible in that the absolute stereochemistry, and ring
sizes can be readily varied to produce many analogues. In this proposed method vinyl
epoxides undergo ring opening with allylamine nucleophiles to give a diene. After amine
protection, a ring closing metathesis reaction gives the pyrrolidine ring, and the resulting
alkene may be further functionalised or removed by hydrogenation. The second
heterocyclic ring may then be easily formed via ring closure of the amine with the alcohol
function (after activation) using standard methods. With this plan in mind a quick literature
search revealed that the use of ring closing metathesis in the synthesis of heterocyclic rings
is not a new idea and studies are numerous.60-71 This topic has been recently reviewed.72
The synthesis of 2,5-dihydropyrroles via ring closing metathesis has also been
extensively investigated (Scheme 1.33). In several studies N-tosyl-diallylamine, when
treated with Grubbs’ catalyst (typically by heating at reflux in DCM at high dilution ~0.004
M) gave N-tosyl-2,5-dihydropyrrole in excellent yield.73-80 Ring closing metathesis also
proceeds well for N-Boc-diallylamine.81 Studies on the synthesis of more substituted 2,5-
37
dihydropyrroles are also abundant. Riera et al. have produced chiral 2,5-dihydropyrroles
via ring closing metathesis, which were substituted at the 2- position.82 Evans and
Robinson used and allylic amination procedure to prepare protected and substituted bis-
allyl amines which, when treated with Grubbs’ catalyst by heating at reflux in benzene gave
chiral 2,5-disubstitiuted-2,5-dihyropyrroles in good yield.83 By using optically active
starting materials the authors were able to directly control the absolute stereochemistry at
carbons 2 and 5. Other examples of substituted 2,5-dihydropyrroles being prepared in this
way are also abundant, featuring 2-,84,85 3-,86,87 2,5-,71,88 and 2,2,4-89 substituted systems.
Generally the Grubbs' ruthenium carbene catalysts are used in these methods, however the
Shrock molybdenum catalyst may also be used.88
NP
NP
P=Boc, Ts P=Boc, Ts
RCM
Scheme 1.33 Ring closing metathesis of protected diallylamines.
The use of ring closing metathesis for the construction of fused bicyclic heterocyclic
systems has not been overlooked. Cases et al.68 and Martin et al.90,91 have investigated
these systems, with excellent results. In another approach Beak et al. have used ring
closing metathesis of dienes 197 to prepare bicyclic lactams 198 (Scheme 1.34).92
N
O
N
O
RCM
197 198
(
(
)m
)n(
( )m
)n
Scheme 1.34 Ring closing metathesis in the synthesis of bicyclic lactams.
Generally the nitrogen atom must be deactivated in order for ring closing metathesis
to occur, as a free (basic) nitrogen can inhibit the metathesis catalyst.72 This is most
commonly accomplished by using an electron withdrawing protecting group such as a
carbamate, sulfonate or an amide. In the case of β-hydroxy amines an oxazolidinone has
38
also been used. Alternatively ring closing metathesis in the presence of a quaternary
ammonium salt has also been successful. Examples of RCM on molecules containing free
amines exist,57 however these are rare.
Substituted 2,5-dihydropyrroles and pyrrolidines have also been prepared by other
methods. Donohoe et al. have applied a partial reduction of a substituted pyrrole to achieve
a total synthesis of the pyrrolidine alkaloid DMDP.93 Nudelmann et al. have applied an
intramolecular oxime-olefin cycloaddition to prepare substituted chiral pyrrolidines.94
Hanessian and Ninkovic have prepared (-)-kainic acid via a trimethylstannyl radical
carbocyclisation of the diene 199 to the corresponding pyrrolidine 200 (Scheme 1.35).95
ON
O
BuOOC
NO
O
Me3Sn COOtBu
NH
COOH
COOHMe3SnClAIBNNaCNBH3
(-)-kianic acid199 200 Scheme 1.35 An example of a trimethylstannyl radical carbocyclisation.
Organometallic reactions of lithiated pyrrolidines/2,5-dihydropyrroles are gaining
populatity. Several research groups have investigated the (-)-sparteine mediated
asymmetric deprotonation of N-Boc-pyrrolidines using sec-butyllithium96 or iso-
propyllithium.97,98 Reaction with various electrophiles then afforded optically active 2- and
2,5- substituted N-Boc pyrrolidines. While (+)-sparteine is not readily available, a
surrogate is available that gives equivalent results.99 The formation and use of organo-
cuprates in these reactions has also been investigated.100
Encouraged by the success of these methods we began our own investigations. We
felt that if the dienes were produced via an aminolysis of a vinyl epoxide with allyl amine
then an additional stereochemical site (namely the carbon vicinal to the amino carbon)
could be controlled. Furthermore since vinyl epoxides can be readily prepared from
Sharpless epoxy alcohols,101-103 this meant that a wide range of vinyl epoxides were
potentially available in optically active form. Alternatively vinyl epoxides have also been
prepared via a chiral organoborane approach.104-107
39
Hence an important step in our proposed approach is the aminolysis of a vinyl
epoxide. Due to the synthetic importance of β-amino alcohols, epoxide aminolysis has
been extensively studied. A number of catalysts/promotors for this process have been
identified, the majority of which are Lewis acids. These include perchlorates such as
MgClO4,108 LiClO4,108 lithium salts such as LiBF4,108 LiNTf2,109 metal triflates such as
LiOTf,110 Cu(OTf)2,111 Sn(OTf)2,111 Yb(OTf)3,110,112-116 Gd(OTf)3,113 Nd(OTf)3,113
Hf(OTf)4,114 Zr(OTf)4,114 and other miscellaneous promotors such as Ti(iPrO)4,117,118
Al2O3,119-121 hexafluro-2-propanol,122 di-iso-propylaluminium trifluroacetate,123
[Rh(CO)2Cl]2,124 and montmorillonite K10 clay.125 The aminolysis of epoxides generally
proceeds with little regioselectivity, however some substitution patterns can confer
selectivity. For example, terminal epoxides are generally opened at the unsubstituted
epoxide carbon due to steric reasons. When no steric advantage is available (e.g. 1,2-bis-
alkyl epoxides) then electronic effects become an important factor, such as the dramatic
effect of a vinyl or phenyl substituent. When vinyl epoxides undergo nucleophilic ring
opening, attack occurs (almost) exclusively at the carbon bearing the vinyl group.126 This is
thought to be due to stabilisation of the intermediate/transition state incipient cation, which
translates to an activation of the allylic carbon toward nuclephilic attack.102,126
The Somfai group have been prolific researchers in the area of vinyl epoxide
aminolysis (Scheme 1.36). While investigating aminolysis of vinyl epoxides 201 with
ammonia (a notoriously slow reaction) it was found that p-TsOH.H2O significantly
increased the rate of reaction and yield,127,128 giving vic-amino alcohols 202 as single
isomers. The use of a benzylamine/p-TsOH.H2O aminolysis facilitated the synthesis of
(+)-deoxynojimycin.129 Somfai et al. have also investigated the effects of microwave
irradiation on aminolysis of vinyl epoxides,130 reporting a considerable increase in reaction
rate (3 days for p-TsOH.H2O, 8 min for microwave). Not content with only a single isomer
of allylamines from this approach, Somfai et al. have also shown that the vic-amino
alcohols 202 can also be converted into vinyl aziridines 203, which can be ring-opened
with oxygen nuclephiles (H2O/HClO4) giving vic-amino alcohols 204 where the positions
of the amine and hydroxyl group have been reversed.131 Notably, Somfai et al. have also
developed methods for ring opening the epoxides and aziridines with retention of
stereochemistry, which when combined with the SN2 ring openings allows for the synthesis
40
of all four possible isomers of a vic-amino alcohol from a single vinyl epoxide.132 This
divergent approach has already been applied to the syntheses of both (+)- and (-)-
sphingosine and its isomers.133
RR''
R'''O
R'
R'''R''
R
NH2
OH
R'
RR''
R'''NH
R'
R'''R''
R
OH
NH2
R'
SN2aminolysis
aziridineformation
SN2hydrolysis
201 202
203204 Scheme 1.36 Summary of Somfais' divergent approach to amino alcohols.
Regrettably most examples of epoxide aminolysis require a large excess of amine,
for reasons of reaction rate, and because of competition between the amine nucleophile and
the amine product. For our purposes we required a method for aminolysis that did not need
a large excess of amine. This would in turn facilitate the use of more complex amines
which are less readily available, for example from a lengthy synthetic route.
41
Chapter 2: Synthesis of Vinyl
Epoxides
In order to test our proposed synthesis (Scheme 1.32), we required an efficient
method for producing the required optically active vinyl epoxides. Huang et al. have
reported that allyl bromide can be reacted with aldehydes in the presence of diisobutyl
telluride and Cs2CO3 to give vinyl epoxides.134 However ~2:1 mixtures of cis : trans
isomers were obtained, and no provision is available for enantioselectivity, so this approach
was not viable for our purposes.
2.1 Chloroallylboration
Two viable methods for the synthesis of chiral vinyl epoxides are reported in the
literature. The first of these approaches exploits a chloroallylboration reaction,104-107,135,136
where the chiral boron reagent (dIpc)2BOMe is reacted with allyl chloride then LDA at –95 oC. To this mixture was added BF3.OEt2 then an aldehyde. According to the authors this
one pot reaction gives a syn-α-chlorohydrin, which, when treated with aqueous NaOH and
H2O2, gives the corresponding cis-vinyl epoxide with excellent enantio- and
diastereoselectivity. As this method appeared to give a short and optically active route to
the desired vinyl epoxides, we investigated further.
Commercially available 1,4-dihydroxybutane 205 was mono-protected as its TBS
ether 206, using TBSCl as the limiting reagent (Scheme 2.1). Formation of the bis-
protected product was limited by using a large excess (5 equiv) of 1,4-dihydroxybutane,
and the mono-protected adduct 206 was obtained in 62 % yield based on TBSCl. When 1.1
equiv of TBSCl was used the result was a 40 % yield of compound 206, and 40 % of the
bis-protected adduct based on TBSCl. It is debatable which approach was the less wasteful
as both TBSCl and 1,4-butanediol have comparable prices. All spectral data for 206
matched that of the literature.103 Compound 206 was then treated with PCC to give the
42
aldehyde 207 in 81 % yield, and all spectral data for 207 agreed with that previously
reported.103 The aldehyde 207 was surprisingly stable and could even be purified by flash
column chromatography. With the aldehyde 207 in hand we turned our attention to
Oeschlager's chloroallylboration method.104-106
OHOH
TBSOOH
TBSOO
TBSO
Cl
OH
TBSOO
a b
c
d
208a
207206205
Scheme 2.1 Reagents (a) TBSCl, imdiazole, DMF, RT, 3 h (62 %); (b) PCC, CH2Cl2, RT, 2 h (81 %); (c) d(Ipc)2BOMe, CH2=CHCH2Cl, LDA, THF, -95 oC, 30 min, then BF3.OEt2, 207, THF, -95 oC, 4 h, warm to RT (d) NaOH, H2O2, THF, H2O, RT, 16 h (29 % 2 steps).
First and foremost we were dismayed to find that (dIpc)2BOMe was very expensive,
in short supply with slow delivery times, and extremely air sensitive. The reaction system
required six individual air sensitive reagents, and constant attention due to that fact the
reaction was required to be conducted at -93 oC (N2(l)/toluene). In fact it was difficult to
see how one person alone could undertake all the necessary tasks without compromising
the reaction or personal safety. In our hands the best overall yield of vinyl epoxide 208a
was 29 % based on the (dIpc)2BOMe reagent, and among the multiple by-products only the dIpc chiral auxiliary could be identified. Furthermore, this reaction gave no direct provision
for the synthesis of trans-vinyl epoxides, thus this approach was abandoned. The
characterisation of the vinyl epoxide 208a will be discussed at a later stage.
2.2 Nicolaou's six step approach Regarding the second and preferred approach to vinyl epoxide synthesis, a number
of researchers101-103,137-139 had converted Sharpless epoxy alcohols 213 into vinyl epoxides.
After oxidation of the epoxy alcohol to the corresponding aldehyde 214, the double bond
can then be formed via Wittig olefination giving the vinyl epoxides 208. The method used
43
by Nicolaou et al. appeared to be easily adaptable to the vinyl epoxides required for this
project. Nicolaou's method for the synthesis of vinyl epoxides is shown in Scheme 2.2. As
can be seen in Scheme 2.2 the approach is very flexible and variation can be introduced by
changing the protecting group, the alkyl chain length, and the alkene and epoxide
stereochemistry. Variation of the Wittig reagent can also allow for more substituted
alkenes.
OHn
OPn OPn
OH
OPn OH
OPn OH O
OPn O O
OPn
O
hydroxylprotection
alkyne homologation
alkynereduction
epoxidation
oxidation
Wittigolefination
cis or trans
209 210211
212213
214 208 Scheme 2.2: General method for the preparation of vinyl epoxides.
For use in our own studies, commercially available 4-pentyn-1-ol (n=1) 209a or 5-
hexyn-1-ol (n=2) 209b were treated with TBSCl and imidazole in DMF to give the
corresponding known TBS ethers140 210a (n=1) and 210b (n=2) respectively, in excellent
yield without complication. The TBDPS ether 210c (n=1) of 4-pentyn-1-ol was also
prepared in an identical manner. Alternatively the two alkynes were also protected in
excellent yield as their PMB ethers 210d (n=1) and 210e (n=2), by treatment with PMB-Br
and NaH in THF. The methods used were standard and all protected starting alkynes were
known compounds, where all spectral data matched that reported in the literature (see
Experimental section for specific details).
44
2.2.1 Alkyne Homologation
OPn
OPn
OHnBuLi, (CH2O)nTHF, 0 oC-RT210 211
SM # n P Best yield* (%) Prod. #
210a
210b
210c
210d
210e
1
2
1
1
2
TBS
TBS
TBDPS
PMB
PMB
94
96
84**
86
82
211a
211b
211c
211d
211e
*Yields were reproducible to within 5 %. **Unoptimized
Table 2.1 - Summary of alkyne homologation results.
Alkyne homologation101-103,141 was effected by first deprotonating the terminal
alkyne using n-BuLi, then reacting the resulting anion with formaldehyde, which was
generated in situ from paraformaldehyde. This transformation gave significantly better
yields when dry finely powdered paraformaldehyde was used, as this allowed for a faster
dissolution of this reagent (Table 2.1). Critical to a good yield in this reaction was the
amount of n-BuLi added, and if more than one equivalent was used then unidentified by-
products were obtained. It was interesting to note that an exact knowledge of the
concentration of the n-BuLi solution was not necessary. The alkyne acted as its own
indicator, in that removal of a single proton gave no colour change, but when a second
proton was removed the resulting dianion is a bright yellow colour. With this in mind n-
BuLi was added until the colour change was seen, and this approach almost eliminated any
side products in this reaction.
Table 2.1 shows that higher yields were obtained when TBS was used as the
protecting group. We attributed this to a higher stability of this moiety to n-BuLi. Each of
the five products above were all known compounds and all spectral data match that
described in the literature. Success of the homologation reaction was inferred from the
disappearance of the alkyne proton signal present in the starting material (1.9 ppm) and the
appearance of new signals for the CH2OH group at 4.20 ppm (CH2OH) and 1.6-2.2 ppm
45
(CH2OH, exact frequency was concentration dependant) in the 1H NMR spectra. Similarly
the 13C NMR and DEPT spectra showed a replacement of the alkyne doublet signal (84
ppm) with an alkyne singlet (86 ppm) and an additional triplet signal at 51 ppm for the
CH2OH group.
2.2.2 Reduction of Propargylic alcohols
OPn
OH OPn OH
alkynereduction
211 212 SM # n P E/Z Reagent Solvent Best Yield (%) Prod #
211a
211b
211e
211e
211d
211a
211c
1
2
2
2
1
1
1
TBS
TBS
PMB
PMB
PMB
TBS
TBDPS
Z
Z
Z
E
E
E
E
Pd.CaCO3/H2
Pd.CaCO3/H2
Pd.CaCO3/H2
REDAL
REDAL
REDAL
REDAL
Pet. Sp.
Pet. Sp.
EtOAc
THF
THF
THF
THF
97
95
95
95
93
60*
0
212a
212b
212c
212d
212e
212f
212g
*frequently much lower
Table 2.2 - Summary of alkyne reduction results.
With the extended alkynes 211 in hand reduction to the corresponding alkenes 212
was attempted. Reduction to the Z-alkenes 212a-c was achieved by Lindlar hydrogenation
using Pd/CaCO3 under an atmosphere of hydrogen (1 atm). Over-reduction to the alkane
was prevented by poisoning of the catalyst with quinoline, which was easily removed after
the reaction by column chromatography or extraction with aqueous acid. Petroleum spirit
appeared to be the optimum solvent for the reaction giving the best reaction times and
selectivity between the Z and E isomers (typically 15:1), however the PMB protected
alkyne 211e was not soluble in this solvent, and EtOAc was used here without any
detrimental effect on selectivity. When THF was used as the reaction solvent, higher
amounts of the undesired E isomers were obtained, which were inseparable from the Z
46
isomer. Nevertheless, high yields of the desired Z-alkenes 212a-c were obtained when
using the appropriate solvent.
The alkynes could also be reduced to the E-alkenes 212d-f using the hydride
reagent REDAL and in these cases only one stereoisomer was formed.142 The E-isomer
arises from an intramolecular trans-addition of a propargylic oxy-aluminium hydride
species to the alkyne. Attempts to reduce the alkyne group in compound 211a were met
with limited success, due primarily to the TBS ether being cleaved to the alcohol on a
similar time scale to the alkyne reduction, typically resulting in very low yields of the
allylic alcohol 212f. The use of the TBDPS silyl ether 211c fared no better with almost
complete silyl ether cleavage occurring and hence none of the desired allylic alcohol 212g.
The PMB protecting group showed superb stability to the REDAL reagent, affording the E-
allylic alcohols 212d and 212e in excellent yield after 5 h. While it is likely that other
protecting groups could serve here, none were investigated. The newly formed E and Z
alkenes were identified based on the appearance of a 2 proton multiplet at 5.4-5.7 ppm in
the 1H NMR spectra, and the corresponding 13C NMR signals at 129 and 132 ppm.
Curiously the shape of the 2 proton multiplet was indicative of the stereochemistry
about the double bond (Figure 2.1). The Z geometry showed two distinct spectral peaks
(left) while the E geometry showed only a single peak (right), supplying us with a potential
diagnostic tool for identifying selectivity ratios in product mixtures.
Figure 2.1 - Partial 1H NMR spectra (CDCl3) of 212c and 212d showing the difference between the Z (left) and E (right) alkene protons.
47
2.2.3 Epoxidation of Allylic Alcohols
OPn OH
OPn OH Oepoxidation
212 213 SM # n P E/Z Reagent Best yield (%) R/S Prod. #
212b
212a
212c
212e
212a
212e
212c
2
1
2
1
1
1
2
TBS
TBS
PMB
PMB
TBS
PMB
PMB
Z
Z
Z
E
Z
E
Z
m-CPBA
m-CPBA
m-CPBA
m-CPBA
SAE
SAE
SAE
90
90
68
60
71
52
62
-
-
-
-
(2R,3S)
(2R,3R)
(2R,3S)
213b
213a
213c
213e
213a
213e
213c
Table 2.3 - Summary of epoxidation results.
Epoxidations of the allylic alcohols 212 were effected in racemic form initially,
using m-CPBA as the oxidising reagent in DCM. This reaction can best be described as
unreliable, with yields varying from 40-90% of the racemic epoxides 213 after 24 h. In
some cases the only way to remove the m-chlorobenzoic acid by-product from the desired
epoxide products was to extract it with aqueous NaHCO3 solution, whereas column
chromatography was inadequate due to streaking of both the epoxy alcohol and the acid by-
product.
The epoxidation of the allylic alcohols 212 was also accomplished using the popular
Sharpless asymmetric epoxidation (SAE).143-145 The allylic alcohols 212 were treated with
the Sharpless catalyst (consisting of (-)-DIPT and Ti(i-PrO)4) and t-BuOOH in DCM over
powdered 4Å molecular sieves. The reaction was slow and frequently stopped prior to
completion, but acceptable yields (40-70 %) of the epoxides 213 were obtained
nonetheless.
Crucial to a good result in this reaction was the choice of work up. Simply
quenching with water (or 10 % NaOH as recommended by Sharpless)145 and extracting
with an organic solvent was not sufficient. This gave a thick emulsion, which then required
48
additional care and attention (e.g. filtration through celite was found to aid separation, but
this was complicated as the filter pad became blocked almost instantaneously). It was
found far better to quench the reaction by the addition of a 10 % solution of tartaric acid
(also recommended by Sharpless).145 This vastly aided the separation of phases and
consequently improved the yields obtained for the reaction. A common by-product of this
reaction resulted from the base catalysed Payne rearrangement of the epoxy-alcohol
product, however this was minimized when using the tartaric acid work up.
While this approach worked well for the Z-allylic alcohols 212a and 212c, major
problems were experienced when conducting the epoxidation on the E-allylic alcohol 212e.
A competing reaction occured, whereby an unknown product was formed from the product
epoxide 213e thus reducing the yield. Furthermore, this unwanted material was difficult to
separate from the desired product. This process also appeared to result in a deactivation of
the catalyst prior to the completion of the reaction. The best approach available to us was
to use high catalyst loadings (up to 50 %) and to quench the reaction after only 1 h (c.f. 24
h for epoxidation of the Z-allylic alcohols), whereby the pure product 213e could be
obtained (40-50 % yield), together with some recovered starting material 212e (20-30 %).
The formation of the epoxide was inferred from the disappearance of the alkene
signals in the proton and carbon spectra, and the appearance of two signals at 2.9-3.2 ppm
in the 1H NMR and at 56-58 ppm in the 13C NMR spectra, corresponding to the two newly
formed epoxide CH groups. The enantiomeric purity of epoxide 213e was determined by
converting it to its MTPA (Mosher) ester 215 via reaction with MTPACl, NEt3 and DMAP
(Scheme 2.3). The 1H NMR spectrum (specifically the dd signals for each diastereoisomer
at 4.51 and 4.56 ppm) of the MTPA ester 215 revealed a 96:4 mixture of diastereoisomers
corresponding to a 92 % ee. These signals were observed in a 1:1 ratio when the Mosher
ester derivative was prepared from racemic 213e The absolute stereochemistries of the
three epoxides 213a, 213c and 213e, were inferred using the Sharpless mnemonic (Figure
2.2). In all three cases (-)-DIPT was used, whereby epoxidation occurs from the top face in
Figure 2.2, leading to the assignments of (2R,3S)-213a, (2R,3S)-213c and (2R,3R)-213e for
the three epoxides.
49
O
OOPMB
O
F3C Ph
MeO
O
OHOPMB a
213e 215 Scheme 2.3 Reagents (a) MTPACl, DMAP, NEt3, CH2Cl2, RT, 15 min (97 %).
R OH
R'' R'
D-(-)-DIPT(top face)
L-(+)-DIPT(bottom face)
[O]
[O]
Figure 2.2 Diagram showing the Sharpless mnemonic for the epoxidation of allylic alcohols.
2.2.4 Oxidation of Epoxy Alcohols to Aldehydes
OPn OH O
OPn O O[ox]
213 214 SM # n P cis/trans Reagent Best yield (%) Prod. R/S Prod #
213b
213b
213a
213c
213e
213a
213c
213e
2
2
1
2
1
1
2
1
TBS
TBS
TBS
PMB
PMB
TBS
PMB
PMB
cis
cis
cis
cis
trans
cis
cis
trans
CrO3.2Pyr
Pyr.HCrO3.Cl
TPAP
TPAP
TPAP
Swern
Swern
Swern
<5
40*
86
74**
93 **
quant.
quant.
quant.
(2S,3S) rel
(2S,3S) rel
(2S,3S)
(2S,3S)
(2S,3R)
(2S,3S)
(2S,3S)
(2S,3R)
214b
214b
214a
214c
214e
214a
214c
214e
* impure product. ** unoptimized
Table 2.4 - Summary of results for the oxidation of epoxy alcohols to aldehydes.
50
Four methods were used with respect to oxidizing the epoxy alcohols 213 to the
corresponding aldehydes 214. An attempt to conduct this oxidation with CrO3.2Pyr was
not satisfactory with almost no product obtained. The second reagent attempted was
pyridinium chlorochromate (PCC).146 Treatment of 213b gave the desired aldehyde 214b
but in relatively poor yield (~40-70 %) and purity. It was apparent that the product epoxy
aldehyde was unstable, and that a milder (and cleaner) method of oxidation was required.
Improved results were obtained when using NMO and a catalytic amount of TPAP
in DCM over powdered 4Å molecular sieves.147 This generally gave good yields (80-95 %)
of aldehydes 214 providing fresh TPAP was used. Older samples of TPAP (~2 months)
were inferior and as a result gave incomplete conversion. The one major drawback in this
reaction was that filtration of the reaction mixture through a short column of silica gel was
required to remove ruthenium by-products, and the aldehyde products were not particularly
stable on silica.
The final and preferred method used for oxidation to the aldehydes 214 was the
Swern oxidation.148 The starting alcohol 213 was added to a mixture of COCl2 and DMSO
in dry DCM at –60 oC, then after 1 h NEt3 was added. After work up, excellent yields of
the aldehydes 214 were obtained (90-95 %), contaminated by only a trace amount of the
pungent dimethylsulfide by-product (1-5 %). The crude product was reacted immediately
due to the instability of the aldehyde, with only minimal characterisation. The formation of
the aldehyde group was highlighted by a 1 proton doublet at ~9 ppm in the 1H NMR spectra
and a signal at 199 ppm (d) in the 13C NMR spectra.
2.2.5 Wittig Olefination To complete the synthesis of the vinyl epoxides 208, a Wittig olefination was
conducted to transform the aldehyde group of 214 into the corresponding alkene.
Treatment of CH3PPh3Br in toluene or THF, with a strong base gave an ylide, and to this
was added the appropriate aldehyde 214 under anhydrous conditions. The choice of base
was extremely critical in this reaction. When n-BuLi or LiHMDS were used to deprotonate
CH3PPh3Br, little or no vinyl epoxide was obtained. We attributed these results to the very
hard lithium counter ion, which can coordinate to the oxyrainyl oxygen atom and thereby
catalyse nucleophilic ring opening of the epoxide ring. No attempts were made to isolate
51
the potential products from reactions of this type, primarily because the polarity of such by-
products would be much higher than the desired vinyl epoxide, and they were mistaken for
baseline impurities. This theory was vindicated by the use of KHMDS as the base,101-103
which gave vastly improved yields of the desired vinyl epoxides 208. The newly formed
vinyl group was clearly visible in the 1H NMR spectra with three ddd signals at 5.3, 5.4 and
5.7 ppm corresponding to the alkene CH2 and CH resonances respectively. In the 13C NMR
the presence of the vinyl group was highlighted by signals at 120 (t) and 133 (d) ppm.
OPn O O
OPn
OCH3PPh3Br
base214 208
SM # n P cis/trans Base Best yield (%) Prod R/S Prod #
214b
214b
214a
214a
214c
214e
2
2
1
1
2
1
TBS
TBS
TBS
TBS
PMB
PMB
cis
cis
cis
cis
cis
trans
LiHMDS
n-BuLi
n-BuLi
KHMDS
KHMDS
KHMDS
trace
12
48
82
81*
69*
(2S,3R)
(2S,3R)
(2S,3R)
(2S,3R)
(2R,3S)
(2R,3R)
208b
208b
208a
208a
208c
208e
* yields for 2 steps based on epoxy alcohol
Table 2.5 - Summary of results for Wittig olefination.
52
Chapter 3: Aminolysis of Vinyl
Epoxides and Early Model Studies
3.1 Aminolysis with Allylamine With the vinyl epoxides now available we began our investigations into their
aminolysis reactions (Scheme 3.1). Simply heating vinyl epoxide 208a (0.1 M) with allyl
amine (1.15 M) in THF at 80 oC for 3 d gave none of the desired aminolysis product 216.
The starting material was recovered almost quantitatively indicating a surprising resilience
of the oxirane ring to nucleophilic ring opening. A brief attempt to catalyse this reaction
using activated neutral alumina119-121 was not successful, however it should be noted that
only room temperature experiments were attempted, and it is likely that higher
temperatures would be more effective.
Inspired by the work of Somfai et al., 127,128 the vinyl epoxide 208a was heated with
allylamine (3.2 equiv.) and a catalytic amount of p-TsOH.H2O (0.2 equiv.) at 130 oC for 4 d
in toluene. The results were promising giving the desired N-allyl ring opened product 216
as a single isomer, albeit in low (23 %) yield due to incomplete conversion. Clearly further
optimisation was required. When the same vinyl epoxide was heated in neat allyl amine
(~20 equiv) with p-TsOH.H2O (0.2 equiv.) to 110 oC in a sealed tube, complete conversion
was achieved in 3 d, affording the desired amino alcohol 216 in 92 % yield, and more
importantly as a single isomer. The 1H NMR spectra for the amino alcohol 216 was similar
to that of the starting vinyl epoxide 208a except that additional signals at 2.8 (2H, NH and
OH), 3.1 (1H, ddt, NCH2), 3.3 (1H, m, NCH2), 5.1 (2H, m, CH=CH2) and 5.9 (1H, dddd,
CH=CH2) ppm for the new N-allyl group were now present. The same was true for the 13C
NMR spectra of 216, which had additional signals at 49 (t, NCH2), 119 (t, CH=CH2) and
136 (d, CH=CH2) ppm also corresponding to the new N-allyl group.
53
TBSOO N
H
OTBS
H H OH
a
208a 216 Scheme 3.1 Reagents (a) CH2=CHCH2NH2, p-TsOH.H2O, 110 oC 3 d (93 %).
3.2 Synthesis of the (+)-Croomine CD Ring System In order to test our proposed synthesis of (+)-croomine, a model system of the
pyrrolo-butyrolactone ring system of the Stemona alkaloids (compound 222) was devised
(Schemes 3.2 and 3.4). To this end the amino alcohol 216 was treated with Boc2O and
NEt3 in DMF at RT overnight, which afforded quantitative protection of the nitrogen atom
as its N-Boc derivative 217. The N-Boc group was clearly visible in the 1H NMR spectrum
as a 9H singlet at 1.45 ppm and in the 13C NMR spectrum with signals at 28 (q, Me3CO),
80 (s, Me3CO) and 156 (s, CO) ppm. N-Boc protection also had the additional effect of
broadening some proton signals, presumably due to the double bond character of the new
N-CO bond, which resultin in restricted rotation about this bond.
NH H OH
HOTBS
NH OH
HBoc
OTBS NH OH
HBoc
OTBSa b
217 218216 Scheme 3.2 Reagents (a) Boc2O, NEt3, DMF, RT 18 h (95 %); (b) Grubbs' catalyst, CH2Cl2 reflux (93 %).
The protected material was then ready for the next key step in our proposed
approach, namely ring closing metathesis. The diene 217 was treated with Grubbs' catalyst
(0.1 equiv) at high dilution (0.4 mM) and heated at reflux in CH2Cl2 solution for 16 h. This
gave complete conversion to the 2,5-dihydropyrrole 218 in excellent yield, however
repeated column chromatography was required to remove the highly coloured ruthenium
by-products from the product. The success of the reaction was indicated in the 1H NMR
spectrum by the loss of 4 of the 6 alkene protons and in the 13C NMR spectra by the loss of
the two alkene CH2 signals. Characteristic of the desired product 218 were the two proton
multiplet at 5.8 ppm (1H NMR) and two carbon signals at 126.5 (d) and 126.9 (d) ppm (13C
54
NMR) for the newly formed alkene. The success of this reaction also presented a minor
problem. While the product was pure (except for some trace ruthenium <1 %), the 1H and 13C NMR spectra were complicated by the presence of two distinct rotamers (major rotamer
at 80 % intensity), presumably due to the double bond character of the N-C bond of the Boc
protecting group. While this was only moderately irritating, it was a problem that we
would encounter often throughout the project, sometimes obscuring important issues like
product purity and isomeric ratios.
It was necessary to establish the mechanism of the aminolysis reaction and thus
authenticate the product stereochemistry (Scheme 3.3). While it had previously been
reported that ring opening with other amines was purely SN2, occurring regioselectively at
the allylic epoxide carbon,127,128,130 we felt it necessary to confirm this assertion for
ourselves. Thus the relative stereochemistry of amino alcohol 216 needed to be
determined. Somfai et al. have recently reported a 1H NMR diagnostic approach to this
problem,149 but at the time of this research such knowledge was unavailable. Hence the
above N-Boc-2,5-dihydropyrrole 218 was treated with NaH in THF, to convert the N-Boc
group into an oxazolidinone (Scheme 3.4). This occurs via deprotonation of the alcohol,
followed by an internal attack of the alkoxide at the N-Boc carbonyl atom and then
thedisplacment tert-butoxide. The reaction was sluggish (2 days at RT) and low yielding
(56 %), but a pure sample of the oxazolidinone 219 was obtained nonetheless. The 1H
NMR spectrum showed a complete loss of the N-Boc signal at ~1.4 ppm, and an increase in
the sharpness of the remaining signals also supported the designation of the product as the
rigid oxazolidinone 219. The deshielding of the oxygen bearing CH chemical shift from
3.6 to 4.3 ppm was consistent with that oxygen now being bonded directly to the electron
withdrawing carbonyl group. The 13C NMR spectrum similarly confirmed the loss of the
N-Boc signals, with the exception of the carbonyl, which had moved from 156 to 163 ppm.
Finally mass spectral analysis gave a parent ion at m/z 298 as expected from the desired
oxazolidinone 219.
55
O
R'R
O
R'R
H
R'R
OH
Nu
H
OH
R'R
H OH
R'R
OH
R'R
Nu
OH
R'R
Nu
+
H+ SN2
SN1
+ +
Nu
Nu Nu
single isomer
two isomers
vinyl epoxide
C1 regioisomer Scheme 3.3 - Possible mechanisms for the aminolysis of vinyl epoxides.
NBoc
H
OO
HNO
O
H
OTBSH
NH OH
HBoc
OTBSN
H OHH
Boc
OTBSN
H OHH
Boc
OH
CD
a b
cd
218
219
220 221
222
123
4
5
6 7
7a
Scheme 3.4 Reagents; (a) Pd/C, H2, pet. sp. (91 %); (b) TBAF, THF, RT, 18 h (89 %); (c) TPAP, NMO, 4A mol. sieves, CH2Cl2, RT (94 %); (d) NaH, THF, RT, 2 d (56 %).
Determination of the relative configuration about the oxazolidinone ring in 219 was
inferred from a NOESY spectrum, which revealed no correlation between H1 and H7a,
indicating a trans-arrangement about the oxazolidinone ring, consistent with an SN2 oxirane
ring opening. This is supported by the work of Somfai et al. who showed that the 1H NMR
signals for 1,2-anti amino alcohols were further downfield when compared to the
corresponding signals for syn-1,2-amino alcohols.149 Comparison of the signals for these
protons in amino alcohol 216 (CH-O at 3.35 and CH-N at 2.85 ppm) with those of Somfai
et al. indicate that the configuration of the amino alcohol 216 is syn, again corresponding to
SN2 ring opening. The final piece of evidence for SN2 ring opening lies with the fact that
only one product is seen. This can only occur if mechanism is SN2, whereas an SN1 ring
56
opening would give a 1:1 mixture (assuming that the β-hydroxy substituent has no effect on
facial selectivity) of C3 epimers, and would most likely give a mixture of C1/C3
regioisomers (Scheme 3.3).
The 2,5-dihydropyrrole 218 was hydrogenated, using Pd/C in pet. sp. under an
atmosphere of hydrogen (1 atm), to give the pyrrolidine 220 in good yield without
complication. The loss of the alkene signals at 5.8 ppm confirmed the success of the
reaction, adding 4 protons to the low ppm end of the 1H NMR spectrum, and 13C NMR and
mass spectral analysis also supported this affirmation. The pyrrolidine 220 was treated
with excess TBAF.3H2O overnight at RT giving complete deprotection of the TBS ether in
good yield (89 %). The loss of the characteristic TBS signals at 0.01 ((CH3)2Si) and 0.89
((CH3)3CSi) ppm in the 1H NMR spectrum and corresponding losses from the 13C NMR
spectrum marked the success of the reaction. The resulting diol 221 was then ready to be
oxidised to the lactone 222. Our initial attempt to achieve this with PDC was a dismal
failure, giving uncharacterisable product mixtures only. Fortunately, the alternative
oxidation with TPAP/NMO147,150 gave excellent results, affording a 94 % yield of the
known lactone 222.151 The product lactone was difficult to detect by tlc, since it possessed
no chromophoric group and did not stain well with the molybdenate dip used in our
laboratory. In fact this compound was detectable only as a negatively staining spot upon
the tlc plate. The normally broad spectral peaks of the N-Boc pyrrolidinines were
extremely broad for those of lactone 222, however all peaks were assignable to the product
structure, and agreed well with literature values as did the specific rotation [α]D21: -62 (c
0.77, CHCl3), lit.151 [α]D: -72 (c 3.20, CHCl3).
3.3 Synthesis of 1-Substituted Allyl Amines Armed with the success of our first model system, we next turned our attention to a
more complicated synthesis. In this model of our proposed synthesis of (+)-croomine, a
more highly functionalised amine such as 223 was required with which to conduct the
aminolysis. This amine could be prepared in a number of ways, but in keeping with the
theme of this project, it was decided to prepare this amine via the aminolysis of a vinyl
epoxide, where this time the amine required was simply ammonia. Somfai et al. had
57
reported that this aminolysis was slow and low yielding in hot aqueous ammonia, but using
neat liquid NH3 in a sealed tube with p-TsOH.H2O (5 %) at 130 oC gave good yields of the
vic-amino alcohol in several days.127,128 The same group also reported that this
transformation could be conducted with aqueous ammonia in a microwave reactor in a
matter of minutes.130 As we were not in possession of a microwave reactor (at this time),
we attempted (with trepidation) the used of hot liquid ammonia (Scheme 3.5). Reacting the
vinyl epoxide 208a in this way was not successful in our hands, due primarily to the lack of
a sealed tube efficient enough to retain liquid ammonia (b.p. -35 oC) at such high
temperatures, and by the fact that the TBS ether was being slowly cleaved under such harsh
conditions. Other attempts fared no better. For example, heating the vinyl epoxide 208a in
aqueous ammonia (25 %) with Yb(OTf)3 (0.2 equiv.) at 70 oC overnight gave primarily
cleavage of the TBS ether.
TBSOO
OTBSNH2
HH OH
a
208a 223 Scheme 3.5 Reagents (a) NH3(l), p-TsOH.H2O, 130 oC.
Clearly a different approach was required. A re-examination of the retro-synthetic
analysis of (+)-croomine (Scheme 3.6) revealed that either of the two vinyl epoxides 208a
or 208c could be converted to an amino alcohol initially.
OO
N
H
H
O
H
OHNH
H
H
OH
HOTBS
OPMB
ON
O
O
O H
H
CH3
H
CH3
OPMB
O
OTBSO
three ring closures
spirolactoneformation
(+)-croomine
NH3
α-methylation
aminolysis x 2
208a
208c Scheme 3.6 Retro-synthetic analysis of (+)-croomine.
58
The PMB protected vinyl epoxide 208c was chosen for this task in the hope that the
PMB protecting group would be more stable to the aminolysis conditions. Due to the
trouble experienced with the aminolysis using ammonia, we devised a new approach
whereby the aminolysis would be conducted with allylamine, then a selective deallylation
would give the desired amino alcohol (Scheme 3.7). Aminolysis of 208c with neat allyl
amine (20 equiv) with p-TsOH.H2O (0.2 equiv) as a catalyst, was complete in 3 days at 105 oC as discussed above, giving the amino alcohol 224 as a single isomer in 87 % yield.
Silylation of the alcohol function, using TBSCl and imidazole in DMF did not proceed well
at RT, rather it required heating to 60 oC in a sealed tube for 24 h to obtain complete
conversion, giving compound 225 in 77 % yield. More recent results (see Chapter 5)
suggest that this yield may have been higher if CH3CN had been used in the place of DMF.
The purpose of this silylation was to improve selectivity between the two allyl groups of
225, and to ease the isolation of the expected amine product 226 after deallylation. To
effect the deallyation the amine 225 was reacted with Pd(PPh3)4, using N,N-
dimethylbarbituric acid (NDMBA) as an allyl cation trap.152,153 With no reaction at RT,
heating the mixture in a sealed tube at 60 oC gave complete deallyation in 3 h, giving the
primary amine 226 in 97 % yield, though separation of the product from phosphine by-
products proved somewhat difficult.
O
OPMB
NH
OPMB
OHH
NH
OPMB
OTBSHNH2
OPMB
OTBSH
a
b
c
208c 224
225226
Scheme 3.7 Reagents (a) CH2=CHCH2NH2, p-TsOH.H2O (87 %); (b) TBSCl, imidazole, DMF, 60 oC, 24 h (77 %); (c) Pd(PPh3)4, NDMBA, CH2Cl2, 60 oC, 3 h (97 %).
59
Interestingly an attempt to apply the same conditions to the less hindered allyl
amine 216, gave a surprising result (Scheme 3.8). Deallylation of both N-allyl groups
occurred, liberating ammonia which was detected nasally upon opening the reaction flask,
and giving the two barbituric acid derivatives 227 and 228 each in 21 % yield, which arise
from trapping of the Pd-allyl complex with either NDMBA- or one of its C-allylated
derivatives. Clearly without the extra steric hindrance of the proximal O-silyl group, the
increased temperature was enough to initiate the second deallylation. These unexpected
products were identified initially by mass spectral analysis, and the assigned structures are
consistent with the NMR spectra obtained for the two compounds. The NDMBA adduct
227 had a 6H singlet at 3.22 ppm corresponding to the two N-CH3 groups, and five olefinic
protons (5.0-5.6 ppm) in the 1H NMR spectrum and the 13C NMR spectrum showed all the
expected peaks including the N-CH3 groups at 28 ppm, the four olefinic carbons at 120,
122, 130, 139 ppm and the three carbonyl groups at 150, 171 and 171 ppm consistent with
the assigned structure. The NDMBA adduct 228 is symmetrical and consequently all
spectral peaks except for those on the plane of symmetry (carbons 2 and 5 of the pyrimidine
ring) were of double intensity. The 1H NMR spectrum for 228 showed four olefinic
protons (5.2-5.6 ppm) and a 6H signal for the two N-CH3 groups at 3.24 ppm. The 13C
NMR spectrum of 228 also supported the assigned stucture.
NH OH
OTBSH
NN
OO
O
R' R
NH2 OHOTBS
H OHOTBS
HH3N OH
OTBS
Pd
NN
OO
O
R
a
227 R=H, R'= -CH(OH)(CH2)3OTBS, 21 %228 R=R'= -CH(OH)(CH2)3OTBS, 21 %
NDMBA+
Pd(0) +
R=H or allyl
-:
NDMBA-+
216
-NH3
Scheme 3.8 Reagents (a) Pd(PPh3)4, NDMBA, CH2Cl2, 60 oC, 3 h.
60
With the substituted allylamine 226 in hand we next turned our attention to the
aminolysis of vinyl epoxide 208a with this amine. Our first attempts at this reaction used
p-TsOH.H2O as a catalyst in a minimal volume of toluene at 110 oC and were
unsuccessful, with little material recoverable. A similar fate was suffered when Yb(OTf)3
was used in place of p-TsOH.H2O, and only vinyl epoxide decomposition products were
isolable. Unable to effect aminolysis with hindered amines at this time, we next focused
our attentions on the uses of the products obtained from the aminolysis of vinyl epoxides
with allyl amine.
61
Chapter 4: Indolizidine Alkaloids
4.1 (-)-Swainsonine 4.1.1 Aminolysis and Metathesis
During the first year of the project we noted that substituted 2,5-dihydropyrroles
such as 218 could be useful intermediates in the synthesis of indolizidine alkaloids.
Polyhydroxylated members of this class are often potent glycosidase inhibitors (see Chapter
1), and of these compounds the natural product (-)-swainsonine is a common synthetic
benchmark. Our proposed synthesis of (-)-swainsonine required the trans-vinyl epoxide
208e as a starting point (Scheme 4.1). Once prepared, the vinyl epoxide 208e was then
subjected to aminolysis with allylamine using the aforementioned conditions giving the
amino alcohol 229 in 88 % yield, once again as a single isomer. Standard N-Boc protection
of the amine gave 230 in 98 % yield, then ring closing metathesis gave the 2,5-
dihydropyrrole 231 also in good yield and as before the 1H NMR was complicated by the
presence of rotamers. This chemistry proceeded without complication and was no different
from that described in Chapter 3. Transforming compound 231 into (-)-swainsonine proved
to be much more difficult than expected, though only dihydroxylation and cyclisation of the
piperidine ring remained.
OPMBO
NH
OPMB
OHHH N
Boc
OPMB
OHHH
a c
229 R=H230 R=Boc
208e231b
Scheme 4.1 Reagents (a) CH2=CHCH2NH2, p-TsOH.H2O, 110 oC (88 %); (c) Boc2O, NEt3, CH2Cl2, RT (94 %); (d) Grubbs' cat., CH2Cl2, reflux (92 %).
4.1.2 Cyclisation and Dihydroxylation In our initial approach (Scheme 4.2) we felt it necessary to protect the secondary
alcohol of compound 231, prior to deprotection of the nitrogen and the primary alcohol for
the cyclisation, to prevent possible interference of the secondary alcohol upon the
62
cyclisation reaction. This was first accomplished by converting the alcohol to its benzoyl
ester, via treatment with benzoyl chloride and pyridine in CH2Cl2 giving 232 in 97 % yield.
The newly formed ester was clearly visible in the 1H NMR spectrum as a 3H multiplet at
7.3-7.6 ppm and a 2H triplet at 8.0 ppm and the corresponding phenyl carbon signals at
128-130 ppm in the 13C NMR spectrum. Interestingly the ratio of rotamers which had been
~80:20 in the starting material 231, had now changed to ~60:40 in the ester 232 indicating
that a possible internal H-bond in compound 231 was biasing the rotameric ratio.
N
HOBz
N
H
OH OH
OBz
N
H
AcO OAc
OAcN
HOH
N
H
OH OH
OHN
H
AcO OAc
OAc
NBoc
OPMB
OHHH N
Boc
OPMB
HH
OBz NH
OHH
HOBz
+
a b c
d
e
d f
231 232 233
234 236
237 swainsonine and1,2-di-epi-swainsonine
238 239
Scheme 4.2 Reagents (a) BzCl, pyridine, CH2Cl2, 0 oC (97 %); (b) TFA, anisole, CH2Cl2, RT, 1 h (72 %); (c) CBr4, PPh3, NEt3, CH2Cl2, 0 oC, 24 h (87 %); (d) K2OsO4.2H2O, NMO, acetone, H2O, RT (50 %, dr ~2:1); (e) K2CO3, MeOH, RT (100 %); (f) Ac2O, pyridine, RT, 18 h, separate isomers (238 49 % and 239 25 %).
Attempts to deprotect the O-PMB ether and N-Boc protecting groups of 232 by
treatment with TFA and anisole were only moderately successful. Anisole serves as a trap
for the 4-methoxybenzyl cation, facilitating the removal of the O-PMB group, which would
otherwise reattach itself after its acid catalysed removal. Unfortunately the resulting
unprotected 2,5-dihydropyrrole 233 was highly unstable. The primary complication was
the migration of the benzoyl ester group onto the now free nitrogen atom, as evidenced by
the isolation of the corresponding N-benzoyl amide from both the reaction mixture, and
63
also from samples of the product that had been allowed to age (1 day or more). In addition
the free 2,5-dihydropyrrole 233 has a propensity to aromatise to the corresponding pyrrole,
which can then polymerise to a black tar-like substance. In spite of these problems useable
yields of the amino alcohol 233 were obtained, and we soon learned to react this material
immediately. The 1H NMR spectrum of 233 was much sharper than that of the starting
material, consistent with our theory that the rotamers are a result of restricted C-N bond
rotation of the N-Boc group. In the 1H NMR spectra the 9H singlet at 1.4 ppm for the N-
Boc group and the signals for the O-PMB group at 6.8 and 7.2 ppm were not visible
confirming the success of the deprotection.
The amino alcohol 233 was treated with PPh3 and CBr4 in the presence of NEt3 to
effect cyclisation of the piperidine ring. This reaction was also complicated by the
aforementioned instabilities of the starting material, typically giving yields of 60 % or less
of the desired unstable bicyclic product 234. Mass spectral analysis of the product gave a
mass of m/z 244 (compared with 262 for compound 233) consistent with the loss of water
required for a successful cyclisation. The 1H NMR spectrum of 234 showed signals at 7.4-
8.0 (5H) and 5.9-6.1 (2H) for the O-benzoyl and 2,5-dihydropyrrole respectively, and
interestingly most other protons were now first order where they had previously overlapped
as multiplets. This differentiation of the protons is consistent with the formation of the six
membered ring, where axial and equatorial protons are very different. Furthermore, several
coupling constants for those protons within the new piperidine ring could be identified as
axial-axial couplings (J~11 Hz) also confirming the success of the cyclisation.
Literature precedents exist (see Chapter 1) regarding the dihydroxylation of
dehydroindoizidines such as 235 (Figure 4.1), where the alcohol is either unprotected
(R=H),55 or protected as its TBS ether154 or TIPS ether.55 Dihydroxylation of the double
bond of 234, was conducted using a catalytic amount of K2OsO4.2H2O with NMO used as a
co-oxidant. By conducting this dihydroxylation after the cyclisation rather than before, we
hoped to bias the selectivity to the α-face (cis to the piperidine ring), by taking advantage
of the pseudoaxial hydrogen atoms at C3 and C8a in the bicyclic adduct (Figure 4.1). It
should be noted that this is indeed the case of the TBS protected and unprotected
derivatives of 235, but interestingly not the TIPS silyl ether. Dihydroxylation of our
benzoyl protected substrate gave the diol 236 in low yield, however this was difficult to
64
isolate, but it was clear from the crude 1H NMR and 13C NMR spectra that the diol 236 was
present as a 2:1 mixture of isomers. Attempts to improve isolation by first acetylating the
crude product were most unsuccessful giving multiple products which we attributed to
benzoyl migration occuring in competition with the acetylation reaction.
OsO4
N
OR
H
H8a
H
H3β
235
Figure 4.1 - Diagram showing the preferred face of OsO4 attack.
To circumvent this problem the benzoyl ester was first removed prior to
dihydroxylation, using K2CO3 in methanol, giving the known free alcohol 23755 which was
not characterised due to its instability. Dihydroxylation of 237 has been examined
previously55,154 giving a 3:2 mixture of (-)-swainsonine and (+)-1,2-di-epi-swainsonine,
however we felt it necessary to confirm these results via the reaction of our own material.
Dihydroxylation of 237 using K2OsO4 and NMO as described above gave a 2:1 mixture of
(-)-swainsonine and (+)-1,2-di-epi-swainsonine that could not be separated, and in low
overall yield (50 %). To facilitate separation of the two isomers and indeed isolation of the
product form the dihydroxylation reaction, the mixture was per-acetylated. Hence reacting
the crude reaction product with an excess of acetic anhydride in pyridine afforded the tris-
acetylated products 238 and 239 in good yield, and these two compounds were now easily
separable by column chromatography. The tris-acetate of the major isomer 238 gave
identical 1H and 13C NMR spectra to that obtained from the tris-acetate of an authentic
sample of (-)-swainsonine, kindly supplied by Dr Reg Smith at Phytex Australia. The
minor product 239 was also isolated and this was identified as the tris-acetate of (+)-1,2-di-
epi-swainsonine by comparison of its 1H and 13C NMR spectra with the spectral data from
the literature.39,53,155
65
4.1.3 Failed Alternatives Because of the instability of the precursors, and the low yields corresponding to this
fact, we resolved to improve our approach. One such attempt is shown in Scheme 4.3.
Protection of the secondary alcohol of compound 231 as its silyl ether was accomplished
using standard conditions at 60 oC affording 240 in quantitative yield. The resulting silyl
ether 240 was then treated with DDQ (1.15 equiv) in DCM and water, which resulted in
selective removal of the PMB ether in 3 h at RT, and produced the free alcohol 241 in 78 %
yield. The free alcohol 241 was then converted to the corresponding tosylate by treatment
with p-TsCl in pyridine yielding the tosylate 242 in 70 % yield, with 25 % of the starting
alcohol also recovered. Our idea was that if we could then selectively remove the N-Boc
protecting group, the resulting free amine should displace the tosylate to effect cyclisation
of the 6-membered ring. However attempts to do this were not successful. BF3.OEt2 has
been reported to cleave N-carbamate protecting groups,156 but in our hands this only gave a
complex product mixture. It was evident from the crude 1H NMR that the N-Boc group
remained uncleaved, and the OTBS group had been completely removed. Treatment of 242
with TFA also gave a complex product mixture. This approach would have more potential
given a more acid stable choice of protecting group for the secondary alcohol.
NOTBS
H
NOPMB
BocOHH
H NOPMB
BocOTBSH
HN
OH
BocOTBSH
H
NOTs
BocOTBSH
H
a b
c d
231 240241
242 Scheme 4.3 Reagents (a) TBSCl, imidazole, DMF, 60 oC (99 %); (b) DDQ, CH2Cl2, H2O (78 %); (c) p-TsCl, pyridine, RT (70 %); (d) BF3.OEt2, DCM, 0 oC.
The secondary alcohol of 231 was also protected as its pivaloyl ester (Scheme 4.4),
based on the belief that this might be less likely to migrate to the free nitrogen atom. The
pivaloyl ester 243 was formed easily, via the reaction of 231 with excess pivaloyl chloride
and NEt3 at 60 oC affording the ester in 98 % yield. The newly formed ester was evident in
the 1H NMR spectrum by a 9H singlet at 1.1 ppm and in the 13C NMR spectrum by peaks at
66
27 (q), 39 (s) and 178 (s) ppm. The spectra also revealed a 3:2 mixture of rotamers for this
compound. Unfortunately treatment of 243 with TFA and anisole to effect deprotection,
gave only 28 % yield of the desired amino alcohol 244, with the N-pivaloyl rearrangement
product also present in high amounts. An improved synthesis of (-)-swainsonine is
reported in Section 4.4 of this Chapter.
NOPMB
BocOHH
H NOPMB
BocOPivH
H NH
OH
OPivHH
a b
231 243 244 Scheme 4.4 Reagents (a) PivCl, NEt3, THF 60 oC (98 %); (b) TFA, anisole, CH2Cl2 (28 %).
4.2 Synthesis of (+)-1,2-Di-epi-swainsonine The difficulties experienced with our synthesis of (-)-swainsonine led us to
investigate a somewhat simpler target (Scheme 4.5). One of the complicatations in our
earlier synthesis occurred upon dihydroxylation of the 2,5-dihydropyrrole, whereby the
dihydroxylation reaction also gave significant amounts of the corresponding pyrrole by-
product, and therefore relatively low yields of the desired diol 236. Since this
aromatisation only seemed to occur when the nitrogen atom was not protected, we felt that
if the dihydroxylation was conducted on the N-Boc protected compound 231 then little or
no aromatisation would occur. The price for this improvement would be that the OsO4
would then approach the opposite face of the alkene giving a configuration for the two new
hydroxyl groups opposite that required for (-)-swainsonine. This proved to be the case, as
dihydroxylation of 231 using K2OsO4.H2O and NMO in acetone water gave the triol 245 as
a single isomer in 90 % yield. The 1H NMR spectrum of triol 245 showed no olefinic
signals, and additional proton signals within the multiplet at 3.0-4.5 ppm marked the
success of the dihydroxylation reaction. Due to the presence of two rotamers (80:20) it was
difficult to establish the stereoselectivity for the reaction at this stage, however no other
isomers were detected during later stages of the synthesis (see below), prompting the
conclusion that only one isomer was formed.
67
N
H
BnO OBn
OBn
N
H OH
OHOH
N
H OAc
OAcAcO
NO
O
BnO OBnH
HOPMB
NOPMB
BocOHH
HN
OPMB
BocH OH
OH OH
H
NOPMB
BocH
H
BnO OBn
OBn
NH
OH
HH
BnO OBn
OBn
1,2-di-epi-swainsonine
a
c d e
b
f
+231
245
246
247
246
248
239
1
67
7a
249
Scheme 4.5 Reagents (a) K2OsO4.2H2O, NMO, acetone, H2O, RT (90 %); (b) NaH, BnBr, n-Bu4NI, THF, RT (90 %); (c) TFA, anisole, CH2Cl2, RT (89 %); (d) PPh3, CBr4, NEt3, CH2Cl2 (97 %); (e) Pd/C (10 %), H2, EtOH, RT (94 %); (f) Ac2O, pyridine, RT (93 %).
Benzylation of triol 245 using benzyl bromide and NaH, with nBu4NI used as a
catalyst gave two products. The desired tris-OBn derivative 246 was obtained in 90 %
yield, and also obtained was the oxazolidinone 247 in 6 % yield. The 1H and 13C NMR
spectrum for compound 246 showed a 1:1 mixture of rotamers. The three benzyl groups
were clearly visible in the proton spectrum, giving a 15H multiplet at 7.1-7.4 ppm and
contributing 6H to the 8H multiplet at 4.3-4.7 ppm. Likewise the 13C NMR showed
multiple signals at 127-129 ppm for the aromatic rings, and four (actually eight with both
rotamers) triplet signals at 71-74 ppm corresponding to the four benzylic carbons. The
oxazolidinone 247 gave much clearer spectra as no rotamers are possible for this
compound. The O-PMB and two O-Bn groups were clearly visible in the 1H NMR
spectrum as were other required peaks for the assigned structure. Indicative of
68
oxazolidinone formation is the absence of any signal for the N-Boc group, and this was the
case here also. To support our assignment of the relative stereochemistry of oxazolidinone
247 (and hence of the major product 246), 1H and 13C NMR spectra were also taken in d6-
benzene, which had the effect of resolving peaks that had overlapped in CDCl3. Clearly
evident was a coupling constant between H1 and H7a of 7.5 Hz consistent with a cis
arrangement about the oxazolidinone ring128,130 supporting our earlier assertion of SN2 ring
opening of the epoxide. Protons H7 and H7a share a coupling constant of 10 Hz indicative
of a trans arrangement of these two protons, whereas H6 and H7 share a coupling constant
of only 5 Hz indicative of a cis arrangement as shown.131
Compound 246 was then treated with TFA and anisole, which once again resulted
in the complete removal of the N-Boc and O-PMB protecting groups, giving the amino
alcohol 248 in 89 % yield. In stark contrast to our (-)-swainsonine synthesis, this occurred
without any evidence of protecting group migration (due to the more stable O-Bn group) or
pyrrole formation (as the pyrrolidine ring was now saturated). Cyclisation of the piperidine
ring using PPh3, CBr4 and NEt3 according to the method used earlier, also proceeded
without complication giving tris-OBn-1,2-di-epi-swainsonine 249 in 97 % yield. Attempts
to remove these benzyl protecting groups via hydrogenation over Pd/C, revealed that this
deprotection occurred only sluggishly. Even when 3 wt. equivalents of Pd/C (10 % Pd)
was used, the reaction required 3 days to complete. Nonetheless (+)-1,2-di-epi-
swainsonine was obtained in 94 % yield as a colourless white solid. Its melting point (104-
106 oC) and specific rotation ([α]D26 +4 (c 2.85 MeOH)) values did not agree well with
those of the literature (129-130 oC, [α]D +19 (c 0.55 MeOH)),39 therefore the material was
treated with Ac2O in pyridine to facilitate further purification. This gave the known
triacetate derivative 239 in near quantitative yield as a white solid. The melting point (128-
130 oC) and specific rotation ([α]D23 +57 (c 1.95 CHCl3)) values agreed very well with
those of the literature (132-134 oC, [α]D23 +61 (c 2.11, CHCl3)).39 All spectral data for both
(+)-1,2-di-epi-swainsonine and 239 also agreed closely with that of the literature.39
69
4.3 Synthesis of (+)-1,2,8 tri-epi-swainsonine The simplicity of the above synthesis of (+)-1,2-di-epi-swainsonine prompted us to
prepare (+)-1,2,8-tri-epi-swainsonine in an analogous manner (Scheme 4.6). Thus the
previously prepared 2,5-dihydropyrrole 218 was treated with K2OsO4.2H2O and NMO to
effect dihydroxylation via the in situ generation of OsO4. Only a single isomer of the
product triol 250 was formed, and this was obtained in 91 % yield. The triol 250 was then
benzylated using the now familiar BnBr, NaH and n-Bu4NI method. This gave a good
yield of the tris-benzylated product 251 (86 %). The oxazolidinone by-product common to
these benzylations was present (as evidenced by tlc) but was not isolated in this case.
Compound 251 was then treated with TFA (neat), which removed both the O-TBS and N-
Boc protecting groups within 2 h. After basic workup and column chromatography the
amino alcohol 252 was obtained in 85 % yield. Cyclisation using PPh3, CBr4 and NEt3
using the methods discussed above formed the piperidine ring, giving 253 in an
unoptimised yield of 80 %. It is likely that longer reaction times would improve this result.
Finally removal of the benzyl groups, using PdCl2 (0.9 equiv.) in MeOH under an
atmosphere of hydrogen, was complete within 1 h giving (+)-1,2,8-tri-epi-swainsonine.
This debenzylation was markedly faster than the equivalent reaction using Pd/C, and we
attribute this to the in situ generation of HCl. When PdCl2 reacts with H2, Pd(0) and two
equivalents of HCl are liberated, which in turn protonates the amine and prevents it from
deactivating the Pd catalyst. Using this approach (+)-1,2,8-tri-epi-swainsonine was
obtained after basic ion-exchange chromatography as a white solid. The melting point
(100-102 oC) did not agree well with that of the literature (116-118 oC)36 perhaps due the
hygroscopic nature of the product. The specific rotation ([α]D25 +41 (c 0.9 MeOH)) value
agreed very well with those of the literature ([α]D + 46 (c 0.4, MeOH)),157 as did all other
spectral data.
70
N
OH
H HBoc
TBSO
N
OH OH
OHH
N
H
OBnBnO
OBn
N
OBnBnO
H
OBn
HBoc
TBSO
NH
OBnBnO
H
OBn
HOH
N
OHOH
H
OH
HBoc
TBSO
(+)-1,2,8-tri-epi-swainsonine
a c
d e
b
218 250 251
252 253 Scheme 4.6 Reagents (a) K2OsO4.2H2O, NMO, acetone, H2O, RT (91 %); (b) NaH, BnBr, n-Bu4NI, THF, RT (86 %); (c) TFA, CH2Cl2, RT (85 %); (d) PPh3, CBr4, NEt3, CH2Cl2 (80 %); (e) PdCl2, H2, EtOH, RT (93 %).
4.4 (-)-Swainsonine Revisited The excellent behaviour of the OBn protecting groups in the above two syntheses
led us to test its applicability to our synthesis of (-)-swainsonine (Scheme 4.7). Compound
231 was thus treated with BnBr, NaH and n-Bu4NI, which afforded the benzylated product
254 in 74 % yield. Also obtained was the oxazolidinone by-product 255, common to these
benzylations, isolated in 14 % yield. Once again the N-Boc and O-PMB groups were
removed by reaction with TFA and anisole, giving only the amino alcohol 256 in 88 %
yield, with no evidence of protecting group migration. Cyclisation of the amino alcohol
256 with PPh3, CBr4 and NEt3 then gave the didehydroindolizidine 257 in 74 % yield.
Separation of compound 257 from the Ph3PO based by-products was initially difficult,
however using Et2O and DCM as the flash column solvent system rectified this minor
issue.
71
N
HOBn
NO
O
H
OPMBHN
Boc
OPMB
HH
OHNBoc
OPMBH
HOBn
NH
OHH
HOBn
a
b c
231 254 255
256 257
+
254
Scheme 4.7 Reagents (a) NaH, BnBr, n-Bu4NI, THF, RT (74 %); (b) TFA, anisole, CH2Cl2, RT (88 %); (c) PPh3, CBr4, NEt3, CH2Cl2 (74 %).
Dihydroxylation of 257 (Scheme 4.8) using K2OsO4.H2O and NMO gave an
inseparable 2:1 mixture of diols in low yield, with the corresponding pyrrole also obtained
in even lower yield. To facilitate isolation the crude product was treated with Ac2O and
pyridine to give the bis-acetates 258 and 259. These two compounds were easily separated
by column chromatography giving 43 % and 20 % yields respectively for the two steps.
Deprotection of these two compounds individually gave (+)-1,2-diepi-swainsonine and (-)-
swainsonine respectively. This was accomplished first by hydrogenation over Pd/C to
remove the OBn group, then treatment with K2CO3 in MeOH to remove the two OAc
groups. This approach for deprotection left a difficult purification problem, namely the
removal of the potassium salts from the water soluble products.
N
HOBn
N
H
AcO OAc
OBnN
H
AcO OAc
OBnN
H
OH OH
OH
+
A K2OsO4.2H2O, NMO, R.T. B AD-mix α, 3 oCC AD-mix β, 3 oC
43 %50 %49 %
20 %1 %2 %
(-)-swainsonine
a b
257 258 259
Scheme 4.8 Reagents (a) (i) dihydroxylation (see figure); (ii) Ac2O, pyridine, separate isomers; (b) (i) Pd/C, H2, EtOH (ii) K2CO3, MeOH ( quant. 2 steps).
The lack of selectivity and low yield of the dihydroxylation prompted us to search
for an improvement. While lower temperatures should increase selectivity, we felt that the
use of a bulkier oxidant would also bias dihydroxylation towards the less hindered face. It
72
has been reported that the addition of pyridine to the dihydroxylation mixture can improve
selectivities by increasing the size of the oxidant through pyridine-osmium coordination, at
the expense of the reaction rate.158 Alternatively the Sharpless asymmetric dihydroxylation
catalysts159 are very much larger, and in theory would confer the best facial selectivity if the
steric repulsion model is correct. This proved to be the case, because when indolizidine
257 was treated with AD-mix-α the ratio of desired isomer 260 to the di-epi-isomer was
~50:1. The diol product itself was difficult to isolate from the reaction mix, which also
contained significant amounts of the now familiar pyrrole by-product. Hence the crude
mixture was acetylated to facilitate isolation giving the protected (-)-swainsonine
compound 259 which could be deprotected as before. When AD-mix-β was used the same
major isomer was obtained, but this time with ~19:1 selectivity. These dihydroxylations
were conducted in a cold room at 4 oC and required at least 7 d to complete, and regrettably
aromatisation to the pyrrole was a competing reaction, causing the yields for these reactions
to be low.
To finalise our synthesis of (-)-swainsonine, we required an efficient, clean method
of isolation and deprotection (Scheme 4.9). The solution lay in protecting the crude diol
product 260 as its acetonide 108, which was accomplished by reaction with Me2(OCH3)2C
and p-TsOH.H2O in dry DCM. The pyrrole by-product obtained from the dihydroxylation
reaction, appeared to polymerise under these conditions, as evidenced by the formation of a
pH sensitive, vibrant purple colour, which changed to dark blue upon aqueous base
quenching of the reaction. The resulting acetonide 108 is a known compound and had
spectral data and specific rotation values in close agreement with that in the literature.41
The same authors had converted 108 into (-)-swainsonine via a hydrogenation and acid
hydrolysis. The hydrogenation was conducted using PdCl2 (0.9 eq) in MeOH and using
this method we obtained complete removal of the benzyl group within 30 min. The free
alcohol 261 was obtained excellent yield as its HCl salt, which was converted to its free
amine via silica gel column chromatography with CHCl3:MeOH:NH3(28 %) 100:9:1. The
acetonide group of 261 was then removed by acidic hydrolysis using 2 M HCl in THF (3:2)
giving (-)-swainsonine as its HCl salt. This was purified by basic ion-exchange
chromatography, which afforded (-)-swainsonine in excellent yield. All data was in good
agreement with that of the literature, except for the optical rotation ([α]D26: -71 (c 0.56,
73
MeOH)) which was a little low (lit.160 [α]D26: -83 (c 1.03, MeOH)), but compared well
considering that the starting epoxy alcohol 213e had an ee of 92 %.
N
HOBn
N
H
OH OH
OBnN
H
OH OH
OHN
HOBn
OO
N
HOH
OO
(-)-swainsonine
a b c
257 260 108 261
d
Scheme 4.9 Reagents (a)AD-mix-α, (DHQ)2PHAL, CH3SO2NH2, t-BuOH, H2O, 4 oC, 7 d; (b) Me2(OCH3)2C, p-TsOH, CH2Cl2, RT (50 % 2 steps); (c) PdCl2, H2, MeOH, RT (100 %); (d) HCl (2 M), THF, RT (94 %).
4.5 Synthesis of a Polyhydoxylated Pyrrolo[1,2-a]azepine With the extensive work in the literature towards the synthesis of polyhydroxylated
indolizidine and pyrrolizidine alkaloids, we were surprised to discover that no
investigations into the synthesis of polyhydroxylated pyrrolo[1,2-a]azepines exist. It was
felt that the methods described above could be easily applied to produce molecules of this
type. Furthermore the pyrrolo[1,2-a]azepine system lies at the core of the vast majority of
Stemona alkaloids, so it seemed advantageous to investigate the synthesis of this ring
system (Scheme 4.10).
Another member of our research group173 had shown that LiOTf was a superior
catalyst to p-TsOH.H2O in the aminolysis reaction. When LiOTf was used with allylamine
in the aminolysis of vinyl epoxide 208c for example, excellent yields of the amino alcohol
224 were obtained, and its isolation was greatly simplified. Specifically the vinyl epoxide
208c was heated with allylamine (3 equiv) in a microwave reactor, using LiOTf (1 equiv)
as a catalyst with CH3CN as the solvent, and complete conversion was achieved in 1 h.
The reaction gave only amino alcohol 224 via an SN2 ring opening, with no evidence of any
other regio/stereoisomers.
74
O
PMBO
N
H
OBnBnO
BnO
N
H
OHOH
OH
NHH
PMBO
HOH NH
PMBO
HOHBoc
NH
PMBO
HOHBoc
OH OH
NH
PMBO
HBoc
BnO OBn
BnO
NHH
OH
H
BnO OBn
BnO
NO
O
BnO OBn
PMBOH
H+55 % 21 %
a c
d e
f g h
224 R=H262 R=Boc
b208c 263
264 265 266
265
267 268 269 Scheme 4.10 Reagents (a) allylamine (3 equiv), LiOTf (1 equiv), CH3CN, 120 oC microwave 1 h (97 %); (b) (Boc)2O (2 equiv), Et3N (2 equiv), Et2O, RT, 18 h (94 %); (c) Cl2(Cy3P)2Ru=CHPh (5 %), CH2Cl2 reflux, 20 h (91 %); (d) K2OsO4.2H2O (5 %), NMO (2.2 equiv), acetone, water, RT, 20 h (96 %); (e) NaH (6 equiv), BnBr (5.5 equiv), nBu4NI (0.3 equiv), THF, RT, 3 d (55 %); (f) TFA (10 equiv), anisole (10 equiv), CH2Cl2, RT, 2 h (96 %); (g) PPh3
(2.5 equiv), CBr4 (2.5 equiv), NEt3 (40 equiv) CH2Cl2 4 oC, 20 h (51 %); (h) PdCl2 (0.9 equiv), H2 (1 atm), MeOH, RT, 1 h (98 %).
After protection of amine 224 as its N-Boc derivative 262, ring-closing metathesis
using Grubbs' catalyst (0.1 equiv) in a refluxing solution of CH2Cl2 for 24 h at high dilution
(~4 mM) gave the 2,5-dihydropyrrole 263 in excellent yield using the methods previously
discussed. Compound 263 was treated with 5 mol % K2OsO4.2H2O and NMO (2.1 equiv),
to effect cis-dihydroxylation of the double bond, giving 264, also in good yield. Only one
product was seen, which resulted from delivery of the two hydroxyls to the least hindered
face of the 3,4-double bond in 263. Triol 264 was then reacted with NaH and benzyl
bromide, together with a catalytic amount of nBu4NI. This gave a low yield (55 %) of the
desired tri-O-benzyl derivative 265. The low yield was due primarily to the formation of
an unwanted oxazolidinone 266, which was isolated in 21 % yield. No attempt was made
to optimise the conditions of this reaction to lower the amount of 266 being formed, but it
75
is likely that higher concentrations of n-BuNI and/or benzyl bromide would improve the
ratio of compounds 265 and 266 in the reaction, by increasing the rate of benzylation.
Compound 265 was then reacted with trifluoroacetic acid to accomplish N-
deprotection. Once again using anisole as a cation trap, the p-methoxybenzyl protecting
group was also removed, resulting in the formation of amino alcohol 267 in good yield (96
%). Formation of the 7-membered azepine ring, was achieved by treating 267 with CBr4
and PPh3 in the presence of NEt3 using the methods described above. This gave a moderate
yield (51 %) of the protected bicylic compound 268, but it should be noted that this reaction
was only performed once, and higher yields may be achieved with further optimisation (e.g.
longer reaction time). It is expected that the seven membered ring would form at a slower
rate that the corresponding six membered rings above. Finally, O-benzyl removal with
PdCl2 in MeOH under an atmosphere of H2 (1 atm), gave the novel polyhydroxylated
pyrrolo[1,2-a]azepine 269 in excellent yield as its HCl salt, which was purified by basic
ion-exchange chromatography and isolated as its free amine in 98 % yield [mp. 100-104 oC; [α]D
25: +60 (c 0.46, MeOH)].
4.6 An Oxazolidinone Based Approach to (-)-Swainsonine Another member of our research group had uncovered an interesting fact with
respect to dihydroxylation of oxazolidinones such as 270. Unexpectedly the presence of an
oxazolidinone group directs dihydroxylation to occur at the concave face of the bicyclic
ring system (Figure 4.2).
OsO4
NO
R'
R
H7a
H
H5β
O
270
Figure 4.2 - Diagram showing the attack at the concave face of a 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one.
76
4.6.1 Oxazolidinone Synthesis We decided to investigate whether this result could be applied to the synthesis of
(-)-swainsonine. Some initial difficulty was experienced with respect to the synthesis of the
desired oxazolidinone 255 due to the fact that the cis-oxazolidinone forms less readily than
its trans-counterparts (Scheme 4.11). The previously prepared amine 229 was constructed
using the improved method, whereby microwave assisted aminolysis of vinyl epoxide 208e
with allyl amine in the presence of LiOTf was complete in only 1 h at 110 oC. This was a
significant improvement on the previous p-TsOH.H2O catalysed approach, which required
three days (vide supra). N-Boc protection of 229 proceeded as before, as did ring closing
metathesis. The previously prepared 2,5-dihydropyrrole 231 was treated with NaH in
toluene, which only gave complete conversion to the oxazolidinone 255 when the
temperature was increased to 50 oC overnight. The yield was only 74 % due to some
decomposition under such harsh conditions. Conversion of the amino alcohol 229 directly
to oxazolidinone 271 could be accomplished with triphosgene in the presence of
triethylamine, but in our hands two inseparable products were obtained, the major one
being the desired product. This mixture did not separate after ring closing metathesis. The
successful ring closing metathesis of 271 in 77 % yield is an interesting result and it will be
discussed in more detail later in Chapter 5.6. The only literature precedent for this reaction
had reported it to be unsuccessful at RT in benzene for the attempted preparation of
unsubstituted pyrrolo[1,2-c]oxzazol-3-one.84 Attempts to convert 230 into cis-
oxazolidinone 271 using NaH in THF were not successful even at 80 oC, whereas the
corresponding reaction to form the trans-oxazolidinone proceeds at RT.
77
NO
O
HH
OPMB
OOPMB
NO
O
HH
OPMB
NH
OPMB
H OHH
NOPMB
H OHH
Boc
NOPMB
H OHH
Boca b
c
d
ef
208e
229
230 231
255271
g
Scheme 4.11 Reagents (a) CH2=CHCH2NH2, LiOTf, microwave, 110 oC, 1 h (88 %); (b) Boc2O, NEt3, THF, RT (98 %); (c) Grubbs' cat., DCM, reflux, 18 h (95 %); (d) NaH, toluene, 50 oC (74 %); (e) triphosgene, NEt3, CH2Cl2, 0 oC (77 %); (f) Grubbs' cat., DCM, reflux, 18 h (77 %) (g) NaH, THF, 80 oC.
4.6.2 Dihydroxylation With the oxazolidinone 255 available cleanly, we next investigated the
dihydroxylation reaction (Scheme 4.12). To this end the oxazolidinone 255 was treated
with K2OsO4.2H2O and NMO in acetone-water, which gave a 3:1 inseparable mixture of
diols 272 and 273. Complete conversion was obtained within 18 h at RT giving an 85 %
yield. A pure sample of the major diol 272 was isolated by careful crystallisation from hot
DCM and pet. sp. This crystallisation was not necessary (except for analytical purposes)
however, because benzylation of the mixture of diols, gave the bis-benzyl compounds 274
and 275 in excellent yield, and these were readily separable by column chromatography.
Not content with 3:1 selectivity we investigated other dihydroxyaltion methods, spurred by
the results obtained earlier for the dihydroxylation of the dehydroindolizidine 257 with
bulkier oxidants. Conducting the same dihydroxylation reaction at 0 oC improved
selectivity and yield slightly (3.5:1 and 92 % respectively), and reaction was complete
within 2 days. In some cases it can be advantageous to add pyridine to dihydroxylations of
this type, by increasing the oxidant size via pyridine coordination, but this was not one of
those cases. The use of pyridine extended the reaction time to 7 days and resulted in a
significant reduction in the selectivity to 1.5:1.
78
Sharpless AD-mix reagents were very effective previously, improving selectivity by
providing a bulkier oxidant. When AD-mix-α was used at RT the reaction did not go to
completion within 6 d, and selectivity was only slightly improved (3.7:1). Surprisingly
when AD-mix-β was used a 20:1 ratio of diastereoisomers was obtained, albeit in low
conversion after 6 days at RT, giving a 46 % yield of product diols 272 and 273 (and 45 %
recovered starting material). This result was repeatable, however further work is needed in
order to optimise the conversion here, which perhaps could be accomplished via an increase
in temperature at the expense of a some diastereoselectivity, or by increasing the reaction
time at the expense of a little patience.
NO
OPMB
O
H
H NO
OPMB
O
OH OH
H
HN
OOPMB
O
OH OH
H
H
NO
OPMB
O
BnO OBn
H
HN
OOPMB
O
BnO OBn
H
H
+
+b
a
255 272 273
274 247 Scheme 4.12 Reagents (a) dihydroxylation - see Table 4.1; (b) NaH, BnBr, n-Bu4NI, THF, RT (100 %).
Table 4.1 - Summary of results for the dihydroxylation reactions of 255.
We attribute the disparencies between the α and β AD-mixes to be a result of a
matched/mismatched system (Figure 4.3). The primary factor directing the preferred face
Reagent Temp/oC Yield/%
of 272 + 273
Rec.
255
272:273 time/days
K2OsO4.2H2O/NMO RT 85 - 3:1 1
K2OsO4.2H2O/NMO 0 92 - 3.5:1 2
K2OsO4.2H2O/NMO,
pyridine
RT 90 5 1.5:1 7
AD-mix-α RT 24 56 3.7:1 6
AD-mix-β RT 46 45 20:1 6
79
of attack appears to be the pseudoaxial hydrogen atoms H5 and H7a (see Figure 4.2).
When the Sharpless mnemonic is applied to the alkene 255, it can be seen that AD-mix α
has a natural tendency to attack from the more hindered face, hence the reduced rate and
selectivity when this reagent is used. Conversely, when AD-mix β is used, a 'matched'
system exists whereby both the substrate and chiral ligand direct oxidation to the top face,
therefore the reaction proceeds with a higher selectivity and rate.
NO
O
HH
R
H
AD-mix α(bottom face)
AD-mix β(top face)
H L
M S
57a
Figure 4.3 - Diagram showing the matched and mismatched arrangements with the AD-mix α and β.
After benzylation and separation, direct comparison of the minor product 247 to
the oxazolidinone 247 isolated from the preparation of 246 during the synthesis of (+)-1,2-
di-epi-swainsonine, revealed them to be identical in all respects. It followed that the major
product 274 was the isomer required for the synthesis of (-)-swainsonine.
4.6.3 (-)-Swainsonine Perfected Conversion of 274 into (-)-swainsonine proved to be surprisingly easy (Scheme
4.13). Hydrolysis of the oxazolidinone with NaOH in MeOH-water gave the amino alcohol
275 in good yield (84 %). The formation of the amino alcohol 275 was evident from the
vast increase in the polarity over that of the starting material. The 13C NMR for the product
showed no signal for the carbonyl group, and the mass spectrum gave a parent ion at m/z
492 consistent with the desired product. We thought it prudent to protect the secondary
alcohol of 275, as it might interfere with the cyclisation of the pipiridine ring, by providing
an alternative nucleophile to the nitrogen atom. Chosen for this was the TBDPS protecting
group, which was attached by reaction of 275 with TBDPSCl and imidazole, giving the
80
silyl ether 276 in 97 % yield at 60 oC. Oxidative removal of the O-PMB protecting group
was then conducted by reaction of 276 with CAN, giving the amino alcohol 277 in good
yield. Cyclisation was accomplished as before, by reaction of 277 with PPh3, CBr4 and
NEt3 giving the protected (-)-swainsonine compound 278 in excellent yield. Deprotection
of the silyl ether by reaction with TBAF was slow, requiring 5 days to complete, and
removal of the excess TBAF reagent was challenging, however the desired alcohol 279 was
obtained in 76 % yield. Future work in this area would do well to consider an acid
hydrolysis of this silyl ether. Finally the two benzyl ethers were removed using the mildly
acidic hydrogenation protocol used for the above syntheses, to give (-)-swainsonine in
excellent overall yield and purity (93 %). It should be noted that the last six steps in this
synthesis are not optimised, as each reaction was attempted only once, and all would likely
give higher yields with further improvements of the reaction conditions.
BnO OBn
N
H OTBDPS
BnO OBn
N
HOH
OH OH
N
H OH
NH OH
HH
OPMB
BnO OBn
NH OTBDPS
HH
OPMB
BnO OBn
NH OTBDPS
HH
OH
BnO OBn
NO
O
H
HOPMB
BnO OBn
(-)-swainsonine
a
b
c
d
ef
274 275
276277
278 279 Scheme 4.13 Reagents (a) NaOH, MeOH, H2O, 110 oC, microwave, 2 h (84 %); (b) TBDPSCl, imidazole, 65 oC, 3 d (97 %); (c) CAN, CH3CN, H2O (92 %); (d) PPh3, CBr4, NEt3, CH2Cl2, 0 oC (93 %); (e) TBAF, THF, RT, 5 d (76 %); (f) PdCl2, H2, MeOH, 2 h (93 %).
81
Chapter 5: Stemona alkaloids
revisited
Around halfway through the duration of this project we gained access to a
microwave reactor. Since it had been previously reported that microwave irradiation
greatly accelerates epoxide aminolysis reactions130 we investigated this method further.
Our previous attempts to conduct an aminolysis of vinyl epoxide 208c in either aqueous or
liquid ammonia had not been successful. When vinyl epoxide 208c was suspended in
aqueous ammonia (28 %) in a sealed Teflon vessel and heated within a microwave reactor
to 110 oC with strict temperature control, to our delight this gave complete conversion to
the amino alcohol 280 in only 30 min (Scheme 5.1). With this improvement to the
aminolysis in hand, and armed with the superior aminolysis catalyst LiOTf, we next turned
our attention back to the synthesis of (+)-croomine.
O
OPMB OPMB
NH2 H OHH
a
208c 280 Scheme 5.1 Reagents (a) NH4OH (28 %), 110 oC, 30 min, microwave (98 %).
5.1 Aminolysis with Hindered Amines We next investigated the aminolysis of vinyl epoxides with more hindered amines
(Scheme 5.2). As a trial reaction vinyl epoxide rac-208c and the newly acquired amine
rac-280 were dissolved in a minimal volume of CH3CN, with LiOTf used as a promoter.
When the mixture was heated in the microwave reactor at 120 oC we were delighted to find
that the aminolysis proceeded to 65 % conversion yielding the two symmetrical amines
281a and 281b. The vinyl epoxide 208a could also be reacted with amine 280 in the
microwave reactor and again LiOTf was used as a promoter. Good conversion was
obtained within 90 min at 120 oC, but the isolated yield of 282 was not high. Alternatively
conducting the same reaction in a sealed tube at 130 oC required much longer reaction
82
times (3 days), however the isolated yield of 282 was much higher. We attributed this
difference to the fact the microwave reaction vessel was much larger than necessary, and
consequently the reaction was not mixing efficiently, furthermore product decomposition
was also evident (by a dark brown reaction colour) when using the microwave, which could
have also resulted from inefficient mixing. The aminolysis product 282 was obtained as a
4:1 mixture of diastereoisomers that could not be separated. This ratio is consistent with an
approximate 90 % enantiomeric purity of the two starting materials 208a and 280, although
the possibility of epimerisation and/or SN1 ring opening should not be ruled out for this
more hindered case. The results for the synthesis of 282 are summarised in Table 5.1
which clearly shows the superiority of the sealed tube approach (entries h-k).
OOTBS
O
OPMB
NH OH
PMBO
OH
OPMB
H H
NH OH
OTBSPMBO
HHOH
NH2
PMBO
OH H
a
b
208a
rac-208c
280281
282 Scheme 5.2Reagents (a) LiOTf, CH3CN, 120 oC, microwave (65 %); (b) LiOTf, CH3CN, 130 oC, 3 d (97 %). Entry mol
epoxide mol eq. amine
mol eq. catalyst CH3CN mL
TempoC/ method
Time yield %
a 0.095 0.8 0.3 (p-TsOH.H2O) 0.4 (Tol) 110/∆ 3 d 0 b 0.085 1.2 0.5 (YbOTf) 1.0 (DCM) R.T. 22 h 0 c 0.144 1.2 0.1 (p-TsOH.H2O) 0.5 (Tol) 110/∆ 3d 0 d 0.124 1.1 0.1 (p-TsOH.H2O) 0.25 (Tol) 120/∆ 4d 0 e 0.800 1.45 1.0 (LiOTf) 1.6 120/MW 1.5 h 53 f 0.472 1.5 1.0 (LiOTf) 1.0 120/MW 2 h 36 g 0.788 1.3 1.0 (LiOTf) 2.0 120/MW 2 h 43 h 0.505 1.6 1.4 (LiOTf) 1.0 120/∆ 3 d 84 i 0.800 1.5 1.5 (LiOTf) 1.5 120/∆ 20 h 78 j 0.505 1.5 1.5 (LiOTf) 1.0 120/∆ 3 d 89 k 0.784 1.2 1.5 (LiOTf) 2.0 130/∆ 3 d 97
Table 5.1 - Summary of aminolysis of vinyl epoxide 208a with amine 280.
83
5.2 Early Protection Problems Attempts to protect the nitrogen atom of 282 as its N-Boc derivative 283 were
unsatisfactory (Scheme 5.3). Simply using Boc2O and NEt3 in THF at RT only gave
quantitative recovered starting material. When DMAP (~5 %) was added the N-Boc
derivative 283 was obtained in only 47 % yield, with further reaction to oxazolidinone by-
products 284 accounting for another 33 % of the starting material. The formation of the
oxazolidinones 284 was thought to occur via the previously discussed mechanism, though
we had not thought DMAP would be a strong enough base to catalyse this reaction. We
also investigated conducting the reaction at higher temperatures in the absence of DMAP.
Regrettably this gave similar results and the N-Boc derivative 283 was obtained in only 34
% yield with 26 % of the oxazolidinone by-products 284. Furthermore, the product 283
could only be obtained as an inseparable 4:1 mixture of isomers, and this coupled with the
familiar rotamer problem made ascertaining product purity very difficult.
NH OH
OTBSPMBO
HHOH
NOH
OTBSPMBO
HHOHBoc
NOH
PMBO
HHOHBoc
OTBSN
OH
OHPMBO
HHOHBoc
NO
O
OH H
RR'
a
b c
284a R=CH2OPMB, R'=OTBS284b R=OTBS, R'=CH2OPMB
282
283
285 286
283
Scheme 5.3 Reagents (a) Boc2O, NEt3, DMAP, THF, RT (47 %); (b) Grubbs' cat., CH2Cl2, reflux (57 %); (c) TBAF, THF, RT (68 %).
Attempts to conduct ring closing metathesis on the difficult to obtain 283 were
excruciatingly sluggish and low yielding. For example using 0.8 equiv Grubbs' catalyst and
heating at reflux for 4 days only afforded 57 % yield of the ring closed product 285. In this
84
example the starting material was almost completely consumed (tlc) indicating some
decomposition was occurring. The 2,5-dehydropyrrole 285 was then treated with TBAF (2
equiv.) in THF to remove the TBS protecting group. The deprotected compound 286 was
obtained in only 68 % yield. Three consecutive low yields, coupled with the fact that the
two diastereoisomers still could not be separated at any stage, led to this approach being
abandoned. An attempted TPAP/NMO oxidation of the triol 286 to give the corresponding
keto-lactone was not successful giving only unidentifiable products.
5.3 An Attempted Organolithium Approach The difficulties experienced with the above approach led us to explore a different
approach (Scheme 5.4). Macdonald et al. have reported that N-Boc-2,5-dihydropyrroles
can be deprotonated with LDA, and subsequently alkylated using an appropriate
electrophile.161 The starting 2,5-dihydropyrrole 287 was prepared without complication
from 218 via silylation. We initially attempted to deprotonate compound 287 with LDA
then react the resulting lithiate with an aldehyde. Two aldehydes were used here, namely
benzaldehyde or 288 each with no success. As the starting material 287 was recovered
almost quantitatively, we could only assume that it was never deprotonated.
O
HPh
PMBOO
NBoc
OTBS
H OHH N
Boc
OTBS
H OTBSH
NBoc
OTBS
H OTBSH
Li
NBoc
OTBS
H OTBSH
HOH
PMBO
NBoc
OTBS
H OTBSH
OH
HPh
LDA, THF
a
218 287
288
Scheme 5.4 Reagents (a) TBSCl, imidazole, DMF, 60 oC, (98 %).
The failures of these early LDA deprotonation reactions prompted our investigation
of a model system (Scheme 5.5). Colegate et al. had reported that alkylation will take
place, providing that the electrophile is in solution prior to deprotonation.162 Since we
required the use of an aldehyde as electrophile, this was clearly not possible. In our model
85
system, diallylamine 289 was first protected as its N-ethylcarbamate 290 via reaction with
diethylpyrocarbonate in DCM. This reaction was exothermic and rapid and was generally
complete within 2 h at RT. The now protected diene 290 was treated with Grubbs' catalyst
(0.05 equiv.) in refluxing CH2Cl2, which afforded the known partially volatile 2,5-
dihydropyrrole 291 in excellent yield (96 %).
NCOOEt
NH
NCOOEt
N
NO
OH
COOEt
Pha b c
289 290 291 292 Scheme 5.5 Reagents (a) (EtOCO)2O, CH2Cl2 (77 %); (b) Grubbs' cat., CH2Cl2, reflux (96 %); (c) LDA, THF, then PhCHO, 0 oC (40 %).
The 2,5-dihydropyrrole 291 was treated with LDA at -78 oC, then after 3 min,
benzaldehyde was added and allowed to react at -78 oC for 25 min. After aqueous workup
multiple products were obtained. The two major products were isolated and characterised
as the two diastereoisomers of 292 obtained in 33 % and 7 % yield. These were thought to
have formed via the reaction of the anion 293 with the carbonyl group of the ethyl
carbamate of another molecule of 291 displacing ethoxide (Scheme 5.6). There is literature
precedent for this type of reaction.162 The resulting material 294 has a much more acidic
proton at position 2 and thus deprotonation at this position by base would give the anion
295. This anion, when reacted with benzaldehyde, would give the product 292 after
workup. The use of N-Boc protected 2,5-dihydropyrrole in this reaction gave similar
products, however none were identifiable due to inseparable product mixtures being
isolated.
86
NCOOEt
NLi
COOEt
N
OH
COOEtPh
N N
O
COOEtN N
O Li
COOEt N
NO
OH
COOEt
Ph
O
Ph H
O
Ph H
LDA
LDA or EtOLi
291
292
293
294 295 Scheme 5.6 Proposed mechanism of formation of compound 292.
5.4 Protecting Group Studies Due to the formation of oxazolidinone by-products during the N-Boc protection of
282 (and possibly in subsequent steps), we felt that protection of the two secondary
alcohols might alleviate this problem (Scheme 5.7). To this end the aminolysis product 282
was treated with TBSCl and imidazole at 70 oC overnight to give the silylated product 296
in excellent yield. To our surprise the two diastereoisomers of 296 were now separable
using careful (and often repeated) column chromatography. The separation of these two
isomers should confer an optical enrichment to the desired isomer, however no
investigations were undertaken to determine the magnitude of this enrichment.
Unfortunately the free nitrogen atom of 296 appeared to be chemically inert, presumably
due to steric crowding. For example, treating 296 with Boc2O, NEt3 and DMAP in CH2Cl2
at RT or at reflux gave only quantitative recovery of starting material. An attempted ring
closing metathesis on 296 was not successful, despite of the reduced reactivity of the
amine, though the failure of this RCM could also be due to the increased steric bulk around
the alkenes. Other attempts to protect the nitrogen atom of 296 were also unsuccessful,
with the acetate, trifluoroacetate, Fmoc, Nosyl and Cbz protecting groups all unable to be
attached at this site.
The extremely hindered amine 296 was also reacted with the highly reactive
diethylpyrocarbonate (Scheme 5.8). Complete conversion of the amine required very
87
forcing conditions, namely 4 equivalents of reagent at 160 oC in a sealed tube over 4 d,
however an excellent yield of 297 was obtained nonetheless. We next attempted the ring
closing metathesis of the diene 297 but the highly bulky material failed to react with either
Grubbs' catalyst or Grubbs' second generation catalyst in either refluxing CH2Cl2 or
refluxing benzene.
NH OTBS
OTBSPMBO
HHTBSO NOTBS
OTBSPMBO
HHTBSOBoc
NH OH
OTBSPMBO
HHOHN
OTBSOTBS
PMBO
HHTBSOFmoc
NOTBS
OTBSPMBO
HHTBSOCOCF3
NH OTBS
OTBSPMBO
HHTBSO
ab
c
d
e
282
296
Scheme 5.7 Reagents (a) TBSCl, imidazole, DMF, 70 oC (76 %); (b) FmocCl, dioxane, NaHCO3 (sat. aq.), RT; (c) Boc2O, NEt3, DMAP, CH3CN, 50 oC; (d) (CF3CO)2O, pyridine, RT; (e) Grubbs' second gen. cat. CH2Cl2.
NH OTBS
OTBSPMBO
HHTBSON
OTBSOTBS
PMBO
HHTBSOCOOEt
a
296 297 Scheme 5.8 Reagents (a) (EtOCO)2O, DCM, 160 oC, 4 d (95 %).
Perhaps the best example of the reduced reactivity of the nitrogen atom in 282 was
illustrated by its acetylation in 1:1 Ac2O:pyridine at RT (Scheme 5.9). Only two acetate
groups were detected in the product 298 and from 1H and 13C NMR spectroscopy these
were chemically equivalent. Further evidence for O-acetylation came from the infrared
88
spectrum, which showed a strong absorbance peak at 1740 cm-1 consistent with and O-Ac
carbonyl, but no strong absorbance near 1630-1680 cm-1 for an N-Ac carbonyl. The two
diastereoisomers were not separable as their bis-acetate derivatives. This result, while
highlighting the reduced reactivity of the amine, appears to contradict earlier results (See
Chapter 4.1) for the unhindered systems, where the O-Bz and O-Piv esters had a propensity
to migrate to the free nitrogen atom. An attempt to Boc protect 298 (Boc2O/NEt3/DMAP
80 oC) gave only recovered starting material.
NH OH
OTBSPMBO
HHOH NH OAc
OTBSPMBO
HHAcO
NOAc
OTBSPMBO
HHAcOCOOEt
NOAc
OTBSPMBO
HHAcOCOOEt
a
b
c
282 298
299300 Scheme 5.9 Reagents (a) Ac2O, pyridine (52 %); (b) (EtOCO)2O, CH2Cl2 130 oC (40 %); (c) Grubbs' cat., CH2Cl2, reflux (68 %).
The Boc protecting group is quite large, and it was thought that the smaller ethyl
carbamate might form much easier, especially when the more reactive diethyl
pyrocarbonate is used. When the diacetate 298 was treated with diethyl pyrocarbonate (8
eq) in DCM in a sealed tube, the temperature was increased to 130 oC before the reaction
proceeded at acceptable rates (~10 % conversion after 3 d at 90 oC), affording only 40 %
yield of the N-carbamate product 299, after 4 d at 130 oC with 31 % recovered starting
material. This hindered diene 299 was treated with Grubbs' catalyst (1.0 equiv.) at reflux in
CH2Cl2 for 2 d, which to our surprise afforded complete transformation to the 2,5-
dihydropyrrole 300 in 68 % yield. Unfortunately this protecting group array of 300 was of
little use, leaving no options for continuing the synthesis towards (+)-croomine.
89
5.5 Further Aminolysis Studies At this stage, investigations designed to test the limits of the LiOTf promoted
aminolysis reaction were conducted (Scheme 5.10). As an example of a secondary amine,
diallylamine (1.5 equiv.) and the vinyl epoxide 208a were heated in CH3CN with LiOTf
(1.5 equiv.) in a sealed tube at 140 oC for 2 d. This gave an excellent yield (95 %) of the
aminolysis product 301 after column chromatography. Similarly benzylamine (2 equiv.)
was reacted with 208c. This time microwave irradiation was used and complete conversion
to amino alcohol 302 was obtained in 1 h at 120 oC. The product secondary amine 302 and
vinyl epoxide 208a were heated in a sealed tube to 140 oC in CH3CN with LiOTf (3 equiv.)
for 6 d. When tlc indicated no vinyl epoxide remained, work up and column
chromatography gave the aminolysis product 303 in 72 % yield as a 4:1 mixture of isomers,
which were partially separable by column chromatography. These results indicate that
almost any primary or secondary amine may be used in conjunction with this methodology,
providing patience is exercised for the reaction of more hindered amines. The N-benzyl
amine 303 did not undergo any ring closing metathesis under standard conditions. This
was also true for its bis-OAc derivative. This is not unexpected as RCM usually does not
proceed in the presence of free amines.
NOH
BnOH H H
PMBOOTBS
OPMB
OHNH HBn
NOH
OTBSH
OOTBS
O
OPMB
NOH
BnOH H H
PMBOOTBS
a
b
c
d
301
302
303
208c
208a
Scheme 5.10 Reagents (a) (CH2=CHCH2)2NH, LiOTf, CH3CN 140 oC (97 %); (b)BnNH2, LiOTf, CH3CN, 120 oC, microwave, 1 h (99 %); (c) 208a LiOTf, CH3CN, 140 oC, 6 d (72 %) (d) Grubbs' cat, CH2Cl2, reflux 16 h.
90
Revisiting some of the less hindered model systems, we decided to investigate
whether another carbamate would be tolerated by the ring closing metathesis (Scheme
5.11). For this we chose the Cbz protecting group as we expected that this could be
removed under milder conditions (i.e. hydrogenation) than its N-Boc counterpart (TFA).
To this end secondary amine 224 was treated with CbzCl in a mixture of THF and sat.
Na2CO3 solution. This gave a good yield (89 %) of the N-Cbz derivative 304. This was
then reacted with Grubbs' catalyst (0.075 equiv) by heating at reflux in DCM to afford the
2,5-dihydropyrrole 305 also in excellent yield. In an attempt to model our new proposed
synthetic route to (+)-croomine, we proceeded to investigate the construction of the BC
ring system. Compound 305 was treated with TBSCl and imidazole at 70 oC to give the
TBS ether 306 in 89 % yield.
NHOH
PMBO
HNOH
PMBO
CbzH
NOH
PMBO
CbzH
NTBSO
PMBO
CbzH N
HTBSO
PMBO
HN
TBSO
H
a b c
d e
224 304 305
306307 308
Scheme 5.11 Reagents (a) CbzCl, Na2CO3, THF, H2O, 2 h (84 %); (b) Grubbs' cat, CH2Cl2, reflux, 24 h (93 %); (c) TBSCl, imidazole, DMF, 70 oC, (90 %); (d) Pd/C, H2, EtOAc, (77 %); (e) PPh3, CBr4, NEt3, CH2Cl2, RT or 60 oC.
We had hoped to simultaneously reduce the double bond of 306, and remove the N-
Cbz and O-PMB protecting groups all in a single hydrogenation, however this proved not
to be the case. The double bond was removed rapidly, and the N-Cbz group was quick to
follow, however the O-PMB group was stubborn and remained almost completely intact,
giving the partially deprotected compound 307. We speculated that the newly freed amine
was exerting an inhibitory effect on the palladium catalyst. Other attempts to removed the
O-PMB group of 307 were also thwarted by the free amine group. While the PMB group
was easily removed by treatment with CAN, further reaction (presumably between the
91
nitrogen atom and the newly formed p-methoxybenzaldehyde) gave an unwanted material,
that was not identified, as the only major product. Also attempted was a DDQ oxidation to
remove the PMB group of 307. In stark contrast to other successful DDQ oxidations in
Chapter 4, a blood red colour appeared within the reaction mix immediately after the
addition of the DDQ, which we believe corresponded to reaction of the amine group of 307
with the DDQ reagent, which can also act as an excellent Micheal acceptor. Not
surprisingly this reaction left only a very low yield of the deprotected adduct, which could
not be separated from a blood red impurity. Yadav et al. have reported that PMB ethers
may be converted directly to bromides using PPh3 and CBr4 in NEt3/DCM.163 In our case
cyclisation should then take place, however in our hands the O-PMB was not replaced,
giving only recovered starting material 307 which was difficult to separate from phosphine
(oxide) based impurities. This approach to the BC ring system 308 was abandoned due to a
lack of material, however removing the PMB group prior to hydrogenation might have
rectified the above problems.
5.6 Oxazolidinones as Protecting Groups for Metathesis It became clear that a much smaller protecting group was required to protect the
amine functionality of the more hindered amines, and previous experience had told us that a
very reactive reagent was required to conduct this protection. An obvious choice was an
oxazolidinone, which protects both the amine and secondary alcohol functions, is small and
bears an electron withdrawing carbonyl group which can deactivate the nitrogen. The only
example in the literature whereby the synthesis of the 2,5-dihydropyrole 310 from 2-allyl-
3-vinyl oxazolidinones 309 via ring closing metathesis has been investigated, reports the
reaction to be unsuccessful, albeit at RT in benzene.84
Nevertheless we investigated RCM of the model diene 311 (Scheme 5.12). The
diene 311 was readily prepared from amino alcohol 224 by reacting it with triphosgene as
previously discussed, and the low yield reflects the fact that the conditions are unoptimised
for this substrate. Heating a solution of 311 in DCM at reflux with Grubbs' catalyst (0.1
equiv) over 18 h, afforded the ring closed product 312 in 60 % yield (with 20 % recovered
SM). With the preliminary success of this model system, we then checked whether it was
applicable to our more complex (+)-croomine systems. To this end the amino-diol 282 was
92
treated with triphosgene and NEt3 in CH2Cl2 giving a 1:1 inseparable mixture of
oxazolidinones 284a and 284b in 50 % overall yield. This same mixture of oxazolidinones
284 was also available as a by-product from the N-Boc protection of the amine 282. This
mixture was subjected to the standard RCM conditions, and we were delighted to find that
the metathesis reaction proceeded, albeit slowly and requiring high catalyst loadings, giving
the 1:1 inseparable mixture of 2,5-dihydropyrroles 313a and 313b in 55 % yield.
NO
O
NO
O
NO
OOPMB
NO
OOPMB
NO
O
OH H
RR'
NO
O
OHR
HR'
NH OH
OPMB
NH OHOH H H
PMBOOTBS
a
b
e
313a R=CH2OPMB, R'=OTBS313b R=OTBS, R'=CH2OPMB
284a R=CH2OPMB, R'=OTBS284b R=OTBS, R'=CH2OPMB
c
d
309 310
224 311 312
282
Scheme 5.12 Reagents (a) Grubbs' cat., PhH, RT; (b) triphosgene, NEt3, DCM, 0 oC (53 %); (c) Grubbs' cat., CH2Cl2, reflux (72 %); (d) triphosgene, NEt3, DCM, 0 oC (50 %); (e) Grubbs' cat., CH2Cl2, reflux (55 %).
At least one literature precedent claimed to have effected oxazolidinone hydrolysis
and concomitant heterocyclic ring cyclisation in a single step.164 This was accomplished by
93
first converting the primary alcohol into a chloride, then conducting oxazolidinone
hydrolysis with NaOH. Hence we devised yet another model system, this time aimed at the
synthesis of the BC ring system using the concomitant oxazolidinone hydrolysis/cyclisation
method (Scheme 5.13). The previously prepared N-Boc-amino alcohol 262 was treated
with NaH in THF at RT which quickly converted it into the corresponding oxazolidinone
311 in excellent yield, representing a marked improvement upon the triphosgene based
approach. Ring closing metathesis as described above gave the 2,5-dihydropyrrole 312 in
72 % yield, when the catalyst loading was increased to 20 %. This compound was
hydrogenated (Pd/C and H2) in THF and we were delighted to discover that the O-PMB
group was also removed in only 3 h, give the alcohol 314 in 89 % yield. Compound 314
was next reacted with PPh3 and CCl4 over K2CO3 at reflux to give the chloride 315. The
yield was low (42 %) due in part to incomplete conversion, and starting material 314 was
recovered in 25 % yield. Further optimisation was clearly needed, however this was only a
trial system. Following the literature precedent,164 the chloro-oxazolidinone 315 was
subjected to NaOH hydrolysis in MeOH/water at 80 oC. A complex mixture was obtained
and no product could be attributed to be the desired bicyclic adduct 316.
NO
O
Cl
H
H
NO
O
OHH
H
NO
O
OPMB
H
H
NO
O
OPMBH
H
NH OH
OPMB
HH
NOH
OPMB
Boc
HH
N
HOH
a
b
c
d
e
fg
224
262
311 312
314315316 Scheme 5.13 Reagents (a) Boc2O, NEt3, THF, RT (94 %); (b) triphosgene, NEt3, CH2Cl2, 0 oC, 1 h (54 %); (c) NaH, THF, RT, 2 h (96 %); (d) Grubbs' cat., CH2Cl2, reflux (72 %); (e) Pd/C, H2, pet. sp. (89 %); (f) PPh3, CCl4, K2CO3, CH2Cl2, reflux (42 %); (g) NaOH, MeOH, H2O, 80 oC.
94
5.7 Elaboration Towards (+)-Croomine With respect to our proposed synthesis of (+)-croomine we felt that having a 1:1
mixture of oxazolidinones was not an optimal approach, especially considering that each of
the oxazolidinones was a 4:1 mixture of diastereoisomers. The solution to this lay in
protecting the secondary alcohol of amine 280 prior to aminolysis. While the silylated
compound 226 had previously been prepared via deallylation of 225, preparing it via the
silylation of amine 280 was both shorter and simpler (Scheme 5.14). The treatment of the
amino alcohol 280 with TBSCl and imidazole in DMF however, gave an unexpected result.
While silylation of the alcohol did occur, we discovered that the major product was the
unstable N-formyl derivative 317 obtained in 48 % yield. Base catalysed formyl transfer
from DMF to amines is a known reaction.165 This problem was easily rectified by
switching the reaction solvent to CH3CN, and in this solvent the desired amine 226 was
obtained in 85 % yield. If any of the trans-isomer from the Lindlar hydrogenation (5 steps
prior, the E/Z ratio for the Lindlar reduction was ~15:1) still remained, then any anti/syn
isomeric mixtures of amine 226 could also be separated at this stage.
OH
OPMB
HNH2H
OH
OPMB
HNH2H
OTBS
OPMB
HNH
HO
H
OTBS
OPMB
HNH2H
a
b
280
280
317
226 Scheme 5.14 Reagents (a) TBSCl, imidazole, DMF, RT, 3 h (48 %); (b) TBSCl, imidazole, CH3CN, RT (85 %).
Use of the silylated amine 226 in the aminolysis of vinyl epoxide 208a proceded
well in CH3CN with LiOTf (1.5 equiv) used as a promoter, requiring 4 d to complete at
135-140 oC (Scheme 5.15). Approximately a 4:1 mixture of diastereoisomers 318 and 319
was obtained consistent with a 90 % enantiomeric purity of the starting materials, and these
were separated by careful (frequently repeated) silica gel column chromatography. The
major isomer 318 was obtained in 78 % yield (based on the vinyl epoxide 208a) and the
95
minor isomer 319 in 17 % yield. The minor isomer 319 arises from the reaction of 208a
with ent-226. Its enantiomer ent-319 will form from the reaction of ent-208c and 226.
Thus the enantiomeric purity of 319 was expected to be low, however this was not
determined. The formation of 319 from the unwanted enantiomers of the starting materials
should leed to an enantiomeric enrichment of the desired isomer 318. The silylated amine
226 which was used in excess (1.5 equiv), was also recoverable but it frequently required
further purification to separate it from LiOTf and coloured impurities.
OOTBS
NH2
PMBO
TBSO NH OH
OTBS
TBSO
PMBO
H H
NH OH
OTBS
TBSO
PMBO
H H
TBSO
PMBO
NO
OTBS
O
H
TBSO
PMBO
N OTBSH
TBSO
PMBO
NO
OTBS
O
H
++
+
78 %
17 %
84 %
14 %
a
b
c
208a
226
318
319
320
321
322318
Scheme 5.15 Reagents (a) LiOTf, CH3CN, 130 oC, 4 d (95 %); (b) triphosgene, NEt3, CH2Cl2 -40 oC (84 %); (c) Grubbs' cat., CH2Cl2, reflux, 7 d (93 %).
The amino alcohol 318 was next treated with triphosgene and NEt3 in DCM, which
gave the desired oxazolidinone 320 in 84 % yield. Also obtained form this reaction was the
easily separable aziridine compound 321 in 14 % yield, which presumably forms via the
reaction of phosgene with the hydroxyl group (Scheme 5.16). This transforms it into a good
leaving group and hence facilitates the formation of the 3 membered ring via intramolecular
nitrogen attack. Initially conducting this reaction at 0 oC gave 320 in 78 % yield and 321 in
19 % yield. In order to reduce the amount of 321 formed, the reaction was conducted at
96
lower temperatures. At -20 oC the oxazolidinone 320 and aziridine 321 were obtained in 80
% and 17 % yield respectively. At -40 oC (the optimum reaction temperature) the yields
were 85 % and 14 % respectively. At -78 oC the yield of oxazolidinone 320 was slightly
reduced to 81 %, and the reaction time was greatly increased. The identity of the minor
product as the aziridine 321 was indicated by mass spectrometry which showed a parent ion
at m/z 618.4. The 1H and 13C NMR spectra confirmed this assignment. The coupling
constant between H2 and H3 was 6 Hz, consistent with a cis-arrangement about the aziridine
ring, which would arise from an internal SN2 displacement of the oxygen atom by the
nitrogen.
NH OH
OTBSRH H
NH O
OTBSRH H
OO
CCl2Cl
RN OTBSH
PMBO
TBSOCOCl2
CO2
triphosgene
HCl
+2
3
R=+
+
318
321 Scheme 5.16 - Mechanism of formation of the aziridine by-product 321.
Oxazolidinone 320 was then reacted under standard RCM conditions (Grubbs'
catalyst, high dilution). The reaction was slow (7 d), and required high catalyst loadings
(50 %), however excellent yields (93 %) of the 2,5-dihydropyrrole 322 were obtained
nonetheless (Scheme 5.15). Hydrogenation of 322 using Pd/C in EtOAc revealed that the
newly formed alkene was rapidly hydrogenated (Scheme 5.17), however the O-PMB group
was very slow to cleave so that compound 323 was obtained as the major product in good
yield (95 %). The stubborn O-PMB group was easily removed via reaction with DDQ in
DCM and water, giving the alcohol 324 in 92 % yield. Next we attempted to selectively
cleave the oxazolidinone group. Stirring 324 in MeOH over basic ion-exchange resin (OH-
form) at RT according to literature precedent,166 gave only recovered staring material after
3 d. Conversely heating 324 at reflux in 2:1 MeOH:H2O with excess NaOH gave complete
97
removal of the oxazolidinone, but the OTBS groups (especially the primary one) did not
survive such harsh conditions. Evidence of this was seen in the LRMS spectra of the crude
product, which gave a major peak at m/z 376 corresponding to the mono-TBS amino triol
325.
PMBO
NO
OTBS
O
TBSO H
OH
PMBO
NO
OH
O
HOH
PMBO
NH OH
OH
H H
PMBO
NO
OTBS
O
TBSO H
TBSO
PMBO
NH OTBS
OTBS
HH TBSO
OH
NH OTBS
OTBS
HH
OH
NO
OTBS
O
TBSO H
OH
NHTBSO H
OHH OH
A) DDQB) Pd/C/H2
C) Pd/C/H2, TsOHD) CAN
a
b
cd
e
f
OH-
322 323
324325
327
328
326
Scheme 5.17 Reagents (a) Pd/C, H2, EtOAc, RT, 1 h (95 %); (b) DDQ, CH2Cl2, H2O, RT (98 %); (c) n-Bu4NF, THF, RT (100 %); (d) NaOH, MeOH, H2O, reflux; (e) NaOH, MeOH, H2O, 100 oC, microwave, 90 min (93 %); (f) TBSCl, imidazole, CH3CN, 70 oC (69 %).
With the direct approach thwarted, a different protecting group strategy was
attempted. To this end the fully protected compound 323 was hydrolysed, using NaOH in
MeOH and H2O at reflux. As before the oxazolidinone and TBS groups were cleaved. The
crude product 327 was then treated with TBSCl and imidazole in CH3CN in order to
reprotect any cleaved TBS groups, affording 328. The yields of 328 using this approach
98
were low (even for 2 steps), due primarily to the slow hydrolysis of the oxazolidinone and
poor solubility of the starting material 323. Both of these problems could be directly
attributed to the two silyl ethers, so we resolved to remove them prior to hydrolysis. The
bis-TBS ether 323 was treated with n-Bu4NF in THF which gave quantitative yield of the
desilylated compound 326. Hydrolysis of 326 proceeded much better than before giving
327 in 93 % yield, then silylation with TBSCl and imidazole afforded compound 328 in 69
% yield for the 2 steps. Attempts to remove the O-PMB group of compound 328 were
unsuccessful. For example treatment of 328 with DDQ did not give the desired amino
alcohol, rather a blood red adduct (see Chapter 5.5). This blood red adduct does not form
when the nitrogen atom is protected. An attempt to remove the PMB group of 328 via
reaction with CAN was also unsuccessful. While the PMB group was cleanly removed, the
primary TBS ether was not stable, and was cleaved under the reaction conditions, which we
attributed to trace acid in the reaction. It is possible that the use of a pH buffer to eliminate
any acidity would improve this reaction. Hydrogenation was not successful presumably to
the combination of steric bulk and amine deactivation of the catalyst. An attempt to block
the amine in this hydrogenation by using p-TsOH (1 equiv) only resulted in cleavage of the
primary silyl ether.
To rectify the above problems triol 327 was protected as its tris-TBDPS ether by
treatment with TBDPSCl and imidazole giving compound 329 in 81 % yield (Scheme
5.18). The TBDPS ether is purported to have a greater stability towards acid,167 and this
proved to be the case, as treatment of 329 with CAN gave the desired amino alcohol 330 in
excellent yield. Cyclisation using PPh3 and CBr4 with NEt3 also proceeded well giving
compound 331, containing the BC ring system of (+)-croomine in good overall yield.
Interestingly the bromide intermediate 333 was also isolated from the cyclisation reaction
mixture, and it appeared to be quite stable in the absence of base. We believe that this
bromide forms as shown in Scheme 5.19 where bromide ion acts as a competing
nucleophile for the activated oxygen of 332. However treating this bromide with NEt3 in
refluxing CH2Cl2 afforded the desired cyclised product. We elected not to heat the
cyclisation reaction itself as silyl ethers have been reported to convert to bromides under
the same reaction conditions.163 Further investigations would be required to verify whether
this would be the case.
99
OH
PMBO
NH OH
OH
H H TBDPSO
PMBO
NH OTBDPS
OTBDPS
HH
TBDPSO
OH
NH OTBDPS
OTBDPS
HHN
OTBDPSOTBDPSHH
TBDPSO
a
b
c
327 329
330331Scheme 5.18 Reagents (a) TBDPSCl, imidazole, CH3CN, 75 oC, 2 d (81 %); (b) CAN, CH3CN, H2O, CH2Cl2 (93 %); (c) PPh3, CBr4, NEt3,CH2Cl2, 0 oC to RT (81 %).
TBDPSO
OH
NHH
R
TBDPSO
O
NHH
RP
PhPh
Ph
NTBDPSO
H
R
TBDPSO
Br
NHH
ROTBDPS
OTBDPS
+PPh3
Br-
NEt3
NEt3(fast)
(slow)
R=
332
333
330
331
CBr4
Scheme 5.19 - Mechanism of the cyclisation reaction of 330 showing the formation of the bromide 333.
In order to remove the three TBDPS protecting groups (Scheme 5.20), compound
331 was treated with anhydrous n-Bu4NF (10 equiv.) in THF, however after 4 d at RT some
silyl ethers remained intact. Heating the reaction mixture at reflux for 16 h completed the
reaction, however separation of the highly polar product 334 from the excess TBAF proved
to be extremely difficult. Removal of the TBDPS ethers of 331 was accomplished in a
much cleaner fashion via acid hydrolysis with conc. HCl (35 %) in MeOH, however this
reaction was also unreliable. Initial solubility problems could be rectified by adding CHCl3
(10 % v/v) to the reaction mixture, however this significantly slowed the reaction.
Generally the reaction would not go to completion on the first acid treatment (90 oC, 3 d)
but after this time the solubility of the partially deprotected material had improved. Thus
the CHCl3 was then omitted from the second acid treatment which gave the triol 334 as a
crude hydrochloride salt. This was then applied to a basic ion-exchange resin (OH- form),
100
which effected both deprotonation to give the free amine, and purification by removing
water insoluble colours and partially hydrolysed materials (these may be recovered by
elution with MeOH and retreated with acid if present in significant amounts). The mass of
triol 334 recovered was always disturbingly small, due to the extreme loss of mass
experienced by removing the three silyl ethers, since 100 mg of starting material 331 would
only give a quantitative yield of 25.4 mg of 334.
With (very little of) the triol 334 in hand we next turned our attention to the
formation of the lactone moiety. A TPAP/NMO protocol had worked well for our N-Boc
protected model system 222, however when the same approach was tried here on 334 none
of the desired lactone product 335 was recovered (Scheme 5.20). The major recovered
product had a clear aldehyde signal in the 1H NMR spectrum (9.0 ppm), indicating that the
secondary alcohols had oxidised up to the corresponding ketones faster than the hemiacetal
formation required for the lactone synthesis. We tentatively assigned the major product for
this reaction as 337, based on mass spectral analysis however this material was highly
unstable and was difficult to purify as a result. Further investigations into this reaction
should be conducted, with a view to slowing the rate of this oxidation to allow formation of
the hemiacetal.
N OTBDPSOTBDPS
TBDPSO
HHN OH
OHOH
HH
NHH O
O
OO N
HH OO
O
N OO
O
HH ON
OO
H
H
a
334331
335
(+)-croomine
336
b / c
d e
337 338
1 2
34
5
67
8
9 9a
1'2'
3'4'
5'
Scheme 5.20 Reagents (a) HCl (38 %), MeOH, CHCl3, 90 oC, 3 d (84 %); (b) TPAP, NMO, CH2Cl2; (c) TEMPO, BAIB, AcOH, RT (28 %) (d) SmI2, methyl acrylate, THF, tBuOH, -78 oC (e) LDA, MeI, THF.
101
TEMPO/BAIB oxidations are considered a mild method of oxidising alcohols to
carbonyl compounds,168 and it has been reported that lactones are formed selectively in the
presence of secondary alcohols.169 After the simple preparation of the BAIB reagent170 we
investigated the applicability of the TEMPO/BAIB method to oxidation of the amino triol
334. Major solubility problems were experienced using non-protic solvents, limiting the
reaction and even in DMF solubility was sparse. TEMPO oxidations are reported to
proceed faster in acetic acid due to the acid catalysed dismutation of the TEMPO reagent
into the active agent.168 We felt that an acidic solvent might also help protect the free
amine from possible oxidation, as well as improve solubility. Gratifyingly when acetic acid
was used the starting material was consumed rapidly. Regrettably a complex mixture of
products was obtained, and the only isolable major product (obtained in 28 % yield) was
unstable, difficult to purify and (painfully) unassignable as the desired lactone 335. Closer
investigations into the 13C NMR spectrum of the major product from this oxidation
indicated five CH carbons and 7 CH2 carbons and a solitary carbonyl signal at 177 ppm.
The mass spectrum of the product gave an m/z at 239. The data for this for the major
product indicates that the product is the hemiaminal 338, which might be formed via an
intermediate imminium ion as shown in Scheme 5.21. This assignment is suppported by
the 13C nmr spectrum which showed a peak at 96 ppm (d) assignable to C5, and a peak at
85 ppm (d) assignable to C5'. Furthermore the 1H NMR spectra showed two 1H signals at
4.82 (s) and 4.37 (dt) ppm assignable to C5 and C5' respectively. All other spectral peaks
also verify the assigned structure, and additionally gCOSY and gHSQC 2D spectra both
showed the appropriate cross peaks.
NOH
OH
H OHH ON
OH H
OH
ON
O
OH HH
X
H
ON
O
OH H
H ON
OH
H
O
+
+
334
338
[O]
Scheme 5.21 - Possible mechanism of formation of 338 during the oxidation of 334.
102
Having by this stage run out of both time and material, this part of the project was
unable to be completed, despite the target (+)-croomine potentially being only three
synthetic steps away from triol 334. If the lactone 335 had been prepared, then it only
remained to prepare the spirolactone 336 via SmI2 mediated radical cyclisation between the
ketone and methyl acrylate according to literature methods.171,172 Compound 336 could
then be converted to (+)-croomine via lactone α-methylation with LDA and methyl iodide.
103
Chapter 6: Conclusions and Future
Directions
6.1 Conclusions The main aim of this project was to develop a flexible asymmetric synthesis of 1-
aza-[n+2.3.0]-bicylic systems and this was achieved. As can be seen in Figure 6.1 the
flexibility of this approach is substantial. The size of each heterocyclic ring can be varied,
ring B by initial choice of starting alkyne (n=0,1,2...) and ring A by the choice of amine
(m=1,2...) for the aminolysis. Additional substitution of these two rings is also tolerated
and can be introduced using substituted alkynes and amines respectively. Dihydroxylation
can install cis-diols into ring A, and the N-Boc and oxazolidinone protected amines confer
complimentary facial selectivity. Additionally trans-diols have also been prepared within
the group via inversion of one of the two hydroxyl group orientations.173 Other
derivatisations of the double bond are also possible, or it can simply be saturated via
hydrogenation. Bridgehead stereochemistry depends on the choice of Sharpless
asymmetric epoxidation catalyst i.e. (+)- vs. (-)-DIPT, which has the added effect of
determining the absolute stereochemistry, hence all other stereocenters are defined relative
to this one. The B ring hydroxyl stereochemistry is dependant upon the choice of alkyne
reduction method which can give either (E)- or (Z)- alkenes. Finally vinyl aziridine
chemistry might be exploitable to produce A ring expanded analogues.
104
N
R''
R'
OH
OHOH
HR
(
)m(
)n
Variation of amine nucleophile
Cis vs trans 1,2-diols,N-Boc vs oxazolidinone protected substrate,
hydrogenation or other alkene derivatisations.
Sharpless Asymmetric Epoxidation
(+) vs (-) DIPT
Alkyne reductionLindlar vs REDAL
Variation of starting alkyne
m=1,2...
n=0,1,2...
A
B
Figure 6.1: Diagram illustrating the flexibility of this approach to 1-aza-bicyclic systems.
The secondary goal of this project was to exploit the above flexibility to prepare
indolizidine and Stemona alkaloids. The synthesis of indolizidine alkaloids was successful
with two different syntheses of (-)-swainsonine completed (Scheme 6.1) each beginning
with the commercially available compound 4-pentyn-1-ol. Each synthesis proceeded from
the common intermediate 231 which was prepared from 4-pentyn-1-ol in 9 steps in 21 %
overall yield. The first successful approach to (-)-swainsonine involved dihydroxylation of
the dehydroindolizidine 257 as the key step and this facilitated the preparation of (-)-
swainsonine in 7 steps in 23 % overall yield from 231. The second approach to (-)-
swainsonine featured a dihydroxylation of the oxazolidinone 255, which made possible the
synthesis of (-)-swainsonine in 9 steps from 231 in 26 % overall yield. While the second
synthesis was longer, this approach was by far easier method, and furthermore the yields
are unoptimised and would likely be higher if the chemistry was to be repeated. Two
epimeric analogues of (-)-swainsonine were also prepared. (+)-1,2-Di-epi-swainsonione
was prepared in 5 steps from 231 in 66 % overall yield. (+)-1,2,8-Tri-epi-swainsonine was
also prepared from 4-pentyn-1-ol in 14 steps in 23 % overall yield (Scheme 6.2).
105
OH
NBoc
OPMB
OHHH
OOPMB
N
HOH
OH OH
NO
OPMB
O
HH
N
HOBn
N
OH
HOH
OH
28 %
76 %
66 %
74 %
48 %
47 %
35 %
6 steps
3 steps
5 steps
1 step
3 steps
4 steps
8 steps
(+)-1,2-di-epi-swainsonine
(-)-swainsonine
208e
231
255
257
Scheme 6.1 Summary of the syntheses of (-)-swainsonine and (+)-1,2-di-epi-swainsonine.
O
OTBSOH
OH OH
NOTBS
BocH OH
HNOH
H
OHOH
NOBoc
H HO
4 steps 6 steps
3 steps
5 steps 3 steps
15 % 57 %
82 %
50 % 76 %
(+)-1,2,8-tri-epi-swainsonine
208a
218 222 Scheme 6.2 Summary of the synthesis of (+)-1,2,8-tri-epi-swainsonine and the CD ring system of (+)-croomine
While no Stemona alkaloids were prepared in this project, models of the
pyrrolo[1,2-c]azepine (Scheme 6.3) and pyrrole-butyrolactone (Scheme 6.2) ring features
of Stemona alkaloids were easily completed. The trihydroxylated pyrrolo[1,2-c]azepine
269 was prepared from 5-hexyn-1-ol in 14 steps in 8.8 % overall yield, however this
chemistry was unoptimised. Additionally the pyrrole-butyrolactone model compound 222
106
was prepared from 4-pentyn-1-ol in 12 steps in 35 % overall yield. The difficulty
experienced with respect to the synthesis of (+)-croomine via this approach can be directly
attributed to the additional alkyl substitution required of the pyrrolidine ring. This provided
extra steric hinderance, such that nitrogen protection, ring closing metathesis and further
derivatisation reactions proceeded only under more forcing conditions, generally giving
reduced yields as a result. Nevertheless our proposed synthesis of (+)-croomine proceeded
as far as the as triol 334 which was prepared in 18 steps (longest linear sequence) from 5-
hexyn-1-ol in a highly convergent fashion, giving an overall yield of 10.8 %. The triol 334
was theoretically only three synthetic steps from (+)-croomine, however we were unable to
complete this chemistry in the time available as oxidation of 334 gave unexpected products.
On a more positive note the unexpected product 338 possesses the BCD ring system of (+)-
croomine, however the additional bridging oxygen is not present in the natural alkaloid.
OH
O
OPMBN
OHOH
HOH
NH2
PMBO
TBSO OOTBS
NH OH
OTBSPMBO
TBSO HH
NOH
OHOH
HH
6 steps 8 steps
2 steps
1 step
9 steps
42 % 21 %
83 %
78 %
40 %
208c
269
226 208a
318334 Scheme 6.3 Summary of the syntheses of pyrrolo[1,2-c]azepines.
6.2 Future Directions The methods developed within this project have already been adopted by other
members of this research group in the synthesis of pyrrolizidine, indolizidine, pyrrolidine
and Stemona alkaloids, and I wish them well in their endeavors. The number of alkaloids
107
having a β-hydroxyl amine structure is substantial, as is the number of pyrrolidine
containing alkaloids, and the methods reported here could be applied to the synthesis of
many of these. Completion of the synthesis of (+)-croomine (Chapter 5) will require only
luck and time, both of which were absent during the latter stages of the project, however we
are convinced the approach was sound and further research in this area is needed. New
analogues of indolizidine alkaloids could easily be prepared that might be potent and
selective glycosidase inhibitors. Somfai's vinyl aziridine isomeriation approach131 can in
principle be applied to afford A-ring expanded versions of these molecules where longer
amine-olefins are not available. Optically pure β-amino alcohols are also easily prepared
using the Petasis reaction,174 which broadens the scope of this method considerably, by
increasing the number of starting amino-dienes available, and reducing the number of steps
required for their synthesis from seven to just one.
108
Chapter 7: Experimental
7.1 General Experimental Nuclear Magnetic Resonance Spectroscopy 1H nmr spectra
These were obtained at either 300 MHz or 500 MHz on a Varian spectrometer. Peak
frequencies were referenced relative to the 7.26 ppm chemical shift signal of CHCl3, or the
residual proton signal of the deuterated solvent used. Resonances were assigned as follows:
Chemical shift (number of protons, multiplicity, coupling constant(s), assigned proton(s)).
Multiplicities are reported by the convention: s (singlet), d (doublet), t (triplet), q (quartet),
p (pentuplet), m (multiplet), br (broad). Uncertainties: Chemical shift (±0.01 ppm),
coupling constants (±0.1 Hz). 13C nmr spectra
These were obtained at 75 MHz on a Varian spectrometer. Peak frequencies were
referenced relative to the 77.0 ppm chemical shift signal of CDCl3 or the carbon signal of
the deuterated solvent used. In D2O ca. 5 % CH3CN is used as an internal reference.
Resonances were assigned as follows: Chemical shift (carbon type, assigned carbon(s)).
Carbon type is reported by the convention: s (quartenary), d (methine), t (methylene), q
(methyl). These assignments were based on DEPT spectra. Uncertainties: Chemical shift
(±0.3 ppm).
Chromatography
Column Chromatography
This was performed using Merck GF 254 flash silica gel (40-63 µm) packed by the slurry
method. Small scale separations (<2.0 g) were performed using either a 10 mm or a 20 mm
diameter column, and large scale separations (>2.0 g) were performed using a 50 mm
diameter column, each with the stated solvent system.
Thin Layer Chromatography
This was performed using aluminium-backed Merck sorbent silica gel. Compounds were
detected under a 254 nm ultraviolet lamp if applicable, or by staining with an acidified,
109
aqueous solution of ammonium molybdate and cerium(IV) sulfate, followed by
development with a 1400 W heat gun.
Melting points
These were obtained using a Gallenkamp MF-370 capillary tube melting point apparatus
and are uncorrected. Uncertainties in the values quoted is ± 2 oC
Polarimetry
Specific rotations were measured using a 10 mm or a 50 mm cell, and a Jasco DIP-370
digital polarimeter. They are reported by the following convention: specific rotation [10-1
.deg.cm3.g-1](concentration, solvent). Uncertainties in the values quoted is ± 5 %.
Mass Spectrometry
These were obtained on a VG Quatro mass spectrometer (low resolution), and on a VG
Autospec mass spectrometer (high resolution). In all cases exact masses were obtained in
lieu of elemental analyses, and 1H and 13C NMR were used as criteria for purity.
Microwave Reactions
These were conducted using a Milestone ETHOS SEL microwave reactor. All reactions
were conducted in a 250 mL teflon tube with a 100 bar pressure cap, and strict control of
the internal temperature.
Reagents and Solvents
Where necessary, these were purified according to methods contained in the literature.175,176
Note to the Reader
The Experimental Protocol section is divided into two parts. In the first part (Chapter 7.2)
the reactions are grouped according to reaction type, where a general method is then used.
The second part (Chapter 7.3) of the experimental describes the synthesis of compounds in
Chapters 2-5 that have not been reported in the first section.
Index
7.2 General Experimental Methods. 110
7.2.1 General method for silylation of primary alcohols. 110
7.2.2 General method for PMB protection of primary alcohols. 112
7.2.3 General method for homologation of alkynes to propargylic alcohols. 114
7.2.4 General method for Lindlar hydrogenation of propagylic alcohols. 117
7.2.5 General method for REDAL reduction of propargylic alcohols. 119
110
7.2.6 General method for m-CPBA epoxidation of allylic alcohols. 120
7.2.7 General method for Sharpless asymmetric epoxidation of allylic.
alcohols. 121
7.2.8 General methods for oxidation of alcohols to aldehydes. 124
7.2.9 General method for Wittig olefination. 127
7.2.10 General methods for aminolysis of vinyl epoxides. 130
7.2.11 General method for N-Boc protection of amines. 134
7.2.12 General method for ring closing metathesis. 137
7.2.13 General method for hydrogenation of 2,5-dihydropyrroles. 142
7.2.14 General method for secondary alcohol silylation. 144
7.2.15 General method for cis-dihydroxylation with OsO4. 150
7.2.16 General method for alcohol benzylation. 153
7.2.17 General method for TFA deprotection of N-Boc and
N-Boc/O-PMB derivatives. 160
7.2.18 General method for Appel cyclisation of amino alcohols. 163
7.2.19 General method for debenzylation of benzyl ethers via
hydrogenation. 167
7.3 Miscellaneous Experimental Methods. 171
7.3.1 Experimental for Chapter 2. 171
7.3.2 Experimental for Chapter 3. 172
7.3.3 Experimental for Chapter 4. 175
7.3.4 Experimental for Chapter 5. 185
7.2 General Experimental Protocol 7.2.1 General method for the silylation of primary alcohols. The starting alcohol (23.78 mmol) was dissolved in DMF (50 mL) then imidazole (4.16 g,
59.45 mmol) and TBSCl (4.00 g, 26.90 mmol) were added. The mixture was stirred at RT
for 3 h, then poured into water (100 mL). The mixture was extracted with EtOAc (150
mL), then the organic portion was washed with water (2 x 100 mL), dried (MgSO4), filtered
111
and evaporated in vacuo to give an oil. The pure product was obtained by column
chromatography using the stated solvent system.
4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1-butanol (206).177
1,4-Butanediol (11.69 g, 129.3 mmol) was reacted as described
above except that 0.43 equiv. of imidazole and 0.2 equiv of TBSCl
were used. Column chromatography (increasing polarity from 5 % to 10 % EtOAc in pet.
sp. as eluant) gave the title compound (3.33 g, 16.3 mmol, 61.7 %) as a clear oil, that had
spectral data identical to that reported in the literature.177
MS (CI+) m/z 205 (87 %) (M+1), HRMS (CI+) found 205.1620, calc for C10H25O2Si
205.1624 (M+1).
δH (300 MHz, CDCl3): 0.01 (6H, s, (CH3)2Si), 0.85 (9H, s, (CH3)3CSi), 1.53-1.65 (4H, m,
H2 and H3), 2.98 (1H, br. s, OH), 3.52-3.65 (4H, m, H1 and H4).
δC (75 MHz, CDCl3): -5.5 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 25.8 (q, (CH3)3CSi), 29.7,
29.9 (t, C2 and C3), 62.5 (t, C4), 63.2 (t, C1).
(1,1-Dimethylethyl)dimethyl(4-pentynyloxy)silane (210a).178
4-Pentyn-1-ol (2.00 g, 23.78 mmol) was reacted as described above.
Column chromatography (2 % EtOAc in pet. sp. as eluant) gave the
title compound (4.53 g, 22.83 mmol, 96.0 %) as a clear oil that had spectral data identical to
that reported in the literature.178
MS (CI+) m/z 199 (23 %) (M+1), HRMS (CI+) found 199.1529, calc for C11H23OSi
199.1518 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.65-1.75 (2H, m,
H2), 1.91 (1H, td, J=2.7, 0.6 Hz, H5), 2.25 (2H, td, J=7.2, 2.7 Hz, H3), 3.68 (2H, t, J=6.0
Hz, H1).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 14.8 (t, C2), 18.3 (s, (CH3)3CSi), 25.9 (q,
(CH3)3CSi), 31.5 (t, C3), 61.4 (t, C1), 68.2 (d, C5), 84.2 (s, C4).
OH OTBS1
2
3
4
OTBS
1
2
3
45
112
(1,2-Dimethylethyl)dimethyl(5-hexynyloxy)silane (210b).179
5-Hexyn-1-ol (890 mg, 9.08 mmol) was reacted as described
above. Column chromatography (2 % EtOAc in pet. sp. as eluant)
gave the title compound (1.87 g, 8.80 mmol, 96.9 %) as a clear oil that had spectral data
identical to that reported in the literature.179
MS (CI+) m/z 213 (49 %) (M+1), HRMS (CI+) found 213.1677, calc for C12H25OSi
213.1675 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.50-1.66 (4H, m,
H2 and H3), 1.91 (1H, t, J=2.7 Hz, H6), 2.14-2.24 (2H, m, H4), 3.61 (2H, t, J=6.0 Hz, H1).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.2 (t, C3), 18.3 (s, (CH3)3CSi), 24.9 (t, C2),
25.9 (q, (CH3)3CSi), 31.8 (t, C4), 62.5 (t, C1), 68.2 (d, C6), 84.4 (s, C5).
(1,1-Dimethylethyl)(4-pentynyloxy)diphenylsilane (210c).180
4-Pentyn-1-ol (2.00 g, 23.78 mmol) was reacted as described above
except that TBDPSCl (7.295 g, 26.54 mmol) was used instead of
TBSCl. Column chromatography (2 % EtOAc in pet. sp. as eluant) gave the title
compound (7.047 g, 21.85 mmol, 91.9 %) as a clear oil that had spectral data identical to
that reported in the literature.180
MS (CI+) m/z 323 (100 %) (M+1), HRMS (CI+) found 323.1827, calc for C21H27OSi
323.1831 (M+1).
δH (300 MHz, CDCl3): 1.09 (9H, s, (CH3)3CSi), 1.81 (2H, app. br. p, J=6.0 Hz, H2), 1.94
(1H, td, J=2.4 and 1.2 Hz, H5), 2.38 (2H, td, J=6.9 and 2.4 Hz, H3), 3.78 (2H, t, J=6.0 Hz,
H1), 7.36-7.50 (6H, m SiPh), 7.68-7.75 (4H, m, SiPh).
δC (75 MHz, CDCl3): 14.9 (t, C2), 19.2 (s, (CH3)3CSi), 26.8 (q, (CH3)3CSi), 31.4 (t, C3),
62.2 (t, C1), 68.3 (d, C5), 84.2 (s, C4), 127.6, 129.6, 135.5 (d, SiPh), 133.8 (s, SiPh).
7.2.2 General method for the PMB protection of primary alcohols. 4-Methoxybenzylalcohol (5.00 g, 36.19 mmol) was dissolved in conc. HBr solution (10
mL, 45 % in acetic acid), then the solution was stirred at RT for 20 min. The mixture was
diluted with Et2O (200 mL), then washed with sat. NaHCO3 solution (200 mL) and water
(200 mL). The organic portion was dried (MgSO4), filtered and evaporated in vacuo to
OTBS
1
2
3
4
56
OTBDPS
12
345
113
give crude, unstable 4-methoxybenzylbromide (7.27 g, 36.19 mmol). Sodium hydride
(1.47 g, 30.6 mmol, 50 % dispersion in paraffin wax) was washed with dry pet. sp. (2 x 10
mL) then suspended in dry THF (50 mL). The starting alcohol (2.34 g, 27.82 mmol) was
added as a solution in dry THF (5 mL), then after 10 min, 4-methoxybenzylbromide (7.27
g, 36.19 mmol) was added as a solution in dry THF (10 mL) via cannula. The mixture was
stirred under N2 at RT for 22 h, then glacial acetic acid (10 mL) was added, followed by
water (250 mL). The mixture was extracted with ethyl acetate (3 x 100 mL), and the
combined organic extracts dried (MgSO4), filtered and evaporated in vacuo to give an oil.
The pure product was obtained by column chromatography using the stated solvent system.
1-Methoxy-4-[(4-pentynyloxy)methyl]benzene (210d).181
4-Pentyn-1-ol (2.34 g, 27.82 mmol) was reacted as described above.
Column chromatography (increasing polarity from 2 % to 7 %
EtOAc in pet. sp. as eluant) gave the title compound (5.50 g, 26.9
mmol, 96.8 %) as a clear oil that had spectral data identical to that reported in the
literature.181
MS (CI+) m/z 203 (27 %) (M-1), HRMS (CI+) found 203.1073, calc for C13H15O2
203.1072 (M-1).
δH (300 MHz, CDCl3): 1.81 (2H, p, J=6.3 Hz, H2), 1.94 (1H, td, J=2.7, 0.6 Hz, H5), 2.30
(2H, td, J=6.9, 2.7 Hz, H3), 3.53 (2H, t, J=6.0 Hz, H1), 3.79 (3H, s, OCH3), 4.43 (2H, s,
OCH2Ar), 6.87 (2H, dt, J=8.4, 2.7 Hz, 2 x ArCH), 7.26 (2H, dt, J=8.4, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 15.2 (t, C2), 28.5 (t, C3), 55.1 (q, OCH3), 68.3 (t, C1), 68.4 (d, C5),
72.6 (t, OCH2Ar), 83.9 (s, C4), 113.7 (d, 2 x ArCH), 129.2 (d, 2 x ArCH), 130.4 (s, ArC),
159.0 (s, ArC).
1-Methoxy-4-[(5-hexynyloxy)methyl]benzene (210e).181
5-Hexyn-1-ol (4.00 g, 10.2 mmol) was reacted as described above.
Column chromatography (increasing polarity from 2 % to 15 %
EtOAc in pet. sp. as eluant) gave the title compound (8.32 g, 38.113 mmol, 93.4 %) as a
clear oil that had spectral data identical to that reported in the literature.181
OPMB
1
2
345
OPMB
1
2
3
4
56
114
MS (CI+) m/z 217 (31 %) (M-1), HRMS (CI+) found 217.1233, calc for C14H18O2
217.1229 (M-1).
δH (300 MHz, CDCl3): 1.55-1.78 (4H, m, H3 and H2), 1.94 (1H, t, J=2.7 Hz, H6), 2.20
(2H, td, J=7.2 and 2.7 Hz, H4), 3.46 (2H, t, J=6.0 Hz, H1), 3.80 (3H, s, OCH3), 4.43 (2H, s,
OCH2Ar), 6.87 (2H, dt, J=8.4, 2.7 Hz, 2 x ArCH), 7.26 (2H, dt, J=8.4, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 18.2 (t, C3), 25.2 (t, C2), 28.7 (t, C4), 55.2 (q, OCH3), 68.3 (d, C6),
69.4 (t, C1), 72.5 (t, OCH2Ar), 84.3 (s, C5), 113.7 (d, 2 x ArCH), 129.2 (d, 2 x ArCH),
130.6 (s, ArC), 159.1 (s, ArC).
5-[(4-Methoxyphenyl)methoxy]-1-pentanol (337).6
1,5-Pentanediol (7.55 g, 72.5 mmol) was reacted as described
above except that 0.3 equiv of NaH (1.05 g, 21.75 mmol) and 0.3
equiv of PMBBr (2.73 g, 13.56 mmol) was used. Column chromatography (increasing
polarity from 30 % to 50 % EtOAc in pet. sp. as eluant) gave the title compound (2.68 g,
11.95 mmol, 82.5 %) as a clear oil that had spectral data identical to that reported in the
literature.6
MS (CI+) m/z 223 (30 %) (M-1), HRMS (EI+) found 224.1408, calc for C13H20O3
224.1412 (M).
δH (300 MHz, CDCl3): 1.34-1.46 (2H, m, H3), 1.46-1.66 (4H, m, H2 and H4), 2.32 (1H,
br. s, OH), 3.44 (2H, t, J=6.3 Hz, H5), 3.56 (2H, t, J=6.3 Hz, H1), 3.78 (3H, s, OCH3), 4.41
(2H, s, OCH2Ar), 6.86 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH), 7.24 (2H, dt, J=8.7, 2.1 Hz, 2 x
ArCH).
δC (75 MHz, CDCl3): 22.4 (t, C3), 29.3, 32.4 (t, C2 and C4), 55.1 (q, OCH3), 62.4 (t, C1),
69.9 (t, C5), 72.4 (t, OCH2Ar), 113.5 (d, 2 x ArCH), 129.0 (d, 2 x ArCH), 130.3 (s, ArC),
158.8 (s, ArC).
7.2.3 General method for homologation of alkynes to propargylic
alcohols. The starting alkyne (10 mmol) was dissolved in dry THF (50 mL), then the mixture was
cooled to 0 oC under N2. n-Butyllithium (6.8 mL, 10.2 mmol, ~1.5 mol L-1) was added
over a period of 5 min, until a bright yellow colour appeared. The mixture was stirred for 5
OH OPMB
12
34
5
115
min, before finely powdered paraformaldehyde (486 mg, 16.2 mmol) was quickly added.
The flask was flushed thoroughly with N2, then allowed to warm to RT before the mixture
was stirred for 18 h. The reaction was quenched with water (120 mL) and extracted with
EtOAc (3 x 100 mL), then the combined organic extracts dried (MgSO4), filtered and
evaporated in vacuo to give an oil. The pure product was obtained by column
chromatography using the stated solvent system.
6-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-hexyn-1-ol (211a).102,182
The alkyne 210a (2.00 g, 10.1 mmol) was reacted as described
above. Column chromatography (increasing polarity from 7.5
% to 12.5 % EtOAc in pet. sp. as eluant) gave the title
compound (2.177 g, 9.53 mmol, 94.4 %) as a clear oil that had spectral data identical to that
reported in the literature.102,182
MS (CI+) m/z 229 (79 %) (M+1), HRMS (CI+) found 229.1631, calc for C12H25O2Si
229.1624 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.68 (2H, m, H5),
2.12 (1H, t, J=5.7 Hz, OH), 2.27 (2H, tt, J=7.2, 2.4 Hz, H4), 3.66 (2H, t, J=6.0 Hz, H6),
4.21 (2H, dt, J=5.7, 2.4 Hz, H1).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 15.1 (t, C5), 18.2 (s, (CH3)3CSi), 25.8 (q,
(CH3)3CSi), 31.5 (t, C4), 51.2 (t, C1), 61.5 (t, C6), 78.4 (s, C3), 85.8 (s, C2).
6-[(4-Methoxyphenyl)methoxy]-2-hexyn-1-ol (211d).181
The alkyne 210d (10.417 g, 51.00 mmol) was reacted as
described above. Column chromatography (increasing
polarity from 10 % to 60 % EtOAc in pet. sp. as eluant) gave
the title compound (10.296 g, 43.94 mmol 86.2 %) as a clear oil that had spectral data
identical to that reported in the literature.181
MS (CI+) m/z 233 (13 %) (M-1), HRMS (CI+) found 233.1175, calc for C14H17O3
233.1178 (M-1).
δH (300 MHz, CDCl3): 1.79 (2H, p, J=6.3 Hz, H5), 2.18 (1H, t, J=5.7 Hz, OH), 2.32 (2H,
tt, J=6.9, 2.1 Hz, H4), 3.52 (2H, t, J=6.3 Hz, H6), 3.80 (3H, s, OCH3), 4.19 (2H, br.s. H1),
OTBSOH
1 2 3 4
5
6
OPMBOH
1 2 3 4
5
6
116
4.44 (2H, s, OCH2Ar), 6.88 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH), 7.26 (2H, dt, J=8.7, 2.1 Hz,
2 x ArCH).
δC (75 MHz, CDCl3): 15.5 (t, C5), 28.5 (t, C4), 51.1 (t, C1), 55.2 (q, OCH3), 68.2 (t, C6),
72.4 (t, OCH2Ar), 78.6 (s, C3), 85.5 (s, C2), 113.6 (d, 2 x ArCH), 129.2 (d, 2 x ArCH),
130.3 (s, ArC), 159.0 (s, ArC).
6-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-2-hexyn-1-ol (211c).183
The alkyne 210c (7.00 g, 21.70 mmol) was reacted as
described above. Column chromatography (increasing
polarity from 10 % to 40 % EtOAc in pet. sp. as eluant)
gave the title compound (6.46 g, 18.32 mmol, 84.4 %) as a clear oil that had spectral data
identical to that reported in the literature.183
MS (CI+) m/z 353 (2 %) (M+1), HRMS (CI+) found 335.1838, calc for C22H27OSi
335.1831 (M-H2O).
δH (300 MHz, CDCl3): 1.06 (9H, s, (CH3)3CSi), 1.65 (1H, br. s, OH), 1.76 (2H, app. br. p,
J=6.6 Hz, H5), 2.38 (2H, tt, J=6.9, 2.4 Hz, H4), 3.75 (2H, t, J=5.7 Hz, H6), 4.20 (2H, app.
br. s, H1), 7.35 (6H, m, SiPh), 7.65 (4H, m, SiPh).
δC (75 MHz, CDCl3): 15.2 (t, C5), 19.2 (s, (CH3)3CSi), 26.8 (q, (CH3)3CSi), 31.4 (t, C4),
51.3 (t, C1), 62.2 (t, C6), 78.4 (s, C3), 86.0 (s, C2), 127.6, 129.6, 135.5 (d, ArCH), 133.7 (s,
ArC).
7-[(4-Methoxyphenyl)methoxy]-2-heptyn-1-ol (211e).181
The alkyne 210e (1.90 g, 8.70 mmol) was reacted as
described above. Column chromatography (increasing
polarity from 7.5 % to 40 % EtOAc in pet. sp. as eluant)
gave the title compound (1.77 g, 7.13 mmol, 81.9 %) as a pale yellow oil that had spectral
data identical to that reported in the literature.181
MS (CI+) m/z 247 (31 %) (M-1), HRMS (CI+) found 247.1342, calc for C15H20O3
247.1334 (M-1).
δH (300 MHz, CDCl3): 1.52-1.76 (4H, m, H5 and H6), 2.02 (1H, br. t, J=5.7 Hz, OH), 2.23
(2H, tt, J=6.9, 1.8 Hz, H4), 3.45 (2H, t, J=6.6 Hz, H7), 3.80 (3H, s, OCH3), 4.21 (2H, dt,
OH OTBDPS
1 2 3 45
6
OPMBOH
12 3 4
5
6
7
117
J=5.7, 1.8 Hz, H1), 4.43 (2H, s, OCH2Ar), 6.87 (2H, dt, J=8.4, 2.7 Hz, 2 x ArCH), 7.25
(2H, dt, J=8.4, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 18.5 (t, C5), 25.2 (t, C6), 28.8 (t, C4), 51.2 (t, C1), 55.2 (q, OCH3),
69.4 (t, C7), 72.5 (t, OCH2Ar), 78.6 (s, C3), 85.9 (s, C2), 113.7 (d, 2 x ArCH), 129.2 (d, 2 x
ArCH), 130.5 (s, ArC), 159.0 (s, ArC).
7-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-heptyn-1-ol (211b).101
The alkyne 210b (900 mg, 4.23 mmol) was reacted as
described above. Column chromatography (increasing
polarity from 5 % to 15 % EtOAc in pet. sp. as eluant) gave
the title compound (890 mg, 3.67 mmol, 86.8 %) as a clear oil that had spectral data
identical to that reported in the literature.101
MS (CI+) m/z 243 (76 %) (M+1), HRMS (CI+) found 243.1780, calc for C13H27O2Si
243.1780 (M+1).
δH (300 MHz, CDCl3): 0.02 (6H, s, (CH3)2Si), 0.86 (9H, s, (CH3)3CSi), 1.45-1.65 (4H, m,
H5 and H6), 1.90 (1H, br. s, OH), 2.15-2.25 (2H, m, H4), 3.60 (2H, t, J=6.0 Hz, H7), 4.20
(2H, br.s, H1).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.3 (s, (CH3)3CSi), 18.5 (t, C5), 25.0 (t, C6),
25.9 (q, CH3)3CSi), 31.8 (t, C4), 51.1 (t, C1), 62.6 (t, C7), 78.6, (s, C3), 86.0 (s, C2).
7.2.4 General method for Lindlar hydrogenation of propagylic alcohols. The starting alkyne (2.19 mmol) was dissolved in pet. sp. (150 mL), then quinoline (367
mg, 2.78 mmol) was added dropwise with stirring. Palladium on CaCO3 (40 mg, 10 % Pd)
was then added and the mixture stirred at RT under an atmosphere of H2 for 30 min or until
reaction was complete by tlc, then the flask was flushed with N2. The mixture was filtered
through celite then the solids washed with EtOAc (40 mL). The combined filtrates were
evaporated in vacuo to give an oil. The pure product was obtained by column
chromatography using the stated solvent system.
OHOTBS
1 2 3 4
5
6
7
118
(2Z)-6-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-hexen-1-ol (212a).102
The alkyne 211a (500 mg, 2.19 mmol) was reacted as
described above for 30 min. Column chromatography (9 %
EtOAc in pet. sp. as eluant) gave the title compound (500 mg, 2.17 mmol, 99.0 %) as a
clear oil that had spectral data identical to that reported in the literature.102
MS (CI+) m/z 231 (70 %) (M+1), HRMS (CI+) found 231.1734, calc for C12H27O2Si
231.1780 (M+1).
δH (300 MHz, CDCl3): 0.02 (6H, s, (CH3)2Si), 0.86 (9H, s, (CH3)3CSi), 1.54 (2H, m, H5),
2.14 (2H, m, H4), 2.27 (1H, br. s, OH), 3.59 (2H, t, J=6.3 Hz, H6), 4.12 (2H, dd, J=5.8, 2.1
Hz, H1), 5.42-5.70 (2H, m, H2 and H3).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 23.3 (t, C5), 25.8 (q,
(CH3)3CSi), 32.1 (t, C4), 58.0 (t, C1), 61.9 (t, C6), 129.2, 132.1 (d, C2 and C3).
(2Z)-7-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-2-hepten-1-ol (212b).101
The alkyne 211b (590 mg, 2.43 mmol) was reacted as
described above for 30 min. Column chromatography (9 %
EtOAc in pet. sp. as eluant) gave the title compound (500 mg,
2.05 mmol, 84.2 %) as a clear oil that had spectral data identical to that reported in the
literature.101 A cis:trans ratio of 15:1 was estimated from analysis of the 1H and 13C NMR
spectra.
MS (CI+) m/z 245 (63 %) (M+1), HRMS (CI+) found 245.1938, calc for C13H29O2Si
245.1937 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.25-1.60 (4H, m,
H5 and H6), 1.90 (1H, br. s, OH), 2.00-2.12 (2H, m, H4), 3.59 (2H, t, J=6.3 Hz, H7), 4.17
(2H, d, H1), 5.40-5.65 (2H, m, H2 and H3).
δC (75 MHz, CDCl3): -5.3 (q, (CH3)2Si), 18.3 (s, (CH3)3CSi), 25.8 (t, C5), 25.9 (q,
CH3)3CSi), 27.1 (t, C6), 32.2 (t, C4), 58.4 (t, C1), 62.9 (t, C7), 128.6, 132.6 (d, C2 and C3).
(2Z)-7-[(4-Methoxyphenyl)methoxy]-2-hepten-1-ol (212c).
The alkyne 211e (6.25 g, 25.17 mmol) was reacted as
described above for 70 min, except that EtOAc was used as
OTBSOH 4
5
61
2 3
OTBSOH1
2 3
4
5
6
7
OPMBOH 1
2 3
4
5
6
7
119
the reaction solvent. Column chromatography (increasing polarity from 2 % to 12.5 %
iPrOH in pet. sp. as eluant) gave the title compound (5.985 g, 23.91 mmol, 95.0 %) as a
clear oil.
MS (CI+) m/z 249 (43 %) (M-1), HRMS (CI+) found 249.1497, calc for C15H21O3
249.1491 (M-1).
δH (300 MHz, CDCl3): 1.36-1.48 (2H, m, H5), 1.50-1.64 (2H, m, H6), 2.07 (2H, br. q,
J=7.2 Hz, H4), 2.42 (1H, br. s, OH), 3.42 (2H, t, J=6.3 Hz, H7), 3.78 (3H, s, OCH3), 4.15
(2H, d, J=6.6 Hz, H1), 4.42 (2H, s, OCH2Ar), 5.43-5.66 (2H, m, H2 and H3), 6.87 (2H, dt,
J=8.7, 2.7 Hz, 2 x ArCH), 7.25 (2H, dt, J=8.7, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 26.1, 27.0 (t, C5 and C6), 29.0 (t, C4), 55.1 (q, OCH3), 58.2 (t, C1),
69.7 (t, C7), 72.4 (t, OCH2Ar), 113.6 (d, 2 x ArCH), 129.1 (d, 2 x ArCH), 130.4 (s, ArC),
128.9, 132.1 (d, C2 and C3), 159.0 (s, ArC).
7.2.5 General method for REDAL reduction of propargylic alcohols. The starting alkyne (39.39 mmol) was dissolved in dry THF (150 mL), then REDAL (42.0
mL, 140.3 mmol, 65 % solution in toluene) was added. The mixture was stirred at RT
under N2 for 3.5 h. The reaction was quenched by careful dropwise addition of water, then
diluted with water (250 mL) and extracted with EtOAc (3 x 100 mL). The combined
organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. The
pure product was obtained by column chromatography using the stated solvent system.
(2E)-6-[(4-Methoxyphenyl)methoxy]-2-hexene-1-ol (212e).181
The alkyne 211d (9.23 g, 39.39 mmol) was reacted as described
above. Column chromatography (increasing polarity form 20 %
to 50 % EtOAc in pet. sp. as eluant) gave the title compound
(9.12 g, 38.59 mmol, 98.0 %) as a clear oil that had spectral data identical to that reported
in the literature.181
MS (CI+) m/z 235 (39 %) (M-1), HRMS (CI+), found 235.1330, calc for C14H19O3
235.1334 (M-1).
OPMBOH 12 3
4
5
6
120
δH (300 MHz, CDCl3): 1.68 (2H, app.br.q, J=6.9 Hz, H5), 2.05-2.20 (3H, m, H4 and OH),
3.44 (2H, t, J=6.3 Hz, H6), 3.78 (3H, s, OCH3), 4.03 (2H, s, OCH2Ar), 5.55-5.72 (2H, m,
H2 and H3), 6.87 (2H, dt, J=8.7, 2.7 Hz, ArCH), 7.25 (2H, dt, J=8.7, 2.7 Hz, ArCH).
δC (75 MHz, CDCl3): 28.7 (t, C5), 29.0 (t, C4), 55.1 (q, OCH3), 63.3 (t, C1), 69.2 (t, C6),
72.4 (t, OCH2Ar), 113.6 (d, 2 x ArCH), 129.2 (d, 2 x ArCH), 129.3, 132.0 (d, C2 and C3),
130.4 (s, ArC), 159.0 (s, ArC).
(2E)-7-[(4-Methoxyphenyl)methoxy]-2-hepten-1-ol (212d).184
The alkyne 211e (200 mg, 0.805 mmol) was reacted as
described above except that the reaction time was 5 h.
Column chromatography (increasing polarity from 20 % to 40
% EtOAc in pet. sp. as eluant) gave the title compound (191 mg, 0.763 mmol, 94.8 %) as a
clear oil that had spectral data identical to that reported in the literature.184
MS (CI+) m/z 249 (14 %) (M-1), HRMS (CI+) found 249.1497, calc for C13H18O3
249.1491 (M-1).
δH (300 MHz, CDCl3): 1.46-1.52 (2H, m, H5), 1.54-1.68 (2H, m, H6), 1.98-2.10 (2H, m,
H4), 2.46 (1H, br. s, OH), 3.42 (2H, t, J=6.6 Hz, H7), 3.77 (3H, s, OCH3), 4.01 (2H, d,
J=4.5 Hz, H1), 4.41 (2H, s, OCH2Ar), 5.52-5.70 (2H, m, H2 and H3), 6.86 (2H, dt, J=8.7,
2.7 Hz, 2 x ArCH), 7.24 (2H, dt, J=8.7, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 25.5 (t, C5), 29.0 (t, C6), 31.8 (t, C4), 55.0 (q, OCH3), 63.2 (t, C1),
69.7 (t, C7), 72.3 (t, OCH2Ar), 113.5 (d, 2 x ArCH), 129.1 (d, 2 x ArCH), 129.2, 132.3 (d,
C2 and C3), 130.4 (s, ArC), 158.9 (s, ArC).
7.2.6 General method for m-CPBA epoxidation of allylic alcohols. The starting alkene (1.84 mmol) was dissolved in DCM (50 mL) then m-CPBA (725 mg,
2.94 mmol, 70 % pure, - remainder H2O and m-chlorobenzoic acid) was added. The
mixture was stirred at 0 oC for 6 h then at RT for 18 h, before all solvent was removed in
vacuo. The white solid was dissolved in EtOAc (100 mL), then washed with sat. NaHCO3
solution (3 x 60 mL) and water (60 mL), before it was dried (MgSO4), filtered and
evaporated in vacuo to give an oil. The pure racemic product was obtained by column
chromatography using the stated solvent system.
OPMBOH 1 2 3
45
67
121
7.2.7 General method for Sharpless asymmetric epoxidation of allylic
alcohols. Powdered 4Å molecular sieves (6.4 g) were placed in a 250 mL flask with a magnetic
stirrer. The flask was heated with a 1400 W heat gun under vacuum for 10 min, then sealed
and flushed with nitrogen. It was then charged with DCM (195 mL) and cooled to –40 oC
(CH3CN/CO2(s)). D-(-)-diisopropyl tartrate (2.61 g, 11.14 mmol), Ti(iPrO)4 (3.19 g, 11.22
mmol) and tert-butylhydroperoxide (22.1 mL, 110.5 mmol, 5M solution in decane) were
added via syringe. The mixture was stirred at –40 oC for 40 min, then the starting alkene
(38.416 mmol) dissolved in DCM (20 mL) was added via cannula. The mixture was stirred
at –40 oC for 2 h, then left to stand at –20 oC for 20 h. The reaction was quenched with 10
% aqueous tartaric acid solution (200 mL), then extracted with DCM (3 x 100 mL). The
combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give
an oil. The pure enatiomerically enriched product was obtained by column
chromatography using the stated solvent system.
(2R,3S)-rel-3-[4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]butyl]-oxiranemethanol
(213b).101
Racemic 213b:
The allylic alcohol 212b (500 mg, 2.05 mmol) was reacted as
described above. Column chromatography (20 % EtOAc in pet.
sp. as eluant) gave the title compound (500 mg, 1.92 mmol, 93.6 %) as a clear oil that had
spectral data identical to that reported in the literature.101
MS (CI+) m/z 261 (89 %) (M+1), HRMS (CI+) found 261.1861, calc for C13H29O3Si
261.1886 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.40-1.65 (6H, m,
H1' H2' and H3'), 2.23 (1H, br. s, OH), 2.95-3.05 (1H, m, H3), 3.10-3.20 (1H, m, H2), 3.55-
3.70 (3H, m, H4a and H4'), 3.83 (1H, dd, J=12.3, 3.9 Hz, H4b).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 22.9 (t, C2'), 25.8 (q,
(CH3)3CSi), 27.6, 32.3 (t, C1' and C3'), 56.9, 57.1 (d, C2 and C3), 60.7 (t, C4'), 62.7 (t, C4).
O
OH OTBS
4'
4
2'
3'
1
2 31'
122
(5R,4S)-4,5-Anhydro-2,3-dideoxy-1-O-[(1,1-dimethylethyl)dimethylsilyl]-D-erythro-
hexitol (213a).102
Racemic 213a:
The allylic alcohol 212a (425 mg, 1.84 mmol) was reacted as
described above. Column chromatography (20 % EtOAc in pet. sp.
as eluant) gave the title compound (330 mg, 1.34 mmol, 72.8 %) as a clear oil that had
spectral data identical to that reported in the literature.102
Asymmetric (-)-213a:
The allylic alcohol 212a (8.85 g, 38.416 mmol) was reacted as described above except that
the crude product was treated with 2M NaOH (100 mL) to remove diisopropyl tartarate.
Column chromatography (increasing polarity from 20 % to 40 % EtOAc in pet. sp. as
eluant) gave the title compound (7.47 g, 30.31 mmol, 78.9 %) as a clear oil that had spectral
data identical to that reported in the literature for the racemate.102
[α]D22: -7 (c 1.03, CHCl3).
MS (CI+) m/z 247 (64 %) (M+1), HRMS (CI+) found 247.1716, calc for C12H27O3Si
247.1729 (M+1).
δH (300 MHz, CDCl3): 0.01 (6H, s, (CH3)2Si), 0.84 (9H, s, (CH3)3CSi), 1.50-1.75 (4H, m,
H2 and H3), 2.94-3.02 (1H, m, H4), 3.12 (1H, td, J=6.0, 4.2 Hz, H5), 3.34 (1H, br. s, OH),
3.56-3.66 (2H, m, H1), 3.68 (2H, d, J=5.7 Hz, H6).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.6 (s, (CH3)3CSi), 23.7 (t, C2), 25.8 (q,
(CH3)3CSi), 29.4 (t, C3), 56.7, 56.8 (d, C4 and C5), 60.3 (t, C6), 62.2 (t, C1).
(2R,3S)-3-[4-[(4-Methoxyphenyl)methoxy]butyl]-oxiranemethanol (213c).
Racemic 213c:
The allylic alcohol 212c (5.93 g, 23.69 mmol) was reacted as
described above. Column chromotography (increasing polarity
from 30 % to 70 % EtOAc in pet. sp. as eluant) gave the title compound (4.296 g, 16.13
mmol, 68.1 %) as a clear oil.
O
OHOTBS45
6 1
2
3
O
OH OPMB
4'
4
2'
3'
1
2 31'
123
Asymmetric (+)-213c:
The allylic alcohol 212c (7.415 g, 29.620 mmol) was reacted as described above. Column
chromatography (increasing polarity from 40 % to 100 % EtOAc in pet. sp. as eluant) gave
the title compound (5.790 g, 21.739 mmol, 73.4) as a clear oil.
[α]D23: +5 (c 1.0, CHCl3).
MS (CI+) m/z 265 (16 %) (M-1), HRMS (CI+) found 265.1442, calc for C15H21O4
265.1440 (M-1).
δH (300 MHz, CDCl3): 1.50-1.70 (6H, m, H1', H2' and H3'), 2.68 (1H, br. s, OH), 3.01
(1H, m, H3), 3.13 (1H, dt, J=6.6, 4.5 Hz, H2), 3.45 (2H, t, J=6.3 Hz, H4'), 3.63 (1H, dd,
J=12.0, 6.6 Hz, H4a), 3.78 (1H, dd, J=12.0, 4.5 Hz, H4b), 3.79 (3H, s, OCH3), 4.43 (2H, s,
OCH2Ar), 6.87 (2H, dt, J=9.0, 2.7 Hz, 2 x ArCH), 7.26 (2H, dt, J=9.0, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 23.3 (t, C2'), 27.5, 29.2 (t, C1' and C3'), 55.1 (q, OCH3), 56.8, 57.0
(d, C2 and C3), 60.6 (t, C4), 69.6 (t, C4'), 72.5 (t, OCH2Ar), 113.6 (d, 2 x ArCH), 129.2 (d,
2 x ArCH), 130.3 (s, ArC), 159.0 (s, ArC).
(4R,5R)-Anhydro-2,3-dideoxy-1-O-[(4-methoxyphenyl)methyl]-D-threo-hexitol (213e).
Racemic 213e:
The allylic alcohol 212e (155 mg, 0.656 mmol) was reacted as
described above. Column chromatography (increasing polarity
from 40 % to 60 % EtOAc in pet. sp. as eluant) gave the title compound (100 mg, 0.396
mm, 60.4 %) as a clear oil.
Asymmetric (+)-213e:
The allylic alcohol 212e (6.91 g, 29.24 mmol) was treated as described above except that
the reaction time was 1 h to limit the formation of a by-product. Column chromatography
(increasing polarity from 40 % to 100 % EtOAc in pet. sp. as eluant) gave the title
compound (3.82 g, 15.14 mmol, 51.8 %) and recovered starting material (1.50 g, 6.35
mmol, 21.7 %) as clear oils.
[α]D29: +21 (c 2.2, CHCl3).
MS (ES+) m/z 253.1 (6 %) (M+1), (CI+) m/z 251 (M-1) (5 %), HRMS (CI+) found
251.1256, calc for C14H19O4 251.1283 (M-1).
O
OHOPMB
1
2
3
45
6
124
δH (300 MHz, CDCl3): 1.00-1.80 (5H, m, H2, H3 and OH), 2.89 (1H, td, J=8.4, 4.8 Hz,
H5), 2.92-3.00 (1H, m, H4), 3.47 (2H, t, J=6.3 Hz, H1), 3.54 (1H, dd, J=12.6, 4.8 Hz, H6a),
3.77 (3H, s, OCH3), 3.81 (1H, dd, J=12.6 and 3.0 Hz, H6b), 4.41 (2H, s, OCH2Ar), 6.86
(2H, dt, J=8.7, 2.7 Hz, 2 x ArCH), 7.24 (2H, dt, J=8.7, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 25.9, 28.2 (t, C2 and C3), 55.1 (q, OCH3), 55.7 (d, C4), 58.5 (d, C5),
61.6 (t, C6), 69.1 (t, C1), 72.4 (t, OCH2Ar), 113.6 (d, 2 x ArCH), 129.6 (d, 2 x ArCH),
130.2 (s, ArC), 159.0 (s, ArC).
7.2.8 Methods for oxidation of alcohols to aldehydes. Method A: TPAP and NMO oxidation of alcohols to aldehydes.
The starting alcohol (2.14 mmol) was dissolved in DCM (7 mL) then activated powdered
4Å molecular sieves (850 mg) and N-methylmorpholine-N-oxide (336 mg, 2.78 mmol)
were added. The mixture was cooled to 0 oC then TPAP (42 mg, 0.161 mmol) was added.
The mixture was stirred at RT for 30 min then applied directly to a short (5cm long, 5 cm
diameter) silica gel column. Elution with EtOAc (250 mL) followed by evaporation of the
eluant in vacuo gave the aldehyde.
Method B: Swern oxidation of alcohols to aldehydes. Oxalyl chloride (2.22 mL, 24.11 mmol) was dissolved in dry DCM (33 mL) and the
solution cooled to -60 oC (CHCl3/CO2(s)). Dimethylsulfoxide (3.71 mL, 52.6 mmol) was
added slowly over 5 min, then stirring was continued for 5 min, before the starting alcohol
(10.96 mmol) dissolved in DCM (18 mL) was added via cannula. The mixture was stirred
at -60 oC for 1 h, then triethylamine (7.77 mL, 55.00 mmol) was added and a solid mass
formed. The reaction was warmed to RT then diluted with dichloromethane (100 mL) and
washed with water (100 mL) and sat. NaCl solution (100 mL). The organic portion was
concentrated to 50 mL in vacuo then washed with 1M HCl (100 mL), 5 % sodium
carbonate solution (100 mL) and water (100 mL) before it was dried (MgSO4), filtered and
evaporated in vacuo to give the crude aldehyde.
125
(2S,3S)-Anhydro-4,5-dideoxy-6-O-[(1,1-dimethylethyl)dimethylsilyl]-L-erytho-hexose
(214a).102
Method A
The epoxy alcohol 213a (200 mg, 0.812 mmol) was reacted with
TPAP as described above giving the unstable title compound (170
mg, 0.696 mmol 85.7 %) as a pale grey oil which was not purified any further and had
spectral data identical to that reported in the literature for the racemate.102
Method B
The epoxy alcohol 213a (2.70 g, 10.96 mmol) was reacted according to the Swern
oxidation described above to give the crude, unstable title compound (2.75 g, ~95% pure
10.69 mmol, 97.5 %) as a colourless pungent oil which was not purified any further and
had spectral data identical to that reported in the literature for the racemate.102
MS (CI+) m/z 245 (100 %) (M+1), HRMS (CI+) found 245.1588, calc for C12H25O3Si
245.1573 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.55-1.90 (4H, m,
H4 and H5), 3.25-3.40 (2H, m, H2 and H3), 3.60-3.70 (2H, m, H6), 9.45 (1H, d, J=5.4 Hz,
H1).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 24.8 (t, C5), 25.8 (q,
(CH3)3CSi), 29.6 (t, C4), 57.9, 59.0 (d, C2 and C3), 62.0 (t, C6), 199.0 (d, C1).
(2S,3S)-3-[4-[[(4-Methoxyphenyl)methyl]oxy]butyl]-oxiranecarboxaldehyde (214c).
Method A
The epoxy alcohol 213c (1.13 g, 4.24 mmol) was reacted with
TPAP as described above giving the unstable title compound (830
mg, 3.140 mmol, 74.1 %) as a pale grey oil that was not purified any further.
Method B
The epoxy alcohol 213c (3.30 g, 13.18 mmol) was reacted according to the Swern
oxidation described above to give the crude unstable title compound (3.166 g, 11.98 mmol,
90.9 %) as a pungent yellow oil that was not purified any further.
[α]D26: -35 (c 1.0, CHCl3).
O
OOTBS
4
5
6
1 2 3
O
O OPMB
4'
4
2'
3'
1
2 31'
126
MS (CI+) m/z 263 (76 %) (M-1), HRMS (ES+) found 265.1445, calc for C15H21O4
265.1440 (M+1).
δH (300 MHz, CDCl3): 1.45-1.80 (6H, m, H1', H2' and H3'), 3.16-3.26 (1H, dt, J=6.9, 5.1
Hz, H3), 3.31 (1H, t, J=5.1 Hz, H2), 3.43 (2H, t, J=5.7 Hz, H4'), 3.78 (3H, s, OCH3), 4.40
(2H, s, OCH2Ar), 6.85 (2H, d, J=9.0 Hz, 2 x ArCH), 7.23 (2H, d, J=9.0 Hz, 2 x ArCH),
9.41 (1H, d, J=5.1 Hz, H4).
δC (75 MHz, CDCl3): 23.4 (t, C2'), 27.8, 29.2 (t, C1' and C3'), 55.1 (q, OCH3), 57.7, 58.9
(d, C2 and C3), 69.3 (t, C4'), 72.5 (t, OCH2Ar), 113.6 (d, ArCH), 129.0 (d, ArCH), 130.3
(s, ArCH), 158.9 (s, ArCH), 198.7 (s, C4).
(2S,3R)-Anhydro-4,5-dideoxy-6-O-[(4-methoxyphenyl)methyl]-D-threo-hexose (214e).
Method A
The epoxy alcohol 213e (540 mg, 2.14 mmol) reacted with TPAP
as described above giving the unstable title compound (500 mg,
1.998 mmol, 93.3 %) as a pale grey oil.
Method B
The epoxy alcohol 213e (4.48 g, 17.76 mmol) was reacted according to the Swern
oxidation described above to give the crude, unstable title compound (4.40 g, 95 % pure,
4.18 g, aldehyde, 16.7 mmol, 94.0 %) as a pungent yellow oil, that was not purified any
further.
δH (300 MHz, CDCl3): 1.60-1.90 (4H, m, H4 and H5), 3.13 (1H, dd, J=6.3, 1.8 Hz, H2),
3.25 (1H, m, H3), 3.40-3.55 (2H, m, H6), 3.80 (3H, s, OCH3), 4.43 (2H, s, OCH2Ar), 6.88
(2H, d, J=8.7 Hz, 2 x ArCH), 7.24 (2H, d, J=8.7 Hz, 2 x ArCH), 8.99 (1H, d, J=6.3 Hz,
H1).
δC (75 MHz, CDCl3): 26.0, 28.3 (t, C4 and C5), 55.3 (q, OCH3) 56.6, 59.2 (d, C2 and C3),
68.9 (t, C6), 72.6 (t, OCH2Ar), 113.7 (d, 2 x ArCH), 129.2 (d, 2 x ArCH), 130.2 (s, ArC),
159.0 (s, ArC), 198.1 (d, C1).
5-[(4-Methoxyphenyl)methoxy]-pentanal (288).184
The alcohol 337 (269 mg, 1.20 mmol) was reacted according to the
Swern oxidation described above. Column chromatography
O
OOPMB
1
2 3
4
5
6
O OPMB
12
34
5
127
(increasing polarity from 15 % to 30 % EtOAc in pet. sp. as eluant) gave the title
compound (240 mg, 1.080 mmol, 90.0 %) as a clear oil that had spectral data identical to
that reported in the literature.184
MS (CI+) m/z 221 (20 %) (M-1), HRMS (EI+) found 222.1242, calc for C13H18O3
222.1256 (M).
δH (300 MHz, CDCl3): 1.56 (4H, m, H3 and H4), 2.42 (2H, td, J=7.2, 1.8 Hz, H2), 3.44
(2H, t, J=6.0 Hz, H5), 3.77 (3H, s, OCH3), 4.40 (2H, s, OCH2Ar), 6.86 (2H, dt, J=8.7, 2.1
Hz, 2 x ArCH), 7.24 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH), 9.72 (1H, t, J=1.8 Hz, H1).
δC (75 MHz, CDCl3): 18.9 (t, C3), 29.0 (t, C4), 43.4 (t, C2), 55.1 (q, OCH3), 69.2 (t, C5),
72.4 (t, OCH2Ar), 113.5 (d, 2 x ArCH), 128.9 (d, 2 x ArCH), 130.3 (s, ArC), 158.8 (s,
ArC), 202.0 (d, C1).
7.2.9 General method for Wittig olefination. Methyltriphenylphosphonium bromide (2.84 g, 7.98 mmol) was placed in a dry 50 mL
flask with a magnetic stirrer, then the flask was sealed and flushed with nitrogen. Dry THF
(8 mL) was added and the suspension was cooled to –10 oC. KHMDS solution (14.4 mL,
7.2 mmol, 0.5 mol L-1 in toluene) was added over a period of 5 min, then the mixture was
stirred for 10 min, before the addition of the starting aldehyde (2.66 mmol) in dry THF (7
mL) via cannula. The mixture was stirred at 0 oC for 1 h then at RT for 30 min, before it
was poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined
organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. The
pure product was obtained by column chromatography using the stated solvent system.
(1,1-Dimethylethyl)dimethyl[3-[(2S,3R)-3-ethenyloxiranyl]propyloxy]-silane (208a).102
The crude aldehyde 214a (650 mg, 2.66 mmol) was reacted as
described above. Column chromatography (2 % EtOAc in pet. sp.
as eluant) gave the title compound (530 mg, 2.19 mmol, 82.2 %) as a
clear oil that had spectral data identical to that reported in the literature.102
Alternative method: dIpcBOMe (624 mg, 1.98 mmol) was placed in a dry 50 mL RBF with a magnetic stirrer,
then the flask flushed with N2. Dry THF (9 mL), then allyl chloride (1.98 mg, 2.58 mmol)
OOTBS
3'2'' 1
2
31''
1'
2'
128
were added and the mixture cooled to -95 oC (toluene-N2(l)). In a separate flask, was
placed dicyclohexylamine (467 mg, 2.58 mmol) under N2. THF (9 mL) then n-butyllithium
(2.0 mL, 2.58 mmol, ~1.3 mol L-1) were added. After brief stirring at RT this mixture was
transferred to the first RBF via cannula. The mixture was stirred at -95oC for 30 min, then
BF3.OEt2 (730 mg, 5.16 mmol), and finally aldehyde 207 (400 mg, 1.98 mmol) dissolved in
THF (3 mL) were added. The mixture was stirred at -95 oC for 4 h, then allowed to warm
to R.T. All volatiles were removed in vacuo, then the semi-solid was triturated with pet. sp.
(40 mL). The supernatant was decanted, then the solid treated further with pet. sp. (2 x 40
mL). The combined supernatants were evaporated in vacuo to give a colourless oil. This
was dissolved in THF (20 mL), then NaOH (384 mg, 9.60 mmol) dissolved in water (3.2
mL) and H2O2 (2.0 mL, 30 % w/w solution in H2O) were added. The mixture was stirred at
R.T. for 16 h, then diluted with water (80 mL) and extracted with EtOAc (3 x 70 mL). The
combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give a
clear oil. The pure product was obtained by column chromatography (increasing polarity
from 1.5 % to 4 % EtOAc in pet. sp. as eluant), which gave the title compound (140 mg,
0.577 mmol, 29.2 %) as a clear oil that had spectral data identical to that reported in the
literature for the racemate.102
[α]D23: -12 (c 1.05, CHCl3).
MS (CI+) m/z 243 (19 %) (M+1), HRMS (CI+) found 243.1775, calc for C13H27O2Si
243.1780 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.50-1.65 (4H, H2
and H3), 3.05-3.15 (1H, m, H2'), 3.39 (1H, ddt, J=7.2, 4.2, 0.8 Hz, H3'), 3.56-3.70 (2H, m,
H1), 5.34 (1H, ddd, J=10.5, 1.8, 0.8 Hz, H2''a), 5.46 (1H, ddd, J=17.1, 1.8, 0.8 Hz, H2''b),
5.71 (1H, ddd, J=17.1, 10.5, 7.2 Hz, H1'').
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 24.4 (t, C2), 25.9 (q,
(CH3)3CSi), 29.4 (t, C3), 57.2, 58.5 (d, C2' and C3'), 62.5 (t, C1), 120.4 (t, C2''), 132.5 (d,
C1'').
(2R,3S)-2-Ethenyl-3-[4-[(4-methoxyphenyl)methoxy]butyl]-oxirane (208c).
The crude aldehyde 214c (6.18 g, 93 %, 5.75 g aldehyde, 21.739
mmol) was reacted as described above. Column chromatography
O
OPMB
4''
3''1''
2''1
2 3
1'2'
129
(increasing polarity from 10 % to 25 % EtOAc in pet. sp. as eluant) gave the title
compound (4.944 g, 18.845 mmol, 86.7 %) as a clear oil.
[α]D25: -8 (c 1.0, CHCl3).
MS (CI+) m/z 261 (76 %) (M-1), HRMS (EI+), found 262.1554, calc for C16H21O3
262.1569 (M).
δH (300 MHz, CDCl3): 1.44-1.70 (6H, m, H1'', H2'' and H3''), 3.03-3.10 (1H, m, H3), 3.39
(1H, ddt, J=7.2, 4.5, 0.9 Hz, H2), 3.44 (2H, t, J=6.0 Hz, H4''), 3.79 (3H, s, OCH3), 4.42
(2H, s, OCH2Ar), 5.33 (1H, ddd, J=10.5, 1.8, 0.9 Hz, H2'a), 5.46 (1H, ddd, J=17.1, 1.8, 0.9
Hz, H2'b), 5.70 (1H, ddd, J=17.1, 10.5, 7.2 Hz, H1'), 6.87 (2H, dt, J=8.7, 2.7 Hz, 2 x
ArCH), 7.25 (2H, dt, J=8.7, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 23.0 (t, C2''), 27.4, 29.4 (t, C1'' and C3''), 55.2 (q, OCH3), 57.1, 58.5
(d, C2 and C3), 69.7 (t, C4''), 72.5 (t, OCH2Ar), 113.6 (d, 2 x ArCH), 120.3 (t, C2'), 129.1
(d, 2 x ArCH), 130.5 (s, ArC), 132.5 (d, C1'), 159.0 (s, ArC).
(2R,3R)-2-Ethenyl-3-[3-[(4-methoxyphenyl)methoxy]propyl]-oxirane (208e).
The crude aldehyde 214e (4.844 g, 19.351 mmol) was reacted as
described above. Column chromatography (increasing polarity
from 5 % to 25 % EtOAc in pet.sp. as eluant) gave the title
compound (3.505 g, 14.11 mmol, 69.3 %) as a clear oil.
[α]D27: + 15 (c 2.0, CHCl3).
MS (CI+) m/z 247 (49 %) (M-1), HRMS (CI+) found 247.1374, calc for C15H19O3
247.1334 (M-1).
δH (300 MHz, CDCl3): 1.55-1.90 (4H, m, H1'' and H2''), 2.70-2.90 (1H, m, H3), 3.09 (1H,
dd, J=7.2, 2.1 Hz, H2), 3.40-3.60 (2H, m, H3''), 3.80 (3H, s, OCH3), 4.43 (2H, s, OCH2Ar),
5.25 (1H, ddd, J=9.6, 1.2, 0.6 Hz, H2'a), 5.43 (1H, ddd, J=17.1, 1.2, 0.6 Hz, H2'b), 5.56
(1H, ddd, J=17.1, 9.6, 7.2 Hz, H1'), 6.88 (2H, dt, J=9.0, 3.0 Hz, 2 x ArCH), 7.25 (2H, dt,
J=9.0, 3.0 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 26.0, 28.7 (t, C1'' and C2''), 55.2 (q, OCH3), 58.7 (d, C3), 60.1 (d,
C2), 69.3 (t, C3''), 72.5 (t, OCH2Ar), 113.7 (d, 2 x ArCH), 119.0 (t, C2'), 129.2 (d, 2 x
ArCH), 130.5 (s, ArC), 135.7 (s, C1'), 159.1 (s, ArC).
OOPMB
3''
1
2 3
1' 1''
2''
2'
130
7.2.10 General methods for aminolysis of vinyl epoxides. Method A:
The starting vinyl epoxide (1.61 mmol) was dissolved in allylamine (2.02 g, 35.3 mmol)
then para-toluenesulfonic acid monohydrate (90 mg, 0.43 mmol) was added. The mixture
was heated at 110 oC in a sealed tube for 4d, then cooled. All volatiles were removed in
vacuo to give a semi-solid. The pure product was obtained by column chromatography
with the stated solvent system.
Method B:
The starting vinyl epoxide (0.825 mmol) was dissolved in CH3CN (2 mL), then allylamine
(250 mg, 4.379 mmol) and LiOTf (130 mg, 0.833 mmol) were added. The mixture was
placed in a teflon tube with a 100 bar pressure cap, then heated in a microwave at 120 oC
for 1h. After cooling all volatiles were removed in vacuo to give an oil. The pure product
was obtained by column chromatography with the stated solvent system.
(3S,4S)-7-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-(2-propenylamino)-1-hepten-4-ol
(216).
The vinyl epoxide 208a was treated using Method A as
described above. Column chromatography (increasing polarity
from 5 % to 15 % MeOH in DCM as eluant) gave the title
compound (440 mg, 1.469 mmol, 91.2 %) as a colourless oil.
The vinyl epoxide 208a (200 mg, 0.825 mmol) was treated using Method B as described
above. Column chromatography (increasing polarity from 5 % to 15 % MeOH in DCM as
eluant) gave the title compound (245 mg, 0.818 mmol, 99.1 %) as a colourless oil.
[α]D22: -4 (c 1.14, CHCl3).
MS (CI+) m/z 300 (100 %) (M+1), HRMS (ES+) found 300.2333, calc for C16H34NO2Si
300.2539 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.20-1.50 (4H, m,
H5 and H6), 2.77 (2H, br.s NH and OH), 2.85 (1H, t, J=8.7 Hz, H3), 3.08 (1H, ddt, J=13.8,
6.6, 1.2 Hz, H1'a), 3.30-3.40 (2H, m, H4 and H1'b), 3.62 (2H, m, H7), 5.06-5.26 (4H, m,
H1 and H3'), 5.52 (1H, ddd, J=17.1, 10.2, 8.7 Hz, H2), 5.86 (1H, dddd, J=17.1, 10.2, 6.6,
5.7 Hz, H2').
NH
OTBSOHH
H4
5
6
1
23
7
1'2'
3'
131
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.3 (s, (CH3)3CSi), 25.9 (q, (CH3)3CSi), 28.8,
30.5 (t, C5 and C6), 49.2 (t, C1'), 63.3 (t, C7), 66.5, 72.3 (d, C3 and C4), 116.7, 119.1 (t,
C1 and C3'), 135.8, 136.5 (d, C2 and C2').
(3S,4S)-8-[(4-Methoxyphenyl)methoxy]-3-(2-propenylamino)-1-octen-4-ol (224).
The vinyl epoxide 208c (250 mg, 0.953 mmol) was reacted
using Method A as described above. Column
chromatography (increasing polarity from 5 % to 15 %
MeOH in DCM as eluant) gave the title compound (265 mg,
0.830 mmol, 87.0 %) as a clear oil.
The vinyl epoxide 208c (500 mg, 1.906 mmol) was reacted using Method B as described
above. Column chromatography (increasing polarity from 5 % to 15 % MeOH in DCM as
eluant) gave the title compound (591 mg, 1.850 mmol, 97.1 %) as a pale yellow oil.
[α]D29: -7 (c 1.3, CHCl3).
MS (CI+) m/z 320 (100 %) (M+1), HRMS (CI+) found 320.2238, calc for C19H30NO3
320.2226 (M+1).
δH (300 MHz, CDCl3): 1.20-1.70 (6H, m, H5, H6 and H7), 2.43 (2H, br.s, NH and OH),
2.77 (1H, t, J=8.7 Hz, H3), 3.07 (1H, ddt, J=13.8. 6.3, 1.2 Hz, H1'a), 3.20-3.50 (5H, m, H4,
H8, H1'b), 3.80 (3H, s, OCH3), 4.42 (2H, s, OCH2Ar), 5.05-5.30 (4H, m, H1 and H3'), 5.49
(1H, ddd, J=16.8, 10.2, 8.4 Hz, H2), 5.87 (1H, m, H2'), 6.87 (2H, dt, J=9.0, 2.7 Hz, 2 x
ArCH), 7.25 (2H, dt, J=9.0, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 22.3 (t, C6), 29.7, 33.4 (t, C5 and C7), 49.2 (t, C1'), 55.2 (q, OCH3),
66.4 (d, C3), 70.0 (t, C8), 72.5 (t, OCH2Ar), 72.6 (d, C4), 113.7 (d, 2 x ArCH), 116.2,
118.5 (t, C1 and C3'), 129.2 (d, 2 x ArCH), 130.6 (s, ArC), 136.4, 136.8 (d, C2 and C2'),
159.0 (s, ArC).
(3S,4R)-7-[(4-Methoxyphenyl)methoxy]-3-(2-propenylamino)-1-hepten-4-ol (229).
The vinyl epoxide 208e (415 mg, 1.671 mmol) was reacted
according to Method A as described above. Column
chromatography (increasing polarity from 5 % to 10 % MeOH
in DCM as eluant) gave the title compound (450 mg, 1.473
NH OHH
H
OPMB
3'
45
6
12
37
81'2'
NH
OPMBOHH
H4
5
6
1
23
7
1'2'
3'
132
mmol, 88.2 %) as a clear oil.
[α]D28: +10 (c 1.9, CHCl3).
MS (CI+) m/z 306 (71 %) (M+1), HRMS (CI+) found 306.2066, calc for C18H27NO3
306.2069 (M+1).
δH (300 MHz, CDCl3): 1.35-1.86 (5H, m, H5, H6, and NH), 2.30 (1H, v.br.s, OH), 3.07
(1H, dd, J=8.4, 3.3 Hz, H3), 3.14 (1H, ddd, J=14.1, 6.0, 1.2 Hz, H1'a), 3.28 (1H, ddd,
J=14.1, 6.0,1.2 Hz, H1'b), 3.47 (2H, t, J=6.0 Hz, H7), 3.63 (1H, dt, J=9.3, 3.3 Hz, H4), 3.80
(3H, s, OCH3), 4.43 (2H, s, OCH2Ar), 5.05-5.30 (4H, m, H1 and H3'), 5.71 (1H, ddd,
J=17.4, 10.5, 8.7 Hz, H2), 5.88 (1H, ddt, J=17.1, 10.2, 6.0 Hz, H2'), 6.87 (2H, dt, J=8.4, 3.0
Hz, 2 x ArCH), 7.25 (2H, dt, J=8.4, 3.0 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 26.4 (t, C6), 30.1 (t, C5), 49.5 (t, C1'), 55.2 (q, OCH3), 65.1 (d, C3),
70.0 (t, C7), 72.1 (d, C4), 72.5 (t, OCH2Ar), 113.7 (d, 2 x ArCH), 116.0, 118.3 (t, C1 and
C3'), 129.3 (d, 2 x ArCH), 130.3 (s, ArC), 136.0, 136.6 (d, C2 and C2'), 159.1 (s, ArC).
(3S,4S)-3-Amino-8-[(4-methoxyphenyl)methoxy]-1-octen-4-ol (280).
The vinyl epoxide 208c (105 mg, 0.400 mmol) was suspended
in conc. NH3 solution (11 mL, 28 %). The mixture was placed
in a teflon tube with a 100 bar pressure cap, then heated in a
microwave reactor at 110 oC for 20 min. After cooling, the
mixture was diluted with water (10 mL) and extracted with DCM (3 x 20 mL). The
combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give the
title compound (110 mg, 0.394 mmol, 98.1 %) as a soft white solid. Longer reaction times
were required on scale up (e.g. 500 mg requires 60-90 min heating).
m.p. 38-42 oC (Et2O).
[α]D26: +9 (c 1.36, CHCl3).
MS (CI+) m/z 280 (80 %) (M+1), HRMS (CI+) found 280.1905, calc for C16H26NO3
280.1913 (M+1).
δH (300 MHz, CDCl3): 1.10-1.70 (6H, m, H5, H6 and H7), 2.76 (3H, br.s, NH2 and OH),
3.09 (1H, t, J=7.2 Hz, H3), 3.27 (1H, t, J=6.3 Hz, H4), 3.42 (2H, t, J=6.0 Hz, H8), 3.77
(3H, s, OCH3), 4.40 (2H, s, OCH2Ar), 5.09 (1H, d, J=10.2 Hz, H1a), 5.16 (1H, d, J=17.1
NH2 HH
OPMB
OH
45
6
1
23
7
8
133
Hz, H1b), 5.77 (1H, ddd, J=17.1, 10.2, 7.2, H2), 6.84 (2H, d, J=8.7 Hz, 2 x ArCH), 7.23
(2H, d, J=8.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 22.5 (t, C6), 29.7, 33.4 (t, C5 and C7), 55.1 (q, OCH3), 59.2 (d, C3),
69.9 (t, C8), 72.4 (t, OCH2Ar), 73.7 (d, C4), 113.5 (d, 2 x ArCH), 115.5 (t, C1), 129.0 (d, 2
x ArCH), 130.5 (s, ArC), 139.0 (d, C2), 158.9 (s, ArC).
(3S,4S)-7-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[bis(2-propenyl)-amino]-1-hepten-
4-ol (301).
The vinyl epoxide 208a (100 mg, 0.412 mmol) was dissolved
in CH3CN (1 mL), then diallylamine (167 mg, 1.648 mmol)
and LiOTf (100 mg, 0.618 mmol) were added. The mixture
was heated in a sealed tube at 140 oC for 2 d then cooled. The
mixture was applied directly to a silica gel column, and eluted
(increasing polarity from 2.0 % to 10 % MeOH in DCM) to give the title compound (135
mg, 0.398 mmol, 96.4 %) as a clear oil.
[α]D22: -29 (c 1.35 CHCl3).
MS (CI+) m/z 340 (100 %) (M+1), HRMS (CI+) found 340.2668, calc for C19H37NO2Si
340.2672 (M+1).
δH (300 MHz, CDCl3): 0.02 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.12-1.26 (1H, m,
H5a), 1.52-1.65 (2H, m, H5b and H6a), 1.65-1.82 (1H, m, H6b), 2.79 (2H, d, J=14.1, 8.4
Hz, H1'a), 2.92 (1H, t, J=9.9 Hz, H3), 3.33 (2H, ddt, J=14.1, 4.2, 1.8 Hz, H1'b), 3.50 (1H,
td, J=9.9, 2.1 Hz, H4), 3.55-3.70 (2H, m, H7), 5.07-5.20 (5H, m, H1a and H3'), 5.33 (1H,
dd, J=10.2, 2.1 Hz, H1b), 5.55 (1H, dt, J=17.1, 9.9 Hz, H2), 5.76 (2H, dddd, J=16.8, 10.2,
8.4, 4.5 Hz, H2').
δC (75 MHz, CDCl3): -5.3 (q, (CH3)2Si), 18.3 (s, (CH3)3CSi), 25.9 (q, (CH3)3CSi), 29.1,
30.1 (t, C5 and C6), 52.5 (t, C1'), 63.1 (t, C7), 67.7, 68.2 (d, C3 and C4), 117.5 (t, C3'),
121.4 (t, C1), 131.9 (d, C2), 136.2 (d, C2').
(3S,4S)-8-[(4-Methoxyphenyl)methoxy]-3-[(phenylmethyl)amino]-1-octen-4-ol (302).
The vinyl epoxide 208c (100 mg, 0.381 mmol) was reacted
using Method B as described above except that benzylamine
NOTBS
OHHH
1'2'
3'
45
6
1
23
7
1'
2'
3'
NH OHH
H
OPMB
Bn4
5
6
1
23
7
8
134
was used in place of allylamine. Column chromatography (increasing polarity from 4 % to
11 % MeOH in DCM as eluant) gave the title compound (140 mg, 0.379 mmol, 99.4 %) as
a clear oil.
[α]D27: -2 (c 1.40, CHCl3).
MS (CI+) m/z 370 (90 %) (M+1), HRMS (CI+) found 370.237718, calc for C23H32NO3
370.238219 (M+1).
δH (300 MHz, CDCl3): 1.26-1.70 (6H, m, H5, H6 and H7), 2.60 (2H, br. s, OH and NH),
2.80 (1H, t, J=8.7 Hz, H3), 3.31 (1H, td, J=8.7, 2.1 Hz, H4), 3.45 (2H, t, J=5.7 Hz, H8),
3.60 (1H, d, J=13.2 Hz, NCH2Ph), 3.79 (3H, s, OCH3), 3.88 (1H, d, J=13.2 Hz, NCH2Ph),
4.43 (2H, s, OCH2Ar), 5.18 (1H, dd, J=17.1, 1.8 Hz, H1a), 5.28 (1H, dd, J=10.2, 1.8 Hz,
H1b), 5.55 (1H, ddd, J=17.1, 10.5, 8.7 Hz, H2), 6.88 (2H, dt, J=8.7, 3.0 Hz, 2 x ArCH),
7.22-7.36 (7H, m, 2 x ArCH and NCH2Ph).
δC (75 MHz, CDCl3): 22.2 (t, C6), 29.6, 33.3 (t, C5 and C7), 50.6 (t, NCH2Ph), 55.1 (q,
OCH3), 66.4 (d, C3), 70.0 (t, C8), 72.4 (t, OCH2Ar), 72.7 (d, C4), 113.6 (d, 2 x ArCH),
118.5 (t, C1), 127.0, 128.2, 128.3 (d, 5 x PhCH), 129.1 (d, 2 x ArCH), 130.6 (s, ArC),
136.9 (d, C2), 139.8 (s, PhC), 159.0 (s, ArCH).
7.2.11 General method for N-Boc protection of amines. The starting amine (3.503 mmol) was dissolved in dry THF (35 mL) then triethylamine
(587 mg, 6.12 mmol) and di-tert-butyldicarbonate (1.274 mg, 6.12 mmol) were added. The
mixture was stirred at RT for 24 h then all volatiles removed in vacuo to give an oil. The
pure product was obtained by column chromatography using the stated solvent system.
1,1-Dimethylethyl N-[(1S,2S)-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-ethenyl-2-
hydroxypentyl]-N-(2-propenyl)-carbamate (217).
The amine 216 (100 mg, 0.341 mmol) was reacted as described
above. Column chromatography (15 % EtOAc in pet. sp. as
eluant) gave the title compound (130 mg, 0.325 mmol, 95.4 %)
as a colourless oil.
[α]D27: -12 (c 1.0, CHCl3).
NOTBS
OHHBoc
H
3
4
2'
1'1
5
1''2''
3''
2
135
MS (CI+) m/z 400 (100 %) (M+1), HRMS (CI+) found 400.2857, calc for C21H42NO4Si
400.2883 (M+1).
δH (300 MHz, CDCl3): 0.04 (6H, s, (CH3)2Si), 0.88 (9H, s, (CH3)3CSi), 1.45 (9H, s,
(CH3)3C-O), 1.30-1.50 (1H, m, H3a), 1.50-1.80 (3H, m, H3b and H4), 3.64 (2H, td, J=5.4,
2.1 Hz, H5), 3.70-3.90 (4H, m, H2, H1'' and OH), 3.99 (1H, br. t, J=7.2 Hz, H1), 5.05-5.25
(4H, m, H2' and H3''), 5.75-6.00 (2H, m, H1' and H2'').
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.3 (s, (CH3)3CSi), 25.9 (q, (CH3)3CSi), 28.4 (q,
(CH3)3C-O). 29.0, 31.2 (t, C3 and C4), 50.1 (br.t, C1''), 63.1 (t, C5), 65.5 (d, C1), 72.1 (br.
d, C2), 80.2 (s, (CH3)3C-O), 116.6, 117.9 (br. t, C2' and C3''), 134.5, 135.2 (d, C1' and
C2''), 156.3 (br.s, CO).
1,1-Dimethylethyl N-[(1S,2R)-1-ethenyl-2-hydroxy-5-[(4-
methoxyphenyl)methoxy]pentyl]-N-(2-propenyl)-carbamate (230).
The amine 229 (1.07 g, 3.503 mmol) was reacted as described
above. Column chromatography (increasing polarity from 15
% to 40 % EtOAc in pet. sp. as eluant) gave the title compound
(1.392 g, 3.433 mmol, 98.0 %) as a clear oil.
[α]D25: -12 (c 1.95, CHCl3).
MS (ES+) m/z 406.5 (62 %) (M+1), HRMS (CI+) found 406.2579, calc for C23H36NO5
406.2593 (M+1).
δH (300 MHz, CDCl3): 1.45 (9H, s, (CH3)3C), 1.55-1.85 (4H, m, H3 and H4), 2.01 (1H,
br.s, OH) 3.47 (2H, td, J=6.0, 2.1 Hz, H5), 3.79 (3H, s, OCH3), 3.70-3.92 (4H, m, H1, H2
and H1''), 4.43 (2H, s, OCH2Ar), 5.05-5.30 (4H, m, H2' and H3''), 5.79 (1H, ddd, J=16.5,
11.4, 6.3 Hz, H1'), 6.09 (1H, ddd, J=17.4, 10.2, 7.2 Hz, H2''), 6.89 (2H, dt, J=8.7, 2.4 Hz, 2
x ArCH), 7.25 (2H, dt, J=8.7, 2.4 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 26.1 (t, C4), 28.3 (q, (CH3)3C), 31.5 (br t, C3), 50.5 (br t, C1''), 55.1
(q, OCH3), 65.3 (br d, C1), 69.5 (t, C5), 72.5 (t, OCH2Ar), 73.1 (br d, C2), 80.2 (s,
(CH3)3C), 113.6 (d, 2 x ArCH), 116.4, 118.4 (t, C2' and C3''), 129.2 (d, 2 x ArCH), 130.3
(s, ArC), 132.3, 134.9 (br d and d, C1' and C2''), 159.0 (s, ArC), 171.0 (br s, CO).
NOPMB
OHHH
Boc
34
2'
1'1
5
1''
2''
3''
2
136
1,1-Dimethylethyl N-[(1S,2S)-1-ethenyl-2-hydroxy-6-[(4-
methoxyphenyl)methoxy]hexyl]-N-(2-propenyl)-carbamate (262).
The amine 224 (110 mg, 0.344 mmol) was reacted as
described above. Column chromatography (increasing
polarity from 25 % to 50 % EtOAc in pet. sp. as eluant)
gave the title compound (135 mg, 0.322 mmol, 93.6 %) as a
clear oil.
[α]D29: -15 (c 1.0, CHCl3).
MS (CI+) m/z 420 (30 %) (M+1), HRMS (CI+) found 420.2745, calc for C24H38NO5
420.2750 (M+1).
δH (300 MHz, CDCl3): 1.10-1.65 (7H, m, H3, H4, H5 and OH), 1.42 (9H, s, (CH3)3C),
3.41 (2H, br. t, J=6.0 Hz, H6), 3.77 (3H, s, OCH3), 3.60-3.84 (3H, m, H2 and H1''), 3.94
(1H, br. t, J=7.5 Hz, H1), 4.40 (2H, s, OCH2Ar), 5.02-5.22 (4H, m, H2' and H3''), 5.72-5.96
(2H, m, H1' and H2''), 6.84 (2H, d, J=8.7 Hz, 2 x ArCH), 7.23 (2H, d, J=8.7 Hz, 2 x
ArCH).
δC (75 MHz, CDCl3): 22.4 (t, C4), 28.3 (q, (CH3)3C), 29.7, 34.2 (t, C3 and C5), 50.0 (br. t,
C1''), 55.1 (q, OCH3), 65.6 (d, C1), 69.9 (t, C6), 71.9 (br. d, C2), 72.4 (t, OCH2Ar), 80.2 (s,
(CH3)3C), 113.5 (d, 2 x ArCH), 116.6, 117.8 (t, C2' and C3''), 129.0 (d, 2 x ArCH), 130.5
(s, ArCH), 134.2, 134.9 (d, C1' and C2''), 158.0 (s, ArCH), 171.0 (br. s, CO).
1,1-Dimethylethyl N,N-di(2-propenyl)-carbamate (339).185
Diallylamine (0.93 g, 9.57 mmol) was reacted as described above
except 0.75 equivalents of di-tertbutyldicarbonate was used and
workup consisted only of evaporation to dryness. Column
chromatography (increasing polarity from 2 % to 6 % EtOAc in pet. sp. as eluant) gave the
title compound (1.40 g, 7.097 mmol, 96.8 %) as a clear oil that had spectral data identical to
that reported in the literature.185
MS (CI+) m/z 198 (100 %) (M+1).
δH (300 MHz, CDCl3): 1.42 (9H, s, (CH3)3C), 3.77 (4H, br.s, H1'), 5.00-5.12 (4H, m, H3'),
5.64-5.80 (2H, m, H2').
NOHH
H
OPMB
Boc
3''3
4
2'
1'1
5
61''2''
2
NO
O
3'2' 1' 1
137
δC (75 MHz, CDCl3): 28.4 (q, (CH3)3C), 48.6 (t, C1'), 79.4 (s, (CH3)3C), 116.1 (br.t, C3'),
133.8 (d, C2'), 155.1 (s, C1).
7.2.12 General method for ring closing metathesis. The starting diene (0.75 mmol) was dissolved in dry DCM (180 mL) then benzylidene-
bis(tricyclohexylphosphine)-dichlororuthenium (Grubbs' catalyst) (60 mg, 0.075 mmol)
was added. The mixture was heated at reflux under N2 for 20 h then cooled, before all
solvent was removed in vacuo. The pure product was obtained by column chromatography
using the stated solvent system.
1,1-Dimethylethyl (2S)-2-[(1S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-
hydroxybutyl]-2,5-dihydro-1H-pyrrole-1-carboxylate (218).
The diene 217 (300 mg, 0.751 mmol) was reacted as described
above. Column chromatography (increasing polarity from 10 %
to 20 % EtOAc in pet. sp. as eluant) gave the title compound
(260 mg, 0.700 mmol, 93.2 %) as a colourless oil.
[α]D23: -87 (c 2.05, CHCl3).
MS (CI+) m/z 372 (100 %) (M+1), HRMS (CI+) found 372.2578, calc for C19H38NO4Si
372.2570 (M+1).
δH (300 MHz, CDCl3): 0.02 (6H, s, (CH3)2Si), 0.86 (9H, s, (CH3)3CSi), 1.45 (9H, s,
(CH3)3C-O), 1.30-1.80 (4H, m, H2' and H3'), 1.90 (1/2 H br s. free OH), 3.50-3.75 (3H, m,
H1' and H4'), 3.85-4.05 (1H, m, H5a), 4.10-4.30 (1H, m, H5b), 4.50-4.65 (1H, m, H2), 4.99
(1H, br.s, H-bonded OH), 5.70-5.90 (2H, m, H3 and H4).
δC (75 MHz, CDCl3): major rotamer -5.4 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 25.9 (q,
(CH3)3CSi), 28.3 (t, C3'), 28.4 (q, (CH3)3C-O), 29.9 (t, C2'), 54.0 (t, C5), 63.2 (t, C4'), 69.9
(d, C2), 75.2 (d, C1'), 80.4 (s, (CH3)3C-O), 126.5, 126.9 (d, C3 and C4), 156.6 (s, CO),
minor rotamer inter alia 29.1, 29.6 (t, C2' and C3'), 63.6 (t, C4'), 68.4 (d, C2), 72.8 (d, C1'),
80.0 (s, (CH3)3C-O), 126.7, 127.1 (d, C3 and C4).
NOTBS
OHHBoc
H
4
5 2
3
11'
2'3'
4'
138
1,1-Dimethylethyl (2S)-2,5-dihydro-2-[(1R)-1-hydroxy-4-[(4-
methoxyphenyl)methoxy]butyl]-1H-pyrrole-1-carboxylate (231).
The diene 230 (500 mg, 1.233 mmol) was reacted as described
above except that 0.065 equivalents of Grubbs' catalyst was
used. Column chromatography (increasing polarity from 20 %
to 50 % EtOAc in pet. sp. as eluant) gave the title compound
(443 mg, 1.174 mmol, 95.2 %) as a clear oil.
[α]D24: -85 (c 1.75, CHCl3).
MS (ES+), m/z 378.4 (100 %) (M+1), HRMS (CI+) found 378.2253, calc for C21H32NO5
378.2280 (M+1).
δH (300 MHz, CDCl3): 1.18-1.50 (2H, m, H2'), 1.48 (9H, s, (CH3)3C), 1.54-1.74 (2H, m,
H3'), 3.40-3.56 (2H, m, H4'), 3.68-3.80 (1H, m, H5a), 3.79 (3H, s, OCH3), 3.82-4.32 (2H,
m, H2 and H1'), 4.42 (2H, s, OCH2Ar), 4.58 (1H, d, J=8.4 Hz, H5b), 4.78 (1H, br. s, OH),
5.60-5.98 (2H, m, H3 and H4), 6.85 (2H, d, J=8.7 Hz, 2 x ArCH), 7.25 (2H, d, J=8.7 Hz, 2
x ArCH).
δC (75 MHz, CDCl3): major rotamer 26.2, 28.1 (t, C2' and C3'), 28.3 (q, (CH3)3C), 54.6 (t,
C5), 55.1 (q, OCH3), 69.9 (t, C4'), 70.5 (d, C2), 72.2 (t, OCH2Ar), 73.3 (d, C1'), 80.3 (s,
(CH3)3C), 113.6 (d, 2 x ArCH), 126.5, 127.1 (d, C3 and C4), 129.1 (d, 2 x ArCH), 130.6 (s,
ArC), 156.1 (s, ArC), 158.9 (s, CO), minor rotamer inter alia 26.5, 30.0 (t, C2' and C3'),
54.2 (t, C5), 69.3, 72.4 (d, C2 and C1'), 125.4, 127.9 (d, C3 and C4).
1,1-Dimethylethyl (2S)-2,5-dihydro-2-[(1S)-1-hydroxy-5-[(4-
methoxyphenyl)methoxy]pentyl]-1H-pyrrole-1-carboxylate (263).
The diene 262 (500 mg, 1.193 mmol) was reacted as
described above except that 0.05 equivalents of Grubbs'
catalyst was used. Column chromatography (increasing
polarity from 25 % to 50 % EtOAc in pet. sp. as eluant) gave the title compound (426 mg,
1.088 mmol, 91.2 %) as a clear oil.
[α]D29: -79 (c 0.9, CHCl3).
MS (CI+) m/z 392 (37 %) (M+1), HRMS (CI+) found 392.2409, calc for C22H34NO5
392.2437 (M+1).
NOPMB
OHBoc
HH
4
5 12
3
1'2'
3'
4'
NOHH
H
OPMB
Boc
4
1'
2'
12
3
3'4'
5'5
139
δH (300 MHz, CDCl3): 1.48 (9H, s, (CH3)3C), 1.20-1.73 (6H, m, H2', H3' and H4'), 3.44
(2H, t, J=6.3 Hz, H5'), 3.56-3.66 (1H, m, H2), 3.79 (3H, s, OCH3), 3.99 (1H, br. d, J=15.7
Hz, H5a), 4.18 (1H, br. d, J=15.6 Hz, H5b), 4.41 (2H, s, OCH2Ar), 4.54 (1H, m, H1'), 4.96
(1H, br. s, OH), 5.60-5.90 (2H, m, H3 and H4), 6.86 (2H, dt, J=8.4, 3.0 Hz, 2 x ArCH),
7.24 (2H, dt, J=8.4, 3.0 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 21.7 (t, C3'), 28.4 (q, (CH3)3C), 29.7, 33.3 (C2' and C4'), 53.9 (t,
C5), 55.2 (q, OCH3), 70.0 (t, C5'), 70.0 (d, C2), 72.4 (t, OCH2Ar), 75.4 (d, C1'), 80.4 (s,
(CH3)3C), 113.5 (d, 2 x ArCH), 126.4, 126.7 (d, C3 and C4), 129.0 (d, 2 x ArCH), 130.5 (s,
ArC), 156.6 (CO), 158.8 (s, ArC).
(1R,7aS)-1-[3-[(4-Methoxyphenyl)methoxy]propyl]-5,7a-dihydro-1H,3H-pyrrolo[1,2-
c]oxazol-3-one (255).
The diene 271 (253 mg, 0763 mmol) was reacted as described
above except that 0.2 equivalents of Grubbs' catalyst was used.
Column chromatography (increasing polarity from 30 % to 70 %
EtOAc in pet. sp. as eluant) gave the title compound (179 mg,
0.590 mmol, 77.3 %) as a pale grey oil.
Alternative method:
The carbamate 231 (663 mg, 1.643 mmol) was dissolved in toluene (60 mL) then NaH (290
mg, 6.04 mmol) was added. The mixture was stirred at 45 oC for 18 h, then poured into
water and extracted with EtOAc. The combined organic extracts were dried (MgSO4),
filtered and evaporated in vacuo to give an oil. The pure product was obtained by column
chromatography (increasing polarity from 5 % to 30 % Et2O in DCM as eluant), which
gave the title compound (370 mg, 1.220 mmol, 74.2 %) as a clear oil.
[α]D25: -15 (c 1.0, CHCl3).
MS (CI+) m/z 304 (9 %) (M+1) 302 (26 %) (M-1), HRMS ( EI+) found 303.1464, calc for
C17H21NO4 303.1471 (M+1).
δH (300 MHz, CDCl3): 1.45-2.00 (4H, m, H1' and H2'), 3.38-3.55 (2H, m, H3'), 3.70-3.80
(1H, m, H5a), 3.78 (3H, s, OCH3), 4.40 (2H, s, OCH2Ar), 4.34-4.44 (1H, m, H5b), 4.64-
4.76 (2H, m, H1 and H7a), 5.80-5.86 (1H, m, H6), 5.98-6.04 (1H, m, H7), 6.86 (2H, d,
J=8.4 Hz, 2 x ArCH), 7.23 (2H, d, J=8.4 Hz, 2 x ArCH).
NO
O
OPMB
H
H
1
234
5
6 7
2'3'1'7a
140
δC (75 MHz, CDCl3): 25.8, 28.9 (t, C1' and C2'), 54.8 (t, C5), 55.2 (q, OCH3), 68.3 (d,
C7a), 68.9 (t, C3'), 72.4 (t, OCH2Ar), 78.5 (d, C1), 113.6 (d, 2 x ArCH), 126.4 (d, C6),
129.0 (d, 2 x ArCH), 130.2 (s, ArC), 131.4 (d, C7), 158.9 (s, ArC), 162.5 (s, C3).
Ethyl 2,5-dihydro-1H-pyrrole-1-carboxylate (291).186
The diene 290 (700 mg, 4.137 mmol) was reacted as described above
except 0.02 equivalents of Grubbs' catalyst was used. Column
chromatography (increasing polarity from 10 % to 25 % EtOAc in pet.
sp. as eluant) gave the title compound (556 mg, 3.971 mmol, 96.0 %) as a pale grey oil that
had spectral data identical to that reported in the literature.186
MS (CI+) m/z 142 (88 %) (M+1).
δH (300 MHz, CDCl3): 1.27 (3H, t, J=7.2 Hz, OCH2CH3), 4.10-4.20 (6H, m, H2, H5 and
OCH2CH3), 5.77 (2H, q, J=6.6 Hz, H3 and H4).
δC (75 MHz, CDCl3): 14.8 (q, OCH2CH3), 52.7 (t, C2), 53.2 (t, C5), 60.9 (t, OCH2CH3),
125.5, 125.6 (d, C3 and C4), 154.6 (s, CO).
1,1-Dimethylethyl 2,5-dihydro-1H-pyrrole-1-carboxylate (340).187
The diene 339 (700 mg, 3.549 mmol) was reacted as described above
except that 0.025 equivalents of Grubbs' catalyst was used. Column
chromatography (increasing polarity from 10 % to 25 % EtOAc in pet.
sp. as eluant), which gave the title compound (582 mg, 3.439 mmol, 96.9 %) as a pale grey
oil that had spectral data identical to that reported in the literature.187
MS (EI+) m/z 169 (100 %) (M), HRMS (EI+) found 169.1101, calc for C9H15NO2
169.1103 (M).
δH (300 MHz, CDCl3): 1.41 (9H, s, (CH3)3C), 4.04 (4H, br. d, J=8.4 Hz, H2 and H5), 5.70
(2H, br. d, J=8.4 Hz, H3 and H4).
δC (75 MHz, CDCl3): 28.5 (q, (CH3)3C), 52.7 (t, C2), 53.0 (t, C5), 79.1 (s, (CH3)3C),
125.5, 125.6 (d, C3 and C4).
NO
O12
3
45
NO
O12
3
45
141
1,1-Phenylmethyl (2S)-2,5-dihydro-2-[(1S)-1-hydroxy-5-[(4-
methoxyphenyl)methoxy]pentyl]-1H-pyrrole-1-carboxylate (305).
The diene 304 (385 mg, 0.849 mmol) was reacted as described
above except that 0.07 equivalents of Grubbs' catalyst was
used. Column chromatography (increasing polarity from 20
% to 60 % EtOAc in pet. sp. as eluant) gave the title compound (336 mg, 0.790 mmol, 93.0
%) as a clear oil.
[α]D23: -95 (c 1.4, CHCl3).
MS (ES+) m/z 426.3 (17 %) (M+1), HRMS (ES+) found 426.1990, calc for C25H32NO5
426.2280 (M+1).
δH (300 MHz, CDCl3): 1.24-1.72 (6H, m, H2', H3' and H4'), 2.43 (1/2H, br.s, free OH),
3.34-3.50 (2H, m, H5'), 3.70-3.95 (1H, m, H1'), 3.78 (3H, s, OCH3), 4.00-4.16 (1H, m,
H5a), 4.23-4.34 (1H, m, H5b), 4.42 (2H, s, OCH2Ar), 4.51 (1/2H, br.s, H-bonded OH),
4.60-4.70 (1H, m, H2), 5.10-5.26 (2H, m, OCH2Ph), 5.60-5.92 (2H, m, H3 and H4), 6.87
(2H, dt, J=8.7, 2.1 Hz, 2 x ArCH), 7.25 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH), 7.25-7.40 (5H,
m, OCH2Ph).
δC (75 MHz, CDCl3): 21.7 (t, C3'), 29.6, 32.9 (t, C2' and C4'), 53.7 (t, C5), 55.1 (q, OCH3),
67.3 (OCH2Ph), 69.9 (t, C5'), 70.5 (d, C2), 72.4 (t, OCH2Ar), 74.8 (d, C1'), 113.6 (d, 2 x
ArCH), 126.3 (d, C4), 126.8 (d, OCH2Ph), 127.8 (d, C3), 128.0 (d, OCH2Ph), 128.4 (d,
OCH2Ph), 129.1 (d, 2 x ArCH), 130.6 (s, ArC), 131.4 (s, OCH2Ph), 156.8 (s, CO), 159.0 (s,
ArC).
(1S,7aS)-1-[4-[(4-Methoxyphenyl)methoxy]butyl]-5,7a-dihydro-1H,3H-pyrrolo[1,2-
c]oxazol-3-one (312).
The diene 311 (165 mg, 0.483 mmol) was reacted as described
above except that 0.2 equivalents of Grubbs' catalyst was used.
Column chromatography (increasing polarity from 30 % to 60
% EtOAc in pet. sp. as eluant) gave the title compound (110
mg, 0.347 mmol, 71.8 %) as a clear oil.
[α]D30: -34 (c 0.89, CHCl3).
NOH
Cbz
HH
OPMB1
2
34
5 1'2'
3'
4'
5'
NO
O
OPMBH
H
6
23
4
5 1
7
2'3'
4'7a 1'
142
MS (CI+) m/z 316 (21 %) (M-1), 318 (8 %) (M+1), HRMS (CI+) found 316.1547, calc for
C18H22NO4 316.1522 (M-1).
δH (300 MHz, CDCl3): 1.40-2.00 (6H, m, H1', H2' and H3'), 3.44 (2H, t, J=6.3 Hz, H4'),
3.77 (3H, s, OCH3), 3.72-3.82 (1H, m, H7a), 4.22-4.38 (3H, m, H1 and H5), 4.40 (2H, s,
OCH2Ar), 5.78-5.85 (1H, m, H7), 5.95-6.02 (1H, m, H6), 6.85 (2H, dt, J=8.7, 2.7 Hz, 2 x
ArCH), 7.23 (2H, dt, J=8.7, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 21.3 (t, C2'), 29.2, 34.9 (t, C1' and C3'), 54.4 (t, C5), 55.1 (q, OCH3),
69.3 (t, C4'), 70.3 (d, C7a), 72.4 (t, OCH2Ar), 81.8 (d, C1), 113.6 (d, 2 x ArCH), 128.5 (d,
C7), 129.1 (d, 2 x ArCH), 130.4 (s, ArC), 130.5 (d, C6), 159.0 (s, ArC), 162.5 (s C3).
7.2.13 General method for the hydrogenation of 2,5-dihydropyrroles. The starting alkene (0.404 mmol) was dissolved in pet. sp. (15 mL) then palladium on
carbon (15 mg, 10 % Pd) was added. The mixture was stirred under an atmosphere of H2 at
R.T. for 18 h, and then filtered through celite. The solids were washed with EtOAc and the
filtrates evaporated in vacuo. The pure product was obtained by column chromatography
using the stated solvent system.
1,1-Dimethylethyl (2S)-rel-2-[(1S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-
hydroxybutyl]-1-pyrrolidinecarboxylate (220).
The 2,5-dihydropyrrole 218 (150 mg, 0.404 mmol) was reacted
as described above. Column chromatography (20% EtOAc in
pet. sp. as eluant) gave the title compound (138 mg, 0.369 mmol,
91.4 %) as a clear oil.
MS (CI+) m/z 374 (100 %) (M+1), HRMS (CI+) found 374.2692, calc for C19H40NO4Si
374.2727 (M+1).
δH (300 MHz, CDCl3): 0.01 (6H, s, (CH3)2Si), 0.85 (9H, s, (CH3)3CSi), 1.42 (9H, s,
(CH3)3C-O), 1.20-2.00 (8H, m, H3, H4, H2' and H3'), 3.18-3.30 (1H, m, H5a), 3.36-3.54
(2H, m, H5b and H1'), 3.61 (2H, t, J=5.7 Hz, H4'), 3.70-3.84 (1H, m, H1), 4.88 (1H, br.s,
OH).
NOTBS
OHHBoc
H
4
5 2
3
11'
2'
3'
4'
143
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 24.1 (t, C4), 25.6 (t, C3'),
25.9 (q, (CH3)3CSi), 28.3 (t, C2'), 28.4 (q, (CH3)3C-O), 31.1 (t, C3), 47.2 (t, C5), 62.7 (d,
C2), 63.1 (t, C4'), 75.3 (d, C1'), 80.2 (s, (CH3)3C-O), 157.3 (s, CO).
1,1-Dimethylethyl (2S)-2-[(1S)-1,4-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-butyl]-1-
pyrrolidinecarboxylate (341).
The 2,5-dihydropyrrole 287 (247 mg, 0.508 mmol) was reacted
as described above. Column chromatography (increasing
polarity from 5 % to 15 % EtOAc in pet. sp. as eluant) gave the
title compound (231 mg, 0.473 mmol, 93.2 %) as a clear oil.
[α]D21: -24.4 (c 2.31, CHCl3).
MS (CI+) m/z 488 (14 %) (M+1), HRMS (ES+) found 488.3567, calc for C25H54NO4Si2
488.3591 (M+1).
δH (300 MHz, CDCl3): 0.02 (6H, s, (CH3)2Si), 0.04 (6H, s, (CH3)2Si), 0.86 (18 H, s,
(CH3)3CSi), 1.10-2.08 (8H, m, H3, H4, H2' and H3'), 1.45 (9H, s, (CH3)3C-O), 3.18-3.32
(1H, m, H5a), 3.32-3.54 (1H, m, H5b), 3.57 (2H, t, J=6.3 Hz, H4'), 3.76-3.96 (1H, m, H2),
4.00-4.16 (1H, m, H1').
δC (75 MHz, CDCl3): major rotamer inter alia -5.1 (q, (CH3)2Si), -4.5 (q, (CH3)2Si), 18.0
(s, (CH3)3CSi), 18.4 (s, (CH3)3CSi), 23.6, 25.9 (t, C3 and C4), 25.9 (q, (CH3)3CSi), 26.0 (q,
(CH3)3CSi), 27.2, 30.4 (t, C2' and C3'), 28.8 (q, (CH3)3C-O), 47.5 (t, C5), 60.8 (d, C2), 63.4
(t, C4'), 72.5 (d, C1'), 79.4 (s, (CH3)3C-O), 154.4 (s, CO), minor rotamer inter alia -5.1 (q,
(CH3)2Si), -3.9 (q, (CH3)2Si), 24.4, 25.1 (t, C3 and C4), 27.7, 30.1 (t, C2' and C3'), 28.6 (q,
(CH3)3C-O)47.6 (t, C5), 71.8 (d, C1'), 79.4 (q, (CH3)3C-O), 154.3 (CO).
(2S)-2-[(1S)-1-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(4-methoxyphenyl)methoxy]
pentyl-pyrrolidine (307).
The 2,5-dihydropyrrole 306 (281 mg, 0.521 mmol) was
reacted as described above. Column chromatography
(increasing polarity from 2.5 % to 15 % MeOH in DCM as
eluant) gave the title compound (164 mg, 0.402 mmol, 77.2 %) as a clear oil.
[α]D22: -3 (c 0.8, CHCl3).
NOTBS
OTBSHBoc
H
4
5 2
3
11' 3'
4'2'
NH OTBS
HH
OPMB
1
2
34
5 1'2'
3'
4'
5'
144
MS (CI+) m/z 408 (100 %) (M+1), HRMS (EI+) found 407.2796, calc for C23H41NO3Si
407.2856 (M).
δH (300 MHz, CDCl3): 0.08 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.10-2.00 (10H, m,
H3, H4, H2', H3' and H4'), 3.20-3.47 (4H, m, H5 and H5'), 3.55-3.66 (1H, m, H2), 3.75
(3H, s, OCH3), 3.72-3.84 (1H, m, H1'), 4.37 (2H, s, OCH2Ar), 6.83 (2H, d, J=8.7 Hz, 2 x
ArCH), 7.21 (2H, d, J=8.7 Hz, 2 x ArCH), 7.86 (1H, br. s, NH).
δC (75 MHz, CDCl3): -4.6 (q, CH3Si), -4.2 (q, CH3Si), 17.9 (s, (CH3)3CSi), 21.5 (t, C3'),
25.8 (q, (CH3)3CSi), 24.1, 27.5, 29.5, 34.6 (t, C3, C4, C2' and C4'), 46.1 (t, C5), 55.1 (q,
OCH3), 61.4 (d, C2), 69.7 (t, C5'), 71.4 (d, C1'), 72.5 (t, OCH2Ar), 113.6 (d, 2 x ArCH),
129.2 (d, 2 x ArCH), 130.5 (s, ArC), 159.0 (s, ArC).
(1S,7aS)-1-(4-Hydroxybutyl)-tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (314).
The 2,5-dihydropyrrole 312 (89 mg, 0.281 mmol) was reacted as
described above. Column chromatography (increasing polarity
from 5 % to 10 % MeOH in DCM as eluant) gave the title
compound (50 mg, 0.251 mmol, 89.3 %) as a clear oil.
[α]D28: -49 (c 0.5, CHCl3).
MS (CI+) m/z 200 (100 %) (M+1), HRMS (CI+) found 200.1284, calc for C10H18NO3
200.1287 (M+1).
δH (300 MHz, CDCl3): 1.38-2.10 (10H, m, H6, H7, H1', H2' and H3'), 2.30 (1H, br. s, OH),
3.15 (1H, ddd, J=11.4, 8.7, 3.9 Hz, H5a), 3.45-3.58 (2H, m, H5b and H7a), 3.59 (2H, t,
J=6.3 Hz, H4'), 4.25 (1H, ddd, J=7.2, 5.4, 4.2 Hz, H1).
δC (75 MHz, CDCl3): 20.9 (t, C2'), 25.7, 30.7, 32.0, 34.8 (t, C6, C7, C1' and C3'), 45.3 (t,
C5), 62.1 (t, C4'), 64.5 (d, C7a), 80.8 (d, C1), 161.0 (s, C3).
7.2.14 General method for the silylation of secondary alcohols. The starting alcohol (1.076 mmol) was dissolved in DMF (6 mL) then imidazole (212 mg,
3.026 mmol) and TBSCl (268 mg, 1.812 mmol) were added. The mixture was heated in a
sealed tube at 60 oC for 20 h, then poured into sat. NaHCO3 solution (50 mL) and extracted
with DCM (3 x 40 mL). The combined organic extracts were dried (MgSO4) filtered and
NO
O
OHH
H
1
23
4
5
6 7
2'3'
4'1'
7a
145
evaporated in vacuo to give an oil. The pure product was obtained by column
chromatography using the stated eluant.
(3S,4S)-rel-4-[[(1,1-Dimethylethyl)dimethysilyl]oxy)]-8-[(4-methoxyphenyl)methoxy]-
3-(2-propenylamino)-1-octene (225).
The amino alcohol 224 (195 mg, 0.610 mmol) was reacted as
described above. Column chromatography (increasing
polarity from 5 % to 25 % EtOAc in pet. sp. as eluant) gave
the title compound (203 mg, 0.468 mmol, 76.7 %) as a clear
oil.
MS (CI+) m/z 434 (70 %) (M+1), HRMS (CI+) found 434.3077, calc for C25H44NO3Si
434.3090 (M+1).
δH (300 MHz, CDCl3): 0.05 (3H, s, CH3Si), 0.07 (3H, s, CH3Si), 0.88 (9H, s, (CH3)3CSi),
1.30-1.70 (7H, m, NH, H5, H6 and H7), 2.98-3.08 (2H, m, H3 and H1'a), 3.27 (1H, ddt,
J=14.1, 5.1, 1.5 Hz, H1'b), 3.41 (2H, t, J=6.6 Hz, H8), 3.56-3.64 (1H, m, H4), 3.78 (3H, s,
OCH3), 4.41 (2H, s, OCH2Ar), 5.00-5.20 (4H, m, H1 and H3'), 5.58 (1H, ddd, J=17.1, 10.2,
8.4 Hz, H2), 5.86 (1H, dddd, J=17.4, 10.2, 6.0, 5.1 Hz, H2'), 6.86 (2H, dt, J=8.4, 2.7 Hz, 2
x ArCH), 7.24 (2H, dt, J=8.4, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -4.6 (q, CH3Si), -4.2 (q, CH3Si), 18.1 (s, (CH3)3CSi), 20.9 (t, C6),
25.9 (q, (CH3)3CSi), 30.0, 33.3 (t, C5 and C7), 49.7 (t, C1'), 55.2 (q, OCH3), 64.9 (d, C3),
70.0 (t, C8), 72.4 (t, OCH2Ar), 74.7 (d, C4), 113.6 (d, 2 x ArCH), 115.5, 117.6 (t, C1 and
C3'), 129.1 (d, 2 x ArCH), 130.7 (s, ArC), 137.0, 138.0 (d, C2 and C2'), 159.0 (s, ArC).
(3S,4S)-3-Amino-4-[[(1,1-dimethylethyl)dimethysilyl]oxy]-8-[(4-
methoxyphenyl)methoxy]-1-octene (226).
The amino alcohol 280 (607 mg, 2.173 mmol) was reacted as
described above except that CH3CN was used as the solvent
and the reaction was conducted at RT. Column
chromatography (increasing polarity from 2 % to 8% MeOH in
DCM as eluant) gave the title compound (723 mg, 1.837 mmol, 84.5 %) as a clear oil
NH OTBSH
HOPMB
3'
45
6
1
23
7
81'2'
NH2 OTBSHH
OPMB4
5
6
1
23
7
8
146
Alternative Synthesis:
The N-allylamine 225 (215 mg, 0.496 mmol) was dissolved in dry DCM (1.5 mL), then
N,N-dimethylbarbituric acid (116 mg, 0.744 mmol) and Pd(PPh3)4 (24 mg, 0.0207 mmol)
were added. The mixture was heated in a sealed tube at 60 oC for 3 h, then cooled and
diluted with EtOAc (50 mL), before it was washed with sat. Na2CO3 solution (3 x 30 mL),
dried (MgSO4), filtered and evaporated in vacuo to give an oil. The pure product was
obtained by column chromatography (increasing polarity from 2.5 % to 10 % MeOH in
DCM as eluant), which gave the title compound (190 mg, 0.483 mmol, 97.3 %) as a clear
oil.
[α]D24: -10 (c 1.03, CHCl3).
MS (CI+) m/z 394 (43 %) (M+1), HRMS (CI+) found 394.2754, calc for C22H40NO3Si
394.2777 (M+1).
δH (300 MHz, CDCl3): 0.05 (6H, s, (CH3)2Si), 0.88 (9H, s, (CH3)3CSi), 1.30-1.70 (8H, m,
NH2, H5, H6 and H7), 3.29 (1H, tt, J=5.4, 1.2 Hz, H3), 3.42 (2H, t, J=6.3 Hz, H8), 3.54
(1H, br. q, J=5.1 Hz, H4), 3.79 (3H, s, OCH3), 4.41 (2H, s, OCH2Ar), 5.08 (1H, dt, J=10.2,
1.2 Hz, H1a), 5.16 (1H, dt, J=17.1, 1.2 Hz, H1b), 5.85 (1H, ddd, J=17.1, 10.2, 6.6 Hz, H2),
6.86 (2H, dt, J=8.1, 2.7 Hz, 2 x ArCH), 7.25 (2H, dt, J=8.1, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -4.5 (q, CH3Si), -4.3 (q, CH3Si), 18.1 (s, (CH3)3CSi), 21.7 (t, C6),
25.9 (q, (CH3)3CSi), 29.9, 33.4 (t, C5 and C7), 55.2 (q, OCH3), 57.5 (d, C3), 69.9 (t, C8),
72.5 (t, OCH2Ar), 75.7 (d, C4), 113.7 (d, 2 x ArCH), 114.7 (t, C1), 129.2 (d, 2 x ArCH),
130.6 (s, ArC), 140.5 (d, C2), 159.0 (s, ArC).
1,1-Dimethylethyl (2S)-2,5-dihydro-2-[(1R)-1-[[(1,1-dimethylethyl)dimethysilyl]oxy)]-
4-[(4-methoxyphenyl)methoxy]butyl]-1H-pyrrole-1-carboxylate (240).
The alcohol 231 (200 mg, 0.530 mmol) was reacted as described
above. Column chromatography (increasing polarity from 5 %
to 20 % EtOAc in pet. sp. as eluant) gave the title compound
(225 mg, 0.526 mmol, 99.2 %) as a clear oil.
[α]D22: -108 (c 2.25, CHCl3).
MS (CI+) m/z 492 (56 %) (M+1), HRMS (ES+) found 492.3127, calc for C27H46NO5Si
492.492.3145 (M+1).
NOPMB
Boc OTBSHH
4
5
2'
1
2
3
3'4'
1'
147
δH (300 MHz, CDCl3): major rotamer; -0.13 (3H, s, CH3Si), -0.09 (3H, s, CH3Si), 0.74
(9H, s, (CH3)3CSi), 1.38 (9H, s, (CH3)3C-O), 1.30-1.72 (4H, m, H2' and H3'), 3.37 (2H, t,
J=6.6 Hz, H4'), 3.71 (3H, s, OCH3), 3.80-4.18 (3H, m, H2, H5a and H1'), 4.34 (2H, s,
OCH2Ar), 4.30-4.44 (1H, m, H5b), 5.58-5.78 (2H, m, H3 and H4), 6.78 (2H, d, J=8.7 Hz, 2
x ArCH), 7.17 (2H, d, J=8.7 Hz, 2 x ArCH), minor rotamer inter alia -0.08 (3H, s, CH3Si),
4.35 (2H, s, OCH2Ar).
δC (75 MHz, CDCl3): major rotamer; -4.9 (q, CH3Si), -4.5 (q, CH3Si), 18.0 (s, (CH3)3CSi),
25.9 (q, (CH3)3CSi), 26.4 (t, C2'), 28.7 (q, (CH3)3C-O), 32.0 (t, C3'), 54.2 (t, C5), 55.2 (q,
OCH3), 68.9 (d, C2), 70.1 (t, C4'), 71.0 (d, C1'), 72.3 (t, OCH2Ar), 79.1 (s, (CH3)3C-O),
113.6 (d, 2 x ArCH), 125.8, 126.1 (d, C3 and C4), 129.0 (d, 2 x ArCH), 130.6 (s, ArC),
153.9 (s, CO), 158.8 (s, ArC), minor rotamer inter alia -4.8 (q, CH3Si), -4.4 (q, CH3Si),
25.8 (q, (CH3)3CSi), 26.4 (t, C2'), 28.6 (q, (CH3)3C-O), 32.2 (t, C3'), 54.0 (t, C5), 68.6 (d,
C2), 70.0 (t, C4'), 72.1 (d, C1'), 72.4 (t, OCH2Ar), 79.4 (s, (CH3)3C-O), 113.6 (d, 2 x
ArCH), 125.5, 126.5 (C3 and C4), 129.1 (d, 2 x ArCH), 130.4 (s, ArC), 154.1 (s, CO),
158.9 (s, ArC).
(2R,3S,4S)-2-[(1R)-1-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[(4-
methoxyphenyl)methoxy]butyl]-3,4-bis(phenylmethoxy)pyrrolidine (276).
The amino alcohol 275 (326 mg, 0.663 mmol) was reacted as
described above except that TBDPSCl was used in place of
TBSCl and CH3CN was used as the solvent. Column
chromatography (increasing polarity from 2.5 % to 7.5 %
MeOH in DCM as eluant) gave the title compound (469 mg, 0.642 mmol, 96.9 %) as a
clear gum.
[α]D24: +3 (c 1.2, CHCl3).
MS (ES+) m/z 730.3 (25 %) (M+1), HRMS (ES+) found 730.3942, calc for C46H56NO5Si
730.3928 (M+1).
δH (300 MHz, CDCl3): 1.04 (9H, s, (CH3)3CSi), 1.40-1.60 (4H, m, H2' and H3'), 1.86 (1H,
br. s, NH), 3.02-3.16 (5H, m, H2, H5 and H4'), 3.81 (3H, s, OCH3), 4.04-4.15 (2H, m, H3
and H4), 4.12 (1H, d, J=11.1 Hz, OCH2Ph), 4.20-4.28 (1H, m, H1'), 4.29 (2H, s, OCH2Ph),
NH OTBDPS
OPMB
BnO OBn
HH1
2
34
5 1'2'
3'4'
148
4.56 (2H, s, OCH2Ar), 4.91 (1H, d, J=11.1 Hz, OCH2Ph), 6.87 (2H, dt, J=9.0, 2.7 Hz, 2 x
ArCH), 7.16-7.44 (18H, m, 2 x ArCH, 2 x OCH2Ph, Ph2Si), 7.64-7.70 (4H, m, Ph2Si).
δC (75 MHz, CDCl3): 19.4 (s, (CH3)3CSi), 24.1 (t, C3'), 27.1 (q, (CH3)3CSi), 30.1 (t, C2'),
48.2 (t, C5), 55.2 (q, OCH3), 64.2 (d, C2), 70.2 (t, C4'), 71.3 (d, C1'), 72.2 (t, OCH2Ar),
72.3 (t, OCH2Ph), 72.5 (t, OCH2Ph), 77.1, 82.3 (d, C3 and C4), 113.6 (d, 2 x ArCH), 127.0,
127.3, 127.4, 127.4, 127.5, 127.9, 128.3 (d, Ph), 129.1 (d, 2 x ArCH), 129.4, 129.4 (d, Ph),
130.7 (s, ArC), 133.9, 134.8 (s, SiPh), 135.9, 136.0 (d, SiPh), 138.2, 139.1 (s, OCH2Ph),
159.0 (s, ArC).
1,1-Dimethylethyl (2S)-2-[(1S)-1,4-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-butyl]-
2,5-dihydro-1H-pyrrole-1-carboxylate (287).
The alcohol 218 (400 mg, 1.076 mmol) was reacted as described
above. Column chromatography (increasing polarity from 5 % to
15 % EtOAc in pet. sp. as eluant) gave the title compound (510
mg, 1.050 mmol, 97.6 %) as a clear oil.
[α]D23: -86 (c 2.91, CHCl3).
MS (CI+) m/z 486 (11 %) (M+1), HRMS (CI+) found 486.3445, calc for C25H52NO4Si2
486.3435 (M+1).
δH (300 MHz, CDCl3): major rotamer inter alia -0.06 (6H, s, (CH3)2Si), 0.02 (3H, s,
CH3Si), 0.04 (3H, s, CH3Si), 0.80 (9H, s, (CH3)3CSi), 0.83 (9H, s, (CH3)3CSi), 1.42 (9H, s,
(CH3)3C-O), 1.00-1.65 (4H, m, H2' and H3'), 3.48 (2H, t, J=6.3 Hz, H4'), 3.80-4.20 (3H, m,
H2, H5a and H1'), 4.30-4.58 (1H, m, H5b), 5.60-5.80 (2H, m, H3 and H4), minor rotamer
inter alia 0.01 (3H, s, CH3Si), 0.09 (3H, s, CH3Si), 1.38 (9H, s, (CH3)3C-O).
δC (75 MHz, CDCl3): major rotamer inter alia -5.2 (q, (CH3)2Si), -4.6 (q, (CH3)2Si), 18.0
(s, (CH3)3CSi), 18.4 (s, (CH3)3CSi), 25.9 (q, (CH3)3CSi), 26.0 (q, (CH3)3CSi), 28.6 (q,
(CH3)3C-O), 27.0, 30.0 (t, C2' and C3'), 54.5 (t, C5), 63.3 (t, C4'), 68.2 (d, C2), 72.5 (d,
C1'), 79.6 (s, (CH3)3C-O), 126.2, 127.4 (d, C3 and C4), 153.9 (s, CO), minor rotamer inter
alia -4.1 (q, (CH3)2Si), -4.0 (q, (CH3)2Si), 28.7 (q, (CH3)3C-O), 27.4, 29.7 (t, C2' and C3'),
54.6 (t, C5), 68.5 (d, C2), 71.5 (d, C1'), 79.0 (s, (CH3)3C-O), 125.9, 127.6 (d, C3 and C4).
NOTBS
OTBSHBoc
H
4
5 2
3
11'
2'3'
4'
149
Phenylmethyl (2S)-2,5-dihydro-2-[(1S)-1-[[(1,1-dimethylethyl)dimethysilyl]oxy)]-5-[(4-
methoxyphenyl)methoxy]pentyl]-1H-pyrrole-1-carboxylate (306).
The alcohol 305 (293 mg, 0.689 mmol) was reacted as
described above. Column chromatography (increasing polarity
from 5 % to 25 % EtOAc in pet. sp. as eluant) gave the title
compound (333 mg, 0.617 mmol, 89.6 %) as a clear oil.
[α]D22: -100 (c 1.65, CHCl3).
MS (CI+) m/z 540 (62 %) (M+1), HRMS (CI+) found 540.3166, calc for C31H46NO5Si
540.3145 (M+1).
δH (300 MHz, CDCl3): major rotamer inter alia -0.10 (3H, s, CH3Si), 0.12 (3H, s, CH3Si),
0.85 (9H, s, (CH3)3CSi), 1.00-1.65 (6H, m, H2', H3' and H4'), 3.39 (2H, t, J=6.6 Hz, H5'),
3.80 (3H, s, OCH3), 3.90-4.40 (3H, m, H5 and H1'), 4.41 (2H, s, OCH2Ar), 4.52-4.60 (1H,
m, H2), 5.02-5.25 (2H, m, OCH2Ph), 5.70-5.88 (2H, m, H3 and H4), 6.82-6.92 (2H, m, 2 x
ArCH), 7.20-7.40 (7H, m, 2 x ArCH and OCH2Ph) minor rotamer inter alia -0.09 (3H, s,
CH3Si), 0.19 (3H, s, CH3Si), 0.92 (9H, s, (CH3)3CSi), 3.79 (3H, s, OCH3), 4.42 (2H, s,
OCH2Ar), 4.62-4.70 (1H, m, H2).
δC (75 MHz, CDCl3): major rotamer inter alia -5.0 (q, CH3Si), -4.7 (q, CH3Si), 17.9 (s,
(CH3)3CSi), 22.8 (t, C3'), 25.8 (q, (CH3)3CSi), 29.7, 30.5 (t, C2' and C4'), 55.2 (q, OCH3),
67.3 (t, OCH2Ph), 68.5 (d, C2), 69.9 (t, C5'), 72.2 (d, C1'), 72.4 (t, OCH2Ar), 113.7 (d, 2 x
ArCH), 126.1, 127.3, 128.2, 128.4, 128.5 (d, OCH2Ph), 129.1 (d, 2 x ArCH), 130.8 (s,
ArC), 149.2 (s, OCH2Ph), 154.6 (s, CO), 159.0 (s, ArC), minor rotamer inter alia -4.7 (q,
CH3Si), -4.4 (q, CH3Si), 18.0 (s, (CH3)3CSi), 15.4 (t, C3'), 25.7 (q, (CH3)3CSi), 29.9, 30.8
(t, C2' and C4'), 54.2 (t, C5), 66.6 (t, OCH2Ph), 69.3 (d, C2), 70.0 (t, C5'), 71.3 (d, C1'),
125.8, 127.5, 127.6, 127.9, 128.6 (d, OCH2Ph).
N-[(1S,2S)-2-[[(1,1-Dimethylethyl)dimethysilyl]oxy]-1-ethenyl-6-[(4-
methoxyphenyl)methoxy]hexyl]-formamide (317).
The amino alcohol 280 (94 mg, 0.339 mmol) was reacted as
described above except that the reaction was performed at
RT for 3 h. Column chromatography (increasing polarity
from 2.5 % to 15 % MeOH in DCM as eluant) gave the title
NOTBSCbz
HH
OPMB
1
2
34
5 1'2'
3'
4'
5'
NH OTBSH
H
OPMBO 45
61 231'
2'
150
compound (69 mg, 0.164 mmol, 48.3 %) as a clear oil.
MS (CI+) m/z 422 (100 %) (M+1), HRMS (CI+) found 422.2701, calc for C23H39NO4Si
422.2727 (M+1).
δH (300 MHz, CDCl3): 0.02 (3H, s, CH3Si), 0.03 (3H, s, CH3Si), 0.86 (9H, s, (CH3)3CSi),
1.20-1.66 (6H, m, H3, H4 and H5), 3.41 (2H, dt, J=6.3, 2.7 Hz, H6), 3.78 (3H, s, OCH3),
3.64-3.80 (1H, m, H2), 4.40 (2H, s, OCH2Ar), 4.50-4.62 (1H, m, H1), 5.10-5.26 (2H, m,
H2'), 5.77 (1H, ddd, J=17.1, 10.2, 5.1 Hz, H1'), 5.96 (1H, d, J=8.4 Hz, NH), 6.86 (2H, dt,
J=8.7, 1.8 Hz, 2 x ArCH), 7.24 (2H, dt, J=8.7, 1.8 Hz, 2 x ArCH), 8.28 (1H, s, CHO).
δC (75 MHz, CDCl3): -4.5 (q, CH3Si), -4.3 (q, CH3Si), 18.0 (s, (CH3)3CSi), 22.2 (t, C4),
25.8 (q, (CH3)3CSi), 29.6, 34.4 (t, C3 and C5), 52.4 (d, C1), 55.2 (q, OCH3), 69.7 (t, C6),
72.5 (t, OCH2Ar), 74.0 (d, C2), 113.6 (d, 2 x ArCH), 115.6 (t, C2'), 129.2 (d, 2 x ArCH),
130.5 (s, ArC), 136.7 (d, C1'), 160.7 (d, CHO), 164.2 (s, ArC).
7.2.15 General method for cis-dihydroxylation with OsO4. The starting 2,5-dihydropyrrole (1.088 mmol) was dissolved in acetone (6 mL), then water
(4 mL), N-methyl-morpholine-N-oxide (269 mg, 2.32 mmol) and K2OsO4.2H2O (20 mg,
0.0544 mmol) were added. The mixture was stirred at RT for 20 h, then all volatiles were
removed in vacuo to give a brown oil. The pure product was obtained by column
chromatography using the stated solvent system.
Dimethylethyl (2R,3R,4S)-3,4-dihydroxy-2-[(1R)-1-hydroxy-4-[(4-
methoxyphenyl)methoxy]butyl]-1-pyrrolidinecarboxylate (245).
The 2,5-Dihydropyrrole 231 (255 mg, 0.676 mmol) was
reacted as described above. Column chromatography
(increasing polarity from 2.5 % to 15 % MeOH in DCM as
eluant) gave the title compound (249 mg, 0.605 mmol, 89.5 %)
as a clear oil.
[α]D25: -18 (c 2.4, CHCl3).
MS (CI+) m/z 412 (2 %) (M+1), HRMS (ES+) found 412.2341, calc for C21H34NO7
412.2335 (M+1).
N
OHOH
BocH OH
HOPMB1'
2'3'
4'
1
2
34
5
151
δH (300 MHz, CDCl3): 1.39 (9H, s, (CH3)3C), 1.20-1.90 (4H, m, H2' and H3'), 3.00-4.50
(10H, m, H2, H4, H5, H1', H4' and 3 x OH), 3.73 (3H, s, OCH3), 4.37 (2H, s, OCH2Ar),
4.82 (1H, m, H3), 6.81 (2H, d, J=9.0 Hz, 2 x ArCH), 7.19 (2H, d, J=9.0 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): major rotamer 26.3 (t, C3'), 28.3 (q, (CH3)3C), 28.9 (br. t, C2'), 52.0
(br.t, C5), 55.1 (q, OCH3), 67.4 (br. d, C2), 69.7 (t, C4'), 71.1, 71.8, 72.7 (br. d, C3, C4 and
C1'), 72.3 (t, OCH2Ar), 80.1 (s, (CH3)3C), 113.5 (d, 2 x ArCH), 129.1 (d, 2 x ArCH), 130.0
(s, ArC), 155.9 (s, CO), 158.8 (s, ArC) minor rotamer inter alia 30.5 (br. t, C2'), 50.9 (br. t,
C5), 67.9 (br. d, C2), 69.8 (t, C4'), 71.0 (br. d, C3/C4/C1'), 154.9 (s, CO).
1,1-Dimethylethyl (2R,3R,4S)-2-[(1S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-
hydroxybutyl]-3,4-dihydroxy-1-pyrrolidinecarboxylate (250).
The 2,5-dihydropyrrole 218 (205 mg, 0.552 mmol) was reacted
as described above. Column chromatography (increasing
polarity from 2.5 % to 10 % MeOH in DCM as eluant) gave the
title compound (203 mg, 0.500 mmol, 90.7 %) as a colourless
oil.
[α]D24: -31 (c 2.0, CHCl3).
MS (CI+) m/z 406 (100 %) (M+1), HRMS (ES+), found 406.2631, calc for C19H39NO6Si
406.2625 (M+1).
δH (300 MHz, CDCl3): 0.00 (6H, s, (CH3)2Si), 0.83 (9H, s, (CH3)3Si), 1.39 (9H, s,
(CH3)3C-O), 1.20-1.75 (4H, m, H2' and H3'), 3.02 (1H, br. s, OH), 3.15-4.20 (9H, m, H2,
H3, H4, H5, H6, H4' and OH), 4.64 (1H, br. s, OH).
δC (75 MHz, CDCl3): major rotamer -5.3 (q, CH3Si), -5.3 (q, CH3Si), 18.3 (s, (CH3)3CSi),
25.9 (q, (CH3)3CSi), 28.4 (q, (CH3)3C-O), 29.0, 29.9 (br. t, C2' and C3'), 51.8 (t, C5), 63.3
(d, C4'), 67.2, 70.0, 72.3, 73.0 (br. d, C2, C3, C4 and C1'), 80.3 (s, (CH3)3C-O), 156.6 (br.
s, CO), minor rotamer inter alia 18.2 (s, (CH3)3CSi), 57.9 (t, C4'), 66.8, 69.5, 73.8 (br. d,
C2, C3 and C4), 155.5 (br. s, CO).
NOHH
HOTBS
Boc
OH OH4
5 1'
1
2
3 2'
3'
4'
152
1,1-Dimethylethyl (2R,3R,4S)-2-[(1S)-1-hydroxypentyl-5-[(4-
methoxyphenyl)methoxy]]-3,4-dihydroxy-1-pyrrolidinecarboxylate (264).
The 2,5-dihydropyrrole 263 (426 mg, 1.088 mmol) was
reacted as described above. Column chromatography
(increasing polarity from 2.5 % to 10 % MeOH in DCM as
eluant) gave the title compound (442 mg, 1.039 mmol, 95.5
%) as a clear oil.
[α]D27: -28 (c 1.0, CHCl3).
MS (CI+) m/z 426 (100 %) (M+1), HRMS (CI+) found 426.2482, calc for C22H36NO7
426.2492 (M+1).
δH (300 MHz, CDCl3): 1.40 (9H, s, (CH3)3C), 1.30-1.70 (8H, m, H2', H3', H4' and 2 x
OH), 3.30-4.30 (9H, m, H2, H3, H4, H5, H1', H5' and OH), 3.78 (3H, s, OCH3), 4.40 (2H,
s, OCH2Ar), 6.84 (2H, d, J=8.4 Hz, 2 x ArCH), 7.23 (2H, d, J=8.4 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 22.0 (br. t, C3'), 28.1 (q, (CH3)3C), 29.2, 32.7 (t, C2' and C4'), 51.3
(br. t, C5), 54.9 (q, OCH3), 67.0 (br. d, C2), 69.5 (br. d, C4), 69.7 (t, C5'), 72.2 (t,
OCH2ArCH), 72.9 (br. d, C3), 76.4 (d, C1'), 80.3 (s, (CH3)3C), 113.5 (d, 2 x ArCH), 129.0
(d, 2 x ArCH), 130.1 (s, ArC), 156.8 (br. s, CO), 158.8 (s, ArC).
(1R,6R,7S,7aR)-1-[3-[(4-Methoxyphenyl)methoxy]propyl]-tetrahydro-6,7-dihydroxy-
1H,3H-pyrrolo[1,2-c]oxazol-3-one (272) and (1R,6S,7R,7aR)-1-[3-[(4-
methoxyphenyl)methoxy]propyl]-tetrahydro-6,7-dihydroxy-1H,3H-pyrrolo[1,2-
c]oxazol-3-one (273).
The oxazolidinone 255 (378 mg, 1.246
mmol) was reacted as described
above. Column chromatography
(increasing polarity from 5 % to 10 %
MeOH in DCM as eluant) gave the
mixture of title compounds (356 mg, 1.055 mmol, 84.7 %) as a white solid. Two isomers
were present in a 3:1 ratio. An analytical sample of the major isomer 272 was isolated by
preferential recrystallisation from hot DCM (40 mL) and pet. sp. (5-10 mL), which gave
177 mg as colourless needles.
NOHH
H
OPMB
Boc
OH OH
5'
4
5 1'
1
2
3 2'
3'
4'
NO
OPMB
O
HH
OH OH
NO
OPMB
O
HH
OH OH
2'
4 1
23
5
67
3'1'7a2'
4 1
23
5
67
3'1'7a
272 273
153
Alternative method:
The oxazolidinone 255 (106 mg, 0.349 mmol) was dissolved in acetone (3.3 mL) then H2O
(1.8 mL), AD-mix-β (492 mg), (DHQD)2PHAL (11 mg, µ14 mol) and methane
sulfonamide (66 mg, 0.822 mmol) were added. The mixture was stirred at RT for 6 d, then
Na2SO3 (1.5 g) was added and the mixture stirred for 20 min. The mixture was poured into
water (40 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were
dried (MgSO4), filtered and evaporated in vacuo gave a semi solid. Column
chromatography (increasing polarity from 2 % to 10 % MeOH in DCM as eluant) gave the
mixture of title compounds (54 mg, 0.160 mmol, 45.9 %) as a white solid, and recovered
255 (48 mg, 0.158 mmol, 45.3 %) as a clear oil.
MS (CI+) m/z 338 (17 %) (M+1), HRMS (EI+) found 337.1505, calc for C17H24NO6
337.1525 (M+1).
272:
m.p. 146 oC
[α]D25: -31.0 (c 1.77, CHCl3).
δH (300 MHz, CDCl3): 1.60-1.75 (1H, m, H2'a), 1.75-1.90 (1H, H2'b), 2.00-2.15 (1H, m,
H1'a), 2.15-2.30 (1H, m, H1'b), 2.80 (1H, br. s, OH), 3.10 (1H, br. s, OH), 3.34-3.70 (5H,
m, H5, H7a and H3'), 3.77 (3H, s, OCH3), 3.98 (1H, br. s, H6), 4.35-4.45 (1H, m, H7),
4.40 (2H, s, OCH2Ar), 4.59 (1H, app q, J=7.1 Hz, H1), 6.86 (2H, dt, J=8.7, 1.5 Hz, 2 x
ArCH), 7.23 (2H, dt, J=8.7, 1.5 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 26.3, 26.4 (t, C1' and C2'), 49.9 (t, C5), 55.2 (q, OCH3), 65.1 (d,
C7a), 69.3 (t, C3'), 70.8 (d, C6), 72.6 (t, OCH2Ar), 73.6 (d, C7), 76.7 (d, C1), 113.8 (d, 2 x
ArCH), 129.3 (d, 2 x ArCH), 130.2 (s, ArC), 159.2 (s, ArC), 163.0 (s, C3).
273:
δC (75 MHz, CDCl3): inter alia 25.5, 26.5 (t, C1' and C2'), 52.8 (t, C5), 55.2 (q, OCH3),
63.9 (d, C7a), 69.0 (t, C3'), 70.0 (d, C6), 70.9 (d, C7), 72.6 (t, OCH2Ar), 76.2 (d, C1), 113.8
(d, 2 x ArCH), 129.4 (d, 2 x ArCH), 129.9 (s, ArC), 159.2 (s, ArC), 163.0 (s, C3).
7.2.16 General method for the benzylation of alcohols. The starting alcohol (2.040 mmol) was dissolved in dry THF (16 mL), then sodium hydride
(196 mg, 4.08 mmol, 50 % dispersion in paraffin wax), benzylbromide (0.72 mL, 6.13
154
mmol) and tetra-n-butylammonium iodide (76 mg, 0.204 mmol) were added in quick
succession. The mixture was stirred at RT under nitrogen for 2 d, then quenched with
water (50 mL) and extracted with DCM (3 x 40 mL). The combined organic extracts in
were dried (MgSO4), filtered and evaporated in vacuo to give an oil. The pure products
were obtained by column chromatography using the stated solvent system.
1,1-Dimethylethyl (2R,3R,4S)-2-[(1R)-4-[(4-methoxyphenyl)methoxy]-1-
(phenylmethoxy)butyl]-3,4-bis(phenylmethoxy)-1-pyrrolidinecarboxylate (246) and
(1R,6S,7R,7aR)-tetrahydro-1-[3-[(4-methoxyphenyl)methoxy]propyl]-6,7-
bis(phenylmethoxy)-1H,3H-pyrrolo[1,2-c]oxazol-3-one (247).
The triol 245 (240 mg, 0.583 mmol)
was reacted as described above except
that 5 equiv. of NaH, 7 equiv. of BnBr
and 0.15 equiv. of n-Bu4NI were used.
Column chromatography (increasing polarity from 15 % to 70 % EtOAc in pet. sp. as
eluant) gave 246 (359 mg, 0.526 mmol, 90.3 %) and 247 (18 mg, 0.035 mmol, 6.0 %) as
clear oils.
246:
[α]D22: -10 (c 1.9, CHCl3).
MS (ES+) m/z 682.4 (100 %) (M+1), HRMS (ES+) found 682.3704, calc for C42H52NO7
682.3744 (M+1).
δH (300 MHz, CDCl3): two rotamers were evident in equal intensity 1.42 (4.5H, s,
(CH3)3C), 1.46 (4.5H, s, (CH3)3C), 1.40-1.90 (4H, m, H2' and H3'), 3.30-3.50 (4H. m, H5a,
H2, H4'), 3.78 (3H, s, OCH3), 3.78-3.85 (1H, m, H5b), 3.90-4.00 (1H, m, H1'), 4.16-4.22
(2H, m, H3 and H4), 4.34-4.70 (8H, m, OCH2Ar and 3 x OCH2Ph), 6.84 (2H, d, J=8.7 Hz,
ArCH), 7.15-7.40 (17H, m, ArCH and 3 x OCH2Ph).
δC (75 MHz, CDCl3): 26.5 (t, C3'), 28.6 (q, (CH3)3C), 28.9/29.4 (t, C2'), 48.4/48.9 (t, C5),
55.3 (q, OCH3), 64.9/65.2 (d, C2), 69.8/69.9 (t, C4'), 71.3/71.4, 71.6/71.8, 72.4/72.6,
73.5/74.0 (t, OCH2Ar and 3 x OCH2Ph), 75.5/76.6, 76.8/78.0, 78.2/78.8 (d, C3, C4 and
C1'), 79.5/79.8 (s, (CH3)3C), 113.6 (d, 2 x ArCH), 126.8, 127.4, 127.5, 127.6, 127.7, 127.8,
OBnBnO
NO
OPMB
O
H HNBoc
HH
OPMB
BnO OBn
OBn 1
23
45
67
3'1'2'
3'4'
1
2345 7a
2'1'
246 247
155
127.8, 127.9, 128.2, 128.2, 128.2, 128.4 (3 x OCH2Ph), 129.1 (d, 2 x ArCH), 130.4/130.6
(s, ArC), 137.9, 138.2, 138.3 (s, 3 x OCH2Ph), 154.3/154.6 (s, CO), 158.8/158.9 (s, ArC).
247:
[α]D27: +65 (c 1.25, CHCl3).
MS (ES+) m/z 518.3 (75 %) (M+1), HRMS (ES+) found 518.2565, calc for, C31H35NO6
518.2543 (M+1).
δH (300 MHz, CDCl3): 1.50 (4H, m, H1' and H2'), 3.30-3.50 (3H, m, H5a and H3'), 3.56
(1H, dd, J=9.3, 5.1 Hz, H7), 3.77 (3H, s, OCH3), 3.74-3.82 (1H, m, H5b), 4.04-4.14 (2H,
m, H6 and H7a), 4.30-4.70 (7H, m, H5, OCH2Ar and 2 x OCH2Ph), 6.84 (2H, d, J=8.4 Hz,
2 x ArCH), 7.18-7.38 (12 H, m, 2 x ArCH and 2 x OCH2Ph).
δC (75 MHz, CDCl3): 26.2, 27.0 (t, C1' and C2'), 51.1 (t, C5), 55.2 (q, OCH3), 62.9 (d,
C7a), 69.0 (t, C3'), 71.7, 71.9, 72.5 (t, OCH2Ar and 2 x OCH2Ph), 74.9, 76.3, 76.9 (d, C1,
C6 and C7), 113.6 (d, 2 x ArCH), 127.9, 128.0, 128.1, 128.1, 128.3, 128.4 (d, 2 x
OCH2Ph), 129.0 (d, 2 x ArCH), 130.3 (s, ArC), 136.5, 137.0 (s, 2 x OCH2Ph), 158.9 (s,
ArC), 161.2 (s, C3).
δH (500 MHz, d6-benzene): 1.45-1.70 (4H, m, H1' and H2'), 3.10 (1H, dd, J=10.0, 5.0 Hz,
H7), 3.16-3.24 (3H, m, H5a and H3'), 3.28 (3H, s, OCH3) 3.52 (1H, t, J=5.0 Hz, H6), 3.74
(1H, dd, J=13.0, 5.0 Hz, H5b), 3.82 (1H, dd, J=9.0, 7.5 Hz, H7a), 4.00-4.28 (7H, m, H1,
OCH2Ar and 2 x OCH2Ph), 6.76 (2H, dt, J=9.0, 2.0 Hz, 2 x ArCH), 7.10-7.22 (12H, m, 2 x
ArCH and 2 x OCH2Ph).
δC (75 MHz, d6-benzene): 26.8, 27.6 (t, C1' and C2'), 51.9 (t, C5), 54.9 (q, OCH3), 63.2 (d,
C7a), 69.5 (t, C3'), 71.7, 72.1, 72.8 (t, OCH2Ar and 2 x OCH2Ph), 75.8, 76.1, 78.4 (d, C1,
C6 and C7), 114.1 (d, 2 x ArCH), 127.9, 128.0, 128.0, 128.1, 128.6, 128.6 (d, 2 x
OCH2Ph), 129.4 (d, 2 x ArCH), 131.2 (s, ArC), 138.1, 138.3 (s, 2 x OCH2Ph), 159.6 (s,
ArC), 161.4 (s, C3).
1,1-Dimethylethyl (2R,3R,4S)-2-[(1S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-
(phenylmethoxy)butyl]-3,4-bis(phenylmethoxy)-1-pyrrolidinecarboxylate (251).
The triol 250 (200 mg, 0.493 mmol) was reacted as described
above except 5 equiv. of NaH, 7 equiv. of BnBr and 0.15
equiv n-Bu4NI were used. Column chromatography NH
HOTBS
Boc
BnO OBn
OBn
4
5 1'
1
2
3 2'3'
4'
156
(increasing polarity from 10 % to 25 % EtOAc in pet. sp. as eluant) gave the title
compound (285 mg, 0.422 mmol, 85.5 %) as a clear oil. No attempt was made to isolate
the oxazolidinone by-product.
[α]D23: -20 (c 2.85, CHCl3).
MS (CI+) m/z 676 (9 %) (M+1), HRMS (ES+) found 676.4020, calc for C40H57NO6Si
676.4033 (M+1).
δH (300 MHz, CDCl3): 0.08 (6H, s, (CH3)2Si), 0.94 (9H, s, (CH3)3CSi), 1.51 (9H, s,
(CH3)3C-O), 1.20-1.90 (4H, m, H2' and H3'), 3.40 (1H, m, H5a), 3.50-3.70 (3H, m, H4' and
H5b), 3.80-4.12 (3H, m, H2, H4 and H1'), 4.20-4.84 (7H, m, H3 and 3 x OCH2Ph), 7.20-
7.40 (15H, m, 3 x OCH2Ph).
δC (75 MHz, CDCl3): two rotamers were evident in equal intensity -5.2 (q, CH3Si), -5.2 (q,
CH3Si), 18.3 (s, (CH3)3CSi), 26.0 (q, (CH3)3CSi), 26.6/27.0 (t, C3'), 28.4 (q, (CH3)3C-O),
29.6/30.0 (t, C2'), 48.9/49.6 (t, C5), 62.6/63.7 (d, C2), 62.8/62.9 (t, C4'), 71.2/71.3,
71.4/71.8, 72.2/72.6 (t, OCH2Ph), 75.5/76.6, 77.2/77.9, 78.5/78.6 (d, C3, C4 and C1'),
79.9/79.5 (s, (CH3)3C-O), 127.4, 127.5, 127.8, 128.0, 128.1, 128.1, 128.2, 128.2 (d, 3 x
OCH2Ph), 137.5, 137.7/137.8, 138.3 (s, OCH2Ph), 154.6/155.1 (s, CO).
1,1-Dimethylethyl (2S)-2,5-dihydro-2-[(1R)-4-[(4-methoxyphenyl)methoxy]-1-
(phenylmethoxy)butyl]-1H-pyrrole-1-carboxylate (254) and (1R,7aS)-1-[3-[(4-
methoxyphenyl)methoxy]propyl]-5,7a-dihydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one
(255).
The alcohol 231 (770mg, 2.040 mmol)
was reacted as described above.
Column chromatography (increasing
polarity from 20 % to 60 % EtOAc pet.
sp. as eluant) gave 254 (708 mg, 1.514 mmol, 74.2 %) and 255 (85 mg, 0.280 mmol, 13.7
%) as clear oils.
254:
[α ]D24: -96 (c 1.6, CHCl3).
MS (CI+) m/z 468 (21 %) (M+1), HRMS (CI+) found 466.2585, calc for C28H38NO5
466.2593 (M+1).
NO
OPMB
O
HH
NOPMB
BocH
HOBn
4 1
23
5
6 7
3'4
51'
1
2
33'
4'2'7a
1'2'
254 255
157
δH (300 MHz, CDCl3): two rotamers were evident in equal intensity 1.45 (4.5H, s,
(CH3)3C), 1.49 (4.5H, s, (CH3)3C), 1.40-1.86 (4H, m, H2' and H3'), 3.34-3.49 (2H, m, H4'),
3.80 (3H, s, OCH3), 3.82-4.62 (8H, m, H2, H5, H1', OCH2Ar and OCH2Ph), 5.74-5.97 (2H,
m, H3 and H4), 6.87 (2H, d, J=8.1 Hz, 2 x ArCH), 7.20-7.36 (7H, m, OCH2Ph and 2 x
ArCH).
δC (75 MHz, CDCl3): 26.4/26.5 (t, C2'), 28.5 (q, (CH3)3C), 29.5 (t, C3'), 53.6/53.8 (t, C5),
55.1 (q, OCH3), 68.2/68.4 (d, C2), 69.7/69.8 (t, C4'), 72.2/72.4 (t, OCH2Ar), 73.4/73.9 (t,
OCH2Ph), 78.0/79.0 (d, C1'), 79.2/79.5 (s, (CH3)3C), 113.5/113.5 (d, 2 x ArCH),
125.5/125.7, 126.8/127.0 (d, C3 and C4), 127.2/127.3, 127.5/127.7, 128.0/128.1 (d, PhCH),
128.9/129.0 (d, 2 x ArCH), 130.2/130.4 (s, ArC), 138.4/138.7 (s, PhC), 153.7/153.9 (s,
CO), 158.7/158.8 (s, ArC).
1,1-Dimethylethyl (2R,3R,4S)-2-[(1S)-5-[(4-methoxyphenyl)methoxyoxy)]-1-
(phenylmethoxy)pentyl]-3,4-bis(phenylmethoxy)-1-pyrrolidinecarboxylate (265) and
(1S,6S,7R,7aR)-tetrahydro-1-[4-[(4-methoxyphenyl)methoxy]butyl]-6,7-
bis(phenylmethoxy)-1H,3H-pyrrolo[1,2-c]oxazol-3-one (266).
The triol 264 (440 mg, 1.034 mmol)
was reacted as described above
except 5 equiv. of NaH, 7 equiv. of
BnBr and 0.3 equiv. of n-Bu4NI
were used. Column chromatography (increasing polarity form 20 % to 100 % EtOAc in
pet. sp. as eluant) gave the title compound (396 mg, 0.569 mmol, 55.0 %), and the
oxazolidinone (116 mg, 0.218 mmol, 21.1 %) as clear oils.
265:
[α]D30: -29 (c 3.96, CHCl3).
MS (ES+) m/z 696.4 (100 %) (M+1), HRMS (ES+) found 696.3895, calc for C43H54NO7
696.3900 (M+1).
δH (300 MHz, CDCl3): 1.45 (9H, s, (CH3)3C), 1.20-1.70 (6H, m, H2', H3' and H4'), 3.28-
3.43 (3H, m, H5a and H5'), 3.52 (1H, br. d, J=6.3 Hz, H5b), 3.78 (3H, s, OCH3), 3.75-3.87
(1H, m, H1'), 3.87-4.06 (2H, m, H3 and H4), 4.17-4.74 (7H, m, H2 and 3 x OCH2Ph), 4.40
NO
OPMB
O
OBnBnO
H
HN
HH
OPMB
Boc
BnO OBn
OBn1
234
56
7
5'
4
5 1'
1
2
3 2'
3'
4'7a
1'
2'
3'
4'
265 266
158
(2H, s, OCH2Ar), 6.86 (2H, d, J=9.0 Hz 2 x ArCH), 7.21-7.36 (17 H, m, 2 x ArCH and 3 x
OCH2Ph).
δC (75 MHz, CDCl3): two rotamers were evident in equal intensity 22.9/23.2 (t, C3'), 28.4
(q, (CH3)3C), 29.6 (t, C4'), 30.0/30.4 (t, C2'), 48.8/49.5 (t, C5), 55.2 (q, OCH3), 62.5/63.6
(d, C2), 69.9 (t, C5'), 71.2, 71.3/71.8, 72.4, 72.3/72.6 (t, OCH2Ar and 3 x OCH2Ph),
75.3/76.3, 76.5/77.8, 78.4/78.6 (d, C3, C4 and C1'), 79.7/80.0 (s, (CH3)3C), 113.7 (d,
ArCH), 127.6, 127.7, 127.7, 128.0, 128.0, 128.2, 128.2, 128.3, 128.3 (d, 3 x OCH2Ph),
129.1 (d, 2 x ArCH), 130.6 (s, ArCH), 137.6, 138.0, 138.4 (s, 3 x OCH2Ph), 159.0 (s, 2 x
ArCH), 164.0 (s, CO).
266:
[α]D30: +28 (c 1.03, CHCl3).
MS (ES+) m/z 532.3 (47 %) (M+1), HRMS (ES+) found 532.2698, calc for C32H37NO6
532.2699 (M+1).
δH (300 MHz, CDCl3): 1.40-1.86 (6H, m, H1', H2' and H3'), 3.37 (1H, dd, J=12.9, 1.5 Hz,
H5a), 3.42 (2H, t, J=6.3 Hz, H4'), 3.53 (1H, dd, 9.0, 4.8 Hz, H7), 3.70-3.80 (2H, m, H5b
and H7a), 3.77 (3H, s, OCH3), 4.09 (1H, td, J=5.1, 1.5 Hz, H6), 4.22 (1H, ddd, J=7.2, 5.4,
3.6 Hz, H1), 4.39 (1H, d, J=12.0 Hz, OCH2Ph), 4.41 (2H, s, OCH2Ar), 4.59 (2H, AB
system, J=12.0 Hz, OCH2Ph), 4.65 (1H, d, J=12.0 Hz, OCH2Ph), 6.86 (2H, dt, J=8.4, 3.0
Hz, 2 x ArCH), 7.22-7.38 (12H, m, 2 x ArCH and 2 x OCH2Ph).
δC (75 MHz, CDCl3): 21.1 (t, C2'), 29.2 (C3'), 35.0 (t, C1'), 50.8 (t, C5), 55.1 (q, OCH3),
65.0 (d, C7a), 69.4 (t, C4'), 71.9, 72.2, 72.4 (t, OCH2Ar and 2 x OCH2Ph), 75.8, 79.0 (C6
and C7), 81.5 (d, C1), 113.6 (d, 2 x ArCH), 127.7, 127.9, 127.9, 128.1, 128.4, 128.5 (d, 2 x
OCH2Ph), 129.1 (d, 2 x ArCH), 130.4 (s, ArC), 137.0, 137.2 (s, 2 x OCH2Ph), 159.0 (s,
ArC), 160.9 (s, C3).
159
(1S,6R,7S,7aR)-Tetrahydro-1-[3-[(4-methoxyphenyl)methoxy]propyl]-6,7-
bis(phenylmethoxy)-1H,3H-pyrrolo[1,2-c]oxazol-3-one (274) and (1S,6S,7R,7aR)-
tetrahydro-1-[3-[(4-methoxyphenyl)methoxy]propyl]-6,7-bis(phenylmethoxy)-1H,3H-
pyrrolo[1,2-c]oxazol-3-one (247).
The diol 272 (177 mg, 0.525 mmol)
was reacted as described above except
that 3 equiv. of NaH, 4 equiv. of
BnBr and 0.2 equiv. of nBu4NI were
used. Column chromatography
(increasing polarity from 30 % to 80 % EtOAc in pet. sp. as eluant) gave 274 (272 mg,
0.525 mmol, 100 %) as a clear oil. When starting with a mixture of the diols 272 and 273,
the mixture of products 274 and 247 may also be separated using this method.
274:
[α]D23: -17 (c 1.18, CHCl3).
MS (CI+) m/z 518 (25 %) (M+1), HRMS (CI+) found 518.2524, calc for C31H36NO6
518.2543 (M+1).
δH (300 MHz, CDCl3): 1.50-1.92 (3H, m, H1'a and H2'), 1.98-2.14 (1H, m, H1'b), 3.32
(1H, ddd, J=9.3, 7.5, 5.4 Hz, H3'a), 3.40-3.49 (2H, m, H5a and H3'b), 3.58-3.67 (2H, m,
H5b and H7a), 3.79 (3H, s, OCH3), 3.96 (1H, t, J=2.4 Hz, H7), 4.19 (1H, td, J=8.4, 2.7 Hz,
H6), 4.37 (2H, s, OCH2Ar), 4.52-4.62 (4H, m, H1 and 1.5 x OCH2Ph), 5.04 (1H, d, J=11.7
Hz, 0.5 x OCH2Ph), 6.85 (2H, dt, J=8.4, 3.0 Hz, 2 x ArCH), 7.20 (2H, dt, J=8.4, 3.0 Hz, 2 x
ArCH), 7.22-7.39 (10H, m, 2 x OCH2Ph).
δC (75 MHz, CDCl3): 26.1 (t, C1'), 26.6 (t, C2'), 48.3 (t, C5), 55.2 (q, OCH3), 63.8 (d,
C7a), 69.2 (t, C3'), 72.5 (t, OCH2Ar), 72.6, 72.8 (t, 2 x OCH2Ph), 76.2 (d, C7), 76.2 (d,
C1), 82.4 (d, C6), 113.7 (d, 2 x ArCH), 127.1, 127.3, 127.4, 128.0, 128.2, 128.5 (d, 2 x
OCH2Ph), 129.2 (d, 2 x ArCH), 130.4 (s, ArC), 137.3, 137.9 (s, 2 x OCH2Ph), 159.1 (s,
ArC), 162.2 (s, C3).
NO
OPMB
O
HH
BnO OBn
NO
OPMB
O
HH
BnO OBn
2'4 1
23
5
6 73'
7a1'
2'4 1
23
5
6 73'
7a1'
274 247
160
7.2.17 General method for TFA deprotection of N-Boc and N-Boc/O-PMB
derivatives. The starting N-Boc carbamate (0.569 mmol) was dissolved in DCM (5 mL), then TFA (5
mL) and anisole (0.60 mL, 5.44 mmol) were added. The mixture was stirred at RT for 2 h,
then all volatiles were removed in vacuo. The residue was dissolved in CHCl3 then poured
into sat. Na2CO3 solution (5 mL), and extracted with CHCl3 (3 x 25 mL). The combined
organics were dried (MgSO4), filtered and evaporated in vacuo to give an oil. The pure
product was obtained by column chromatography using the stated solvent system.
(δR,2S)-2,5-Dihydro-δ-[(phenylcarbonyl)oxy]-1H-pyrrole-2-butanol (233).
The carbamate 232 (110 m, 0.229 mmol) was reacted as described
above except that the reaction only proceeded for 1 h. Column
chromatography (increasing polarity from 15 % to 40 % MeOH in
DCM as eluant) gave the unstable title compound (43 mg, 0.165 mmol, 71.9 %) as a pale
yellow oil.
MS (ES+) m/z 262.0 (100 %) (M+1), HRMS (CI+) found 262.1434, calc for C15H20NO3
262.1443 (M+1).
δH (300 MHz, CDCl3): 1.55-1.95 (4H, m, H2' and H3'), 2.55 (2H, br s, NH and OH), 3.62-
3.87 (4H, m, H5 and H1'), 4.34 (1H, m, H2), 5.14 (1H, ddd, J=8.4, 5.4, 4.2 Hz, H4'), 5.81
(1H, ddd, J= 6.3, 3.9, 2.1 Hz, H3), 5.96 (1H, ddd, J=6.0, 3.9, 1.8 Hz, H4), 7.44 (2H, t,
J=7.8 Hz, OBz), 7.57 (1H, tt, J=7.5, 1.2 Hz, OBz), 8.04 (2H, d, J=7.8 Hz, OBz).
δC (75 MHz, CDCl3): 27.5, 28.7 (t, C2' and C3'), 54.0 (t, C5), 62.1 (t, C1'), 68.3 (d, C2),
76.8 (d, C4'), 127.8 (d, OBz), 128.4 (d, OBz), 129.6 (d, OBz), 130.0 (s, OBz), 130.4, 133.0
(d, H3 and H4), 166.5 (s, CO).
(δR,2S)-2,5-Dihydro-δ-(2,2-dimethyl-1-oxopropoxy)-1H-pyrrole-2-butanol (244).
The carbamate 243 (370 mg, 0.802 mmol) was reacted as described
above. Column chromatography (increasing polarity from 15 % to
35 % MeOH in DCM as eluant) gave the unstable title compound
(55 mg, 0.228 mmol, 28.4 %) as a pale yellow oil.
NH
OHOBzH
H
4 1'2'
1
2
3 3'
4'5
NH
OH
OPivHH
4
5
3'
1
2
32'
1'4'
161
MS (ES+) m/z 242.4 (100 %) (M+1), HRMS (CI+) found 242.1794, calc for C13H24NO3
242.1756 (M+1).
δH (300 MHz, CDCl3): 1.21 (9H, s, (CH3)3C), 1.40-1.85 (4H, m, H2' and H3'), 3.18 (2H,
br. s, NH and OH), 3.65 (2H, t, J=6.0 Hz, H1'), 3.72-3.88 (2H, m, H5), 4.24 (1H, br. s, H2),
4.88 (1H, ddd, J=8.4, 5.1, 3.6 Hz, H4'), 5.72 (1H, br. s, H3), 5.92 (1H, br. s, H4).
δC (75 MHz, CDCl3): 27.2 (q, (CH3)3C), 27.7, 28.4 (t, C2' and C3'), 38.9 (s, (CH3)3C), 53.7
(t, C5), 61.6 (t, C1'), 68.2 (d, C2), 75.5 (d, C4'), 127.5, 129.7 (C3 and C4), 178.2 (s, CO).
(δR,2R,3R,4S)-δ,3,4-Tris(phenylmethoxy)-2-pyrrolidinebutanol (248).
The carbamate 246 (359 mg, 0.526 mmol) was reacted as
described above. Column chromatography (increasing polarity
from 5 % to 15 % MeOH in DCM as eluant) gave the title
compound (217 mg, 0.470 mmol, 89.4 %) as a pale yellow solid.
m.p. 62-64 oC (Et2O).
[α]D25: +37 (c 1.03, CHCl3).
MS (CI+) m/z 462 (100 %) (M+1), HRMS (CI+) found 462.2651, calc for C29H36NO4
462.2644 (M+1).
δH (300 MHz, CDCl3): 1.54-1.80 (4H, m, H2' and H3'), 2.74 (2H, br. s, NH and OH), 2.98
(1H, dd, J=11.4, 5.1 Hz, H5a), 3.05 (1H, dd, J=11.4, 5.1 Hz, H5b), 3.36-3.48 (2H, m, H2
and H4'), 3.48-3.58 (2H, m, H1'), 3.82-3.94 (2H, m, H3 and H4), 4.44-4.64 (6H, m, 3 x
OCH2Ph), 7.22-7.35 (15H, m, 3 x OCH2Ph).
δC (75 MHz, CDCl3): 27.3, 28.6 (t, C2' and C3'), 49.1 (t, C5), 62.2 (t, C1'), 64.1 (d, C2),
71.6, 71.6, 71.8 (t, 3 x OCH2Ph), 77.9, 79.1, 79.6 (d, C3, C4 and C4'), 127.4, 127.4, 127.5,
127.6, 127.7, 127.8, 128.1, 128.2, 128.2 (d, 3 x OCH2Ph), 137.9, 138.0, 138.3 (s, 3 x
OCH2Ph).
(δS,2R,3R,4S)-δ,3,4-Tris(phenylmethoxy)-2-pyrrolidinebutanol (252).
The carbamate 251 (285 mg, 0.422 mmol) was reacted as
described above except that the anisole was omitted. Column
chromatography (increasing polarity from 5 % to 12.5 % MeOH
NH
OBnBnO
OBn
OHH
H1
234
53'
2'1'
4'
NH H
HOH
BnO OBn
OBn
4
5 4'
1
2
3 3'2'
1'
162
in DCM as eluant) gave the title compound (166 mg, 0.360 mmol, 85.2 %) as a clear gum.
[α]D23: +64 (c 1.69, CHCl3).
MS (ES+) m/z 462.3 (M+1), HRMS (ES+) found 462.2652, calc for C29H36NO4 462.2644
(M+1).
δH (300 MHz, CDCl3): 1.54-1.82 (4H, m, H2' and H3'), 3.09 (2H, d, J=4.2 Hz, H5), 3.38
(1H, dd, J=7.5, 2.4 Hz, H2), 3.50-3.64 (3H, m, H4' and H1'), 3.70-3.84 (3H, m, H3, NH and
OH), 3.86-3.94 (1H, m, H4), 4.29 (2H, AB system, J=11.7 Hz, OCH2Ph), 4.44-4.64 (4H,
m, 2 x CH2Ph), 7.18-7.40 (15H, m, 3 x OCH2Ph).
δC (75 MHz, CDCl3): 27.5, 28.4 (t, C2' and C3'), 49.1 (t, C5), 62.1 (t, C1'), 62.9 (d, C2).
71.2, 71.7, 72.0 (t, 3 x CH2Ph), 76.1, 77.1, 79.4 (d, C3, C4 and C4'), 127.4, 127.5, 127.6,
127.7, 127.7, 127.8, 128.1, 128.1, 128.1 (d, 3 x OCH2Ph), 137.7, 137.8, 138.0 (s, 3 x
OCH2Ph).
(δR,2S)-2,5-Dihydro-δ-(phenylmethoxy)-1H-pyrrole-2-butanol (256).
The carbamate 254 (665 mg, 1.422 mmol) was reacted as described
above. Column chromatography (increasing polarity from 25 % to
50 % MeOH in DCM as eluant) gave the title compound (310 mg,
1.253 mmol, 88.1 %) as a clear oil.
[α]D24: -83 (c 4.0, CHCl3).
MS (CI+) m/z 248 (100 %) (M+1), HRMS (CI+) found 248.1654, calc for C15H22NO2
248.1651 (M+1).
δH (300 MHz, CDCl3): 1.50-1.80 (4H, m, H2' and H3'), 3.28-3.40 (1H, m, H4'), 3.44-3.78
(6H, m, NH, OH, H5 and H1'), 4.10-4.20 (1H, m, H2), 4.28 (2H, s, OCH2Ph), 5.80-5.90
(2H, m, H3 and H4), 7.20-7.38 (5H, m, OCH2Ph).
δC (75 MHz, CDCl3): 27.5, 28.6 (t, C2' and C3'), 53.5 (t, C5), 62.8 (t, C1'), 67.7 (d, C2),
71.8 (t, OCH2Ph), 81.6 (d, C4'), 127.3, 128.9, 129.0 (d, C3, C4 and OCH2Ph), 127.5, 128.0
(d, OCH2Ph), 138.2 (s, OCH2Ph).
NH
OHH
HOBn
4
5
3'
1
2
3
2'
1'4'
163
(εS,2R,3R,4S)-ε,3,4-Tris(phenylmethoxy)-2-pyrrolidinepentanol (267).
The carbamate 265 (396 mg, 0.569 mmol) was reacted as
described above. Column chromatography (increasing
polarity from 5 % to 15 % MeOH in DCM as eluant) gave the
title compound (260 mg, 0.547 mmol, 96.1 %) as a clear oil.
[α]D26: +81 (c 2.60, CHCl3).
MS (ES+) m/z 476.7 (100 %) (M+1), HRMS (ES+) found 476.2808, calc for C30H38NO4
476.2801 (M+1).
δH (300 MHz, CDCl3): 1.26-1.90 (6H, m, H2', H3' and H4'), 2.96-3.15 (4H, m, H5, NH and
OH), 3.31 (1H, dd, J=7.5, 2.4 Hz, H2), 3.50 (1H, td, J=7.2, 2.4 Hz, H5'), 3.58 (2H, t, J=6.3
Hz, H1'), 3.70 (1H, dd, J=7.5 and 5.1 Hz, H3), 3.90 (1H, q, J=4.5 Hz, H4), 4.23 (1H, d,
J=11.1 Hz OCH2Ph), 4.32 (1H, d, J=11.7 Hz, OCH2Ph), 4.50 (1H, d, J=12.0 Hz, OCH2Ph),
4.55 (1H, d, J=11.4 Hz, OCH2Ph), 4.60 (1H, d, J=12.0 Hz, OCH2Ph), 4.62 (1H, d, J=12.0
Hz, OCH2Ph), 7.15-7.40 (15H, m, 3 x OCH2Ph).
δC (75 MHz, CDCl3): 21.4 (t, C3'), 30.6, 32.5 (t, C2' and C4'), 49.3 (t, C5), 61.6 (t, C1'),
63.0 (d, C2), 71.2, 71.9, 72.0 (t, 3 x OCH2Ph), 76.4, 77.5, 79.6 (C3, C4 and C5'), 127.5,
127.6, 127.6, 127.7, 127.9, 128.0, 128.2, 128.2, 128.2 (d, 3 x OCH2Ph), 137.9, 138.0, 138.3
(s, 3 x OCH2Ph).
7.2.18 General method for Appel cyclisation of amino alcohols. The starting amino alcohol (0.292 mmol) was dissolved in dry DCM (10 mL), then the
solution cooled to 0 oC. Carbon tetrabromide (242mg, 0.704 mmol) and
triphenylphosphine (184 mg, 0.704 mmol) were added, then the mixture was stirred at 0 oC
for 5 min. Triethylamine (1.68 mL, 12.12 mmol) was added, then the mixture was stirred
at 0 oC for 1h, before being left to stand at 4 oC for 16 h. The reaction was quenched with
water (50 mL) and extracted with DCM (3 x 40 mL). The organic extracts were dried
(MgSO4) filtered and evaporated in vacuo to give a semi-solid. The pure product was
obtained by column chromatography using the stated solvent system.
NH H
H
OH
BnO OBn
OBn
1'4
5 5'
1
2
3
3'2'4'
164
(8R,8aS)-3,5,6,7,8,8a-Hexahydro-8-[(phenylcarbonyl)oxy]-indolizine (234).
The amino alcohol 233 (42 mg, 0.161 mmol) was reacted as described
above. Column chromatography (increasing polarity from 60 % to 100
% EtOAc in pet. sp. as eluant) gave the title compound (34 mg, 0.140
mmol, 86.8 %) as a pale yellow oil.
MS (CI+) m/z 244 (70 %) (M+1), HRMS (CI+) found 244.1347, calc for C15H18NO2
244.1338 (M+1).
δH (300 MHz, CDCl3): 1.43 (1H, dddd, J=11.7, 11.1, 10.8, 7.2 Hz, H7a), 1.65-1.90 (2H, m,
H6), 2.27 (1H, dddd, J=11.7, 4.5, 3.6, 3.3 Hz, H7b), 2.56 (1H, ddd, J=11.7, 11.1, 3.6 Hz,
H5a), 3.02 (1H, br. d, J=11.7 Hz, H5b), 3.25-3.42 (2H, m, H3a and H8a), 3.65-3.75 (1H,
m, H3b), 4.87 (1H, ddd, J=10.5, 9.6, 4.5 Hz, H8), 5.90-6.04 (2H, m, H1 and H2), 7.45 (2H,
tt, J=7.2, 1.2 Hz, OBz), 7.57 (1H, tt, J=7.2, 1.2 Hz, OBz), 8.06 (2H, dt, J=7.2, 1.2 Hz,
OBz).
δC (75 MHz, CDCl3): 23.7, 30.0 (t, C6 and C7), 48.4 (t, C3), 57.5 (t, C5), 70.3 (d, C8a),
73.7 (d, C8), 128.3 (d, OBz), 129.3 (d, OBz), 129.5 (d, OBz), 130.4, 132.9 (d, C1 and C2),
138.4 (s, OBz), 165.8 (s, CO).
(1R,2S,8R,8aR)-Octahydro-1,2,8-tris(phenylmethoxy)indolizine (249).
The amino alcohol 248 (135 mg, 0.292 mmol) was reacted as described
above. Column chromatography (increasing polarity from 40 % to 80
% EtOAc in pet. sp. as eluant) gave the title compound (125 mg, 2.82
mmol, 96.5 %) as a pale yellow solid.
m.p. 42-44 oC (Et2O).
[α]D25: -6 (c 1.25, CHCl3).
MS (CI+) m/z 444 (100 %) (M+1), HRMS (CI+) found 444.2540, calc for C29H34NO3
444.2539 (M+1).
δH (300 MHz, CDCl3): 1.20-1.36 (1H, m, H7a), 1.53 (1H, qt, J=13.2, 4.2 Hz, H6a), 1.71
(1H, br. d, J=12.8 Hz, H6b), 2.12 (1H, td, J=11.4, 3.0 Hz, H5a), 2.22 (1H, ddd, J=12.3, 7.8,
4.5 Hz, H7b), 2.36 (1H, dd, J=8.7, 6.3 Hz, H8a), 2.50 (1H, t, J=8.4 Hz, H3a), 2.88 (1H, dd,
J=10.8, 2.7 Hz, H5b), 3.22-3.34 (2H, m, H3b and H8), 3.85 (1H, dd, J=7.2, 6.3 Hz, H1),
N
H OBz
12
34
56
7
88a
OBnBnO
N
HOBn
12
3
4
56
7
8a 8
165
3.98 (1H, q, J=6.9 Hz, H2), 4.46-4.72 (6H, m, 3 x OCH2Ph), 7.18-7.35 (15H, m, 3 x
OCH2Ph).
δC (75 MHz, CDCl3): 24.1 (t, C6), 30.4 (t, C7), 51.6 (t, C5), 58.1 (t, C3), 70.3, 71.9, 72.2
(t, 3 x OCH2Ph), 72.4, 75.1, 78.4, 80.3 (d, C1, C2, C8 and C8a), 127.0, 127.2, 127.4 (d, 3 x
OCH2Ph), 127.6, 127.6, 127.8, 127.9, 128.1, 128.1 (d, 3 x OCH2Ph), 138.1, 138.5, 138.6 (s,
3 x OCH2Ph).
(1R,2S,8S,8aR)-Octahydro-1,2,8-tris(phenylmethoxy)indolizine (253).
The amino alcohol 252 (165 mg, 0.357 mmol) was reacted as described
above. Column chromatography (increasing polarity from 40 % to 80
% EtOAc in pet. sp. as eluant) gave the title compound (126 mg, 0.284
mmol, 79.5 %) as a colourless oil.
[α]D24: +60 (c 1.26, CHCl3).
MS (ES+) m/z 444.3 (M+1), HRMS (ES+) found 444.2531, calc for C29H34NO3 444.2539
(M+1).
δH (300 MHz, CDCl3): 1.15-1.30 (1H, m, H7a), 1.45 (1H, br. d, J=13.2 Hz, H6a), 1.85
(1H, qt, J=13.2, 3.9 Hz, H6b), 1.96-2.12 (2H, m, H5a and H7b), 2.22-2.32 (2H, m, H3a and
H8a), 3.00 (1H, br.d, J=10.2 Hz, H5b), 3.42-3.48 (1H, m, H3b), 3.75 (1H, br. s, H8), 3.86-
4.20 (2H, m, H1 and H2), 4.30 (2H, AB system, J=12.3 Hz, OCH2Ph), 4.46-4.62 (4H, m, 2
x OCH2Ph), 7.20-7.35 (15H, m, 3 x OCH2Ph).
δC (75 MHz, CDCl3): 20.2 (t, C6), 26.6 (t, C7), 52.8 (t, C5), 60.3 (t, C3), 69.4, 70.4 (d, C8
and C8a), 71.0, 71.8, 72.4 (t, 3 x OCH2Ph), 73.5, 76.8 (d, C1 and C2), 127.3, 127.4, 127.4,
127.7, 127.9, 128.0, 128.0, 128.0, 128.1 (d, 3 x OCH2Ph), 138.0, 138.2, 138.4 (s, 3 x
OCH2Ph).
(8R,8aS)-3,5,6,7,8,8a-Hexahydro-8-(phenylmethoxy)-indolizine (257).
The amino alcohol 256 (139 mg, 0.562 mmol) was reacted as described
above except that the reaction required 3 days to complete at 0 oC.
Column chromatography (increasing polarity from 1 % to 5 % MeOH in
DCM as eluant) gave the title compound (95 mg, 0.414 mmol, 73.7 %) as
a clear oil.
OBnBnO
N
HOBn
12
3
4
56
7
8a 8
N
HOBn
12
34
56
7
88a
166
[α]D24: -115 (c 3.85, CHCl3).
MS (CI+) m/z 230 (25 %) (M+1), HRMS (CI+) found 230.1561, calc for C15H20NO
230.1545 (M+1).
δH (300 MHz, CDCl3): 1.14-1.32 (1H, m, H7a), 1.52-1.74 (2H, m, H6), 2.20 (1H, ddd,
J=11.7, 7.1, 3.9 Hz, H7b), 2.43 (1H, dt, J=11.4, 3.3 Hz, H5a), 2.88-3.04 (2H, m, H8a and
H5b), 3.18-3.32 (2H, m, H3a and H8), 3.62 (1H, br.d, J=13.2 Hz, H3b), 4.59 (2H, AB
system, J=12.3 Hz, OCH2Ph), 5.89 (1H, ddd, J=6.0, 3.9, 2.1 Hz, H1), 6.14 (1H, br. d, J=6.3
Hz, H2), 7.20-7.36 (5H, m, OCH2Ph).
δC (75 MHz, CDCl3): 24.2, 30.4 (t, C6 and C7), 48.8 (t, C5), 57.6 (t, C3), 70.9 (t,
OCH2Ph), 72.0 (d, C8a), 78.3 (d, C8), 127.3, 128.6, 131.2 (d, C1, C2 and OCH2Ph), 127.4,
128.1 (d, OCH2Ph), 138.6 (s, OCH2Ph).
(1R,2S,9S,9aR)-Octahydro-1,2,9-tris(phenylmethoxy)-1H-pyrrolo[1,2-a]azepine (268).
The amino alcohol 267 (240 mg, 0.505 mmol) was reacted as described
above. Column chromatography (increasing polarity from 1 % to 5 %
MeOH in DCM as eluant) gave the title compound (118 mg, 0.258
mmol, 51.1 %) as a clear oil.
[α]D27: +64 (c 1.15, CHCl3).
MS (ES+) m/z 458.5 (100 %) (M+1), HRMS (ES+) found 458.2694, calc for C30H36NO3
458.2695 (M+1).
δH (300 MHz, CDCl3): 1.30-1.46 (1H, m, H7a), 1.56-1.94 (5H, m, H6, H7b, H8), 2.51 (1H,
ddd, J=11.7, 8.4, 4.8 Hz, H5a), 2.84 (1H, dd, J=9.3, 7.5 Hz, H3a), 2.90 (1H, dd, J=3.9, 2.4
Hz, H9a), 3.03 (1H, dt, J=11.7, 5.7 Hz, H5b), 3.22 (1H, dd, J=9.3, 5.1 Hz, H3b), 3.56 (1H,
td, J=5.1, 2.4 Hz, H9), 3.85 (1H, t, J=4.5 Hz, H1), 4.02 (1H, dt, J=7.5, 5.1 Hz, H2), 4.22
(1H, d, J=12.0 Hz OCH2Ph), 4.35 (1H, d, J=12.0 Hz OCH2Ph), 4.53 (1H, d, J=12.3 Hz
OCH2Ph), 4.56 (1H, d, J=12.0 Hz OCH2Ph), 4.58 (1H, d, J=12.3 Hz OCH2Ph), 4.59 (1H, d,
J=12.0 Hz OCH2Ph), 7.17-7.42 (15H, m, 3 x OCH2Ph).
δC (75 MHz, CDCl3): 21.7 (t, C7), 30.0, 31.9 (t, C6 and C8), 56.5, 57.9 (t, C3 and C5),
70.5, 71.6, 72.3 (t, 3 x OCH2Ph), 72.3 (d, C9a), 75.9, 76.8 (d, C1 and C2), 80.4 (d, C9),
127.5, 127.5, 127.7, 127.9, 128.2, 128.2, 128.2, 128.3, 128.3 (d, 3 x OCH2Ph), 138.5,
138.5, 138.5 (s, 3 x OCH2Ph).
BnO OBn
NOBnH
6 7
8
99a
123
4
5
167
(1S,2R,8R,8aS)-Octahydro-1,2-bis(phenylmethoxy)-8-[[(1,1-
dimethylethyl)diphenylsilyl]oxy]-indolizine (278).
The amino alcohol 277 (359 mg, 0.588 mmol) was reacted as
described above. Column chromatography (increasing polarity
from 5 % to 30 % EtOAc in pet. sp. as eluant) gave the title
compound (325 mg, 0.549 mmol, 93.4 %) as a clear gum.
[α]D27: -10 (c 1.0, CHCl3).
MS (CI+) m/z 592 (100 %) (M+1), HRMS (CI+) found 592.3256, calc for C38H46NO3Si
592.3247 (M+1).
δH (300 MHz, CDCl3): 1.07 (9H, s, (CH3)3CSi), 1.05-1.26 (1H, m, H7a), 1.34-1.48 (2H, m,
H6), 1.70-1.90 (2H, m, H5a and H7b), 2.10 (1H, dd, J=8.7, 3.3 Hz, H8a), 2.47 (1H, dd,
J=9.6, 8.1 Hz, H3a), 2.90 (1H, d, J=10.2 Hz, H5b), 3.24 (1H, dd, J=9.9, 3.3 Hz, H3b), 4.12-
4.24 (2H, m, H2 and H8), 4.33 (1H, dd, J=5.1, 3.3 Hz, H1), 4.43 (1H, d, J=10.8 Hz,
OCH2Ph), 4.56 (2H, AB system, J=12.0 Hz, OCH2Ph), 4.87 (1H, d, J=10.8 Hz, OCH2Ph),
7.16-7.48 (16H, m, 2 x OCH2Ph and Ph2Si), 7.69 (2H, dd, J=7.8, 1.2 Hz, PhSi), 7.73 (2H,
dd, J=7.8, 1.2 Hz, PhSi).
δC (75 MHz, CDCl3): 19.1 (s, (CH3)3CSi), 23.5 (t, C6), 27.0 (q, (CH3)3CSi), 34.1 (t, C7),
52.2 (t, C5), 58.1 (t, C3), 68.8 (d, C8), 71.9 (t, OCH2Ph), 73.1 (d, C8a), 74.0 (t, OCH2Ph),
77.7 (d, C2), 78.0 (d, C1), 126.9, 127.2, 127.4, 127.6, 127.7, 128.2, 129.3, 129.4 (d, Ph),
134.4, 134.7 (s, PhSi), 135.7, 135.8 (d, PhSi), 138.2, 138.8 (s, OCH2Ph).
7.2.19 General method for debenzylation of benzyl ethers via
hydrogenation. The starting O-benzyl compound (0.280 mmol) was dissolved in MeOH (3 mL), then
palladium(II) chloride (42 mg, 0.237 mmol) was added. The mixture was stirrred at RT
under an atmosphere of H2 for 1 h, then the flask was flushed with N2, before the mixture
was filtered through celite and the solids washed with MeOH (2 x 10 mL). The filtrates
were evaporated in vacuo, then the residue dissolved in water (2 mL) and applied to a
column of Dowex-1 basic ion exchange resin. Elution with water (50 mL) followed by
evapoarion of the eluant in vacuo gave the free alcohol.
BnO OBn
H
NOTBDPS
12
345
6
7
88a
168
(1R,2S,8R,8aR)-Octahydro-1,2,8-indolizinetriol ((+)-1,2-di-epi-swainsonine).39,155
The indolizidine 249 (155 mg, 0.349 mmol) was reacted as described
above giving the title compound (57 mg, 0.329 mmol, 94.3 %) as a white
solid that had spectral data identical to that reported in the literature.39,155
m.p. 104-106 oC; lit.39 m.p.127-128 oC.
[α]D26: +4 (c 2.85, MeOH); lit.39 [α]D
25: +16 (c 1.23, MeOH).
MS (CI+) m/z 174 (100 %) (M+1), HRMS (CI+) found 174.1127, calc for C8H16NO3
174.1130 (M+1).
δH (300 MHz, D2O): 1.30-1.46 (1H, m, H7a), 1.50-1.66 (1H, m, H6a), 1.75-1.88 (1H, m,
H6b), 1.99 (1H, ddd, J=12.3, 8.1, 3.9 Hz, H7b), 2.54-2.66 (2H, m, H5a and H8a), 2.72 (1H,
dd, J=12.0, 5.1 Hz, H3a), 3.07 (1H, dt, J=12.0, 3.6 Hz, H5b), 3.54 (1H, dd, J=11.7, 7.2 Hz,
H3b), 3.64 (1H, ddd, J=9.6, 4.2, 3.9 Hz, H8), 4.06 (1H, t, J=7.2 Hz, H1), 4.28 (1H, dt,
J=6.9, 5.1 Hz, H2).
δC (75 MHz, D2O, ref CH3CN): δ 22.4 (t, C6), 32.0 (t, C7), 50.3 (t, C5), 58.6 (t, C3), 66.3
(d, C2), 70.4 (d, C8), 71.2 (d, C8a), 72.9 (d, C1).
(1R,2S,8S,8aR)-Octahydro-1,2,8-indolizinetriol ((+)-1,2,8-tri-epi-swainsonine).157
The indolizidine 253 (124 mg, 0.280 mmol) was reacted as described
above giving the title compound (45 mg, 0.260 mmol, 92.8 %) as a white
solid that had spectral data identical to that reported in the literature.157
m.p. 100-102 oC; lit.36 116-118 oC.
[α]D25: +41 (c 0.9, MeOH); lit.157 [α]D + 46 (c 0.4, MeOH).
MS (ES+) m/z 174.1 (100 %) (M+1), HRMS (ES+) found 174.1150, calc for C8H16NO3
174.1130 (M+1).
δH (300 MHz, D2O): 1.38-1.52 (2H, m, H6a and H7a), 1.54-1.74 (1H, m, H6b), 1.74-1.84
(1H, m, H7b), 1.98-2.10 (3H, m, H5a, H3a and H8a), 2.86 (1H, br. d, J=11.1 Hz, H5b),
3.30 (1H, dd, J=10.5, 6.9 Hz, H3b), 3.82 (1H, dd, J=9.0, 6.9 Hz, H1), 3.98-4.08 (2H, m, H2
and H8).
δC (75 MHz, D2O ref CH3CN): 19.5 (t, C6), 30.2 (t, C7), 52.8 (t, C5), 60.6 (t, C3), 63.6 (d,
C8a), 67.0, 69.7, 69.7 (d, C1, C2 and C8).
OHOH
N
HOH
12
3
4
56
7
8a 8
OHOH
N
HOH
12
3
4
56
7
8a 8
169
(3aR,9R,9aR,9bS)-Octahydro-2,3-dimethyl-1,3-dioxolo[4,5-a]indolizin-9-ol (261).41,188
The indolizidine 108 (60 mg, 0.198 mmol) was reacted as described above
except that the product was purified by column chromatography
(chloroform:methanol:25 % NH3(aq) 100:9:1 as eluant), which gave the
title compound (42 mg, 0.197 mmol, 100 %) as a white solid that had
spectral data identical to that reported in the literature.41,188
m.p. 80-82 oC; lit.41 100-102 oC.
[α]D26: -49 (c 0.42, CHCl3); lit.41 [α]D
26: -67 (c 0.46, CHCl3).
MS (CI+) m/z 214 (M+1), HRMS (CI+) found 214.1440, calc for C11H20NO3 214.1443
(M+1).
δH (300 MHz, CDCl3): 1.16-1.60 (1H, m, H7a), 1.34 (3H, s, CH3), 1.51 (3H, s, CH3), 1.59-
1.72 (3H, m, H7b, H8a and H9a), 1.86 (1H, ddd, J=10.5, 6.0, 4.2 Hz, H6a), 2.05 (1H, ddd,
J=11.7, 7.5, 3.3 Hz, H8b), 2.13 (1H, dd, J=11.1, 4.2 Hz, H4a), 2.61 (1H, br. s, OH), 2.99
(1H, dt, J=10.5, 3.0 Hz, H6b), 3.15 (1H, d, J=10.5 Hz, H4b), 3.83 (1H, ddd, J=11.1, 9.0,
4.8 Hz, H9), 4.61 (1H, dd, J=6.0, 4.5 Hz, H3a), 4.71 (1H, dd, J=6.3, 4.8 Hz, H9b).
δC (75 MHz, CDCl3): 24.8 (q, CH3), 25.9 (q, CH3), 24.0, 33.0 (t, C7 and C8), 51.6 (t, C6),
59.9 (t, C4), 67.1 (d, C9a), 73.6 (d, C9), 78.1 (d, C3a), 79.1 (d, C9b), 111.1 (s, C2).
(1S,2R,8R,8aR)-Octahydro-1,2,8-indolizinetriol ((-)-swainsonine).41
The indolizidine 279 (147 mg, 0.416 mmol) was reacted as described
above giving the title compound (67 mg, 0.387 mmol, 93.0 %) as a
colourless solid that had spectral data identical to that reported in the
literature.41
Alternative method:
The indolizidine 261 (43 mg, 0.202 mmol) was dissolved in THF (2 mL) then 2 M HCl (aq)
(3 mL) was added. The mixture was stirred at RT for 20 h, then all volatiles were removed
in vacuo to give an amber gum. This was dissolved in water (2 mL) and applied to Dowex-
1 basic ion-exchange resin (OH form), and eluted with water. Evaporation of the eluant
afforded the title compound (33 mg, 0.191 mmol, 94.3 %) as a colourless solid that had
spectral data identical to that reported in the literature.41
m.p. 110-114 oC; lit.41 141-143 oC.
HOH
N
OO 13
4
5
67
8
9a
2
9
9b3a
H
N
OHOH
OH1
34
56
7
88a
2
170
[α]D26: -71 (c 0.56, MeOH); lit.41 [α]D
26: -83 (c 1.03, MeOH).
MS (CI+) m/z 174 (100 %) (M+1), HRMS (ES+) found 174.1186, calc for C8H16NO3
174.1130 (M+1).
δH (300 MHz, D2O): 1.13 (1H, qd, J=12.6, 4.8 Hz, H7a), 1.41 (1H, qt, J=13.5, 4.2 Hz,
H6a), 1.62 (1H, br. d, J=13.6 Hz, H6b), 1.82 (1H, dd, J=7.8, 3.9 Hz, H8a), 1.85-2.00 (2H,
m, H5a, H7b), 2.46 (1H, dd, J=11.1, 7.8 Hz, H3a), 2.75-2.85 (2H, m, H3b, H5b), 3.69 (1H,
ddd, J=11.1, 9.6, 4.8 Hz, H8), 4.15 (1H, dd, J=6.0, 3.9 Hz, H1), 4.24 (1H, ddd, J=8.1, 6.0,
2.4 Hz, H2).
δC (75 MHz, D2O): 22.2 (t, C6), 31.5 (t, C7), 50.6 (t, C5), 59.7 (t, C3), 65.2 (d, C8), 67.9
(C2), 68.5(C1), 71.8 (d, C8a).
(1R,2S,9S,9aR)-Octahydro-1H-pyrrolo[1,2-a]azepine-1,2,9-triol (269).
The tri-O-benzyl compound 268 (115 mg, 0.251 mmol) was reacted as
described above giving the title compound (46 mg, 0.246 mmol, 97.9 %)
as a white solid.
mp. 100-104 oC
[α]D25: +60 (c 0.46, MeOH).
MS (CI+) m/z 188 (100 %) (M+1), HRMS (ES+) found 188.1301, calc for C9H18NO3
188.1287 (M+1).
δH (300 MHz, D2O): 1.22-1.38 (1H, m, H7a), 1.42-4.62 (4H, m, H6, H7b and H8a), 1.76-
1.88 (1H, m, H8b), 2.34 (1H, dt, J=12.0, 6.3 Hz, H5a), 2.46 (1H, dd, J=10.2, 6.6 Hz, H3a),
2.63-2.70 (1H, m, H9a), 2.84 (1H, dt, J=11.7, 5.7 Hz, H5b), 3.00 (1H, dd, J=10.5, 5.4 Hz,
H3b), 3.86-3.97 (3H, m, H1, H2 and H9).
δC (75 MHz, D2O ref CH3CN): 21.4 (t, C7), 29.4, 36.1 (t, C6 and C8), 56.5, 59.7 (t, C3 and
C5), 69.6 (d, C9a), 70.8 (d, C9), 73.6, 74.9 (d, C1 and C2).
OH OH
NOHH
6 7
8
99a
123
4
5
171
7.3 Miscellaneous Experimental Protocol 7.3.1 Experimental for Chapter 2 4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1-butanal (207).177
The alcohol 206 (500 mg, 2.45 mmol) was dissolved in dry DCM (20
mL) then pyridiniumchlorochromate (1.06 g, 4.92 mmol) was added.
The mixture was stirred at RT for 2 h, then Et2O (30 mL) was added,
and the mixture filtered through celite. The solids were washed with ether (2 x 25 mL) and
the combined filtrates evaporated in vacuo to give a black oil. This was dissolved in 25 %
EtOAc in pet. sp. and filtered through a short plug of silica gel. Evaporation of the filtrate
gave the crude title compound (400 mg, 1.98 mmol, 80.7 %) as a pale yellow oil that was
not purified any further and had spectral data identical to that reported in the literature.177
δH (300 MHz, CDCl3): 0.01 (6H, s, (CH3)2Si), 0.86 (9H, s, (CH3)3CSi), 1.83 (2H, p, J=6.0
Hz, H3), 2.47 (2H, td, J=6.0, 1.5 Hz, H2), 3.62 (2H, t, J=6.0 Hz, H4), 9.75 (1H, d, J=1.5
Hz, H1).
δC (75 MHz, CDCl3): -5.5 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 25.4 (t, C3) 25.8 (q,
(CH3)3CSi), 40.7 (t, C2), 62.0 (t, C4), 202.5 (d, C1).
(4R,5R,αR)-Anhydro-2,3-dideoxy-1-O-[(4-methoxyphenyl)methyl]-D-threo-hexitol-α-
methoxy-α-(trifluoromethyl) benzeneacetate (215).
The epoxy alcohol 213e (75 mg, 0.297 mmol) was
dissolved in dry DCM (1.25 mL), then triethylamine
(250 µL, 1.80 mmol), dimethylaminopyridine (36 mg,
0.294 mmol) and (-)-α-methoxy-α-trifluoromethyl-phenylacetyl chloride (60 µL, 81 mg,
0.321 mmol) were added. The mixture was stirred at RT for 15 min, then applied directly
to a silica gel column. Elution with 40 % EtOAc in pet. sp. afforded the title compound
(135 mg, 0.288 mmol, 97.0 %) as a clear oil.
MS (CI+) m/z 467 (42 %) (M-1), HRMS (CI+) found 467.1645, calc for C24H26F3O6
467.1681 (M-1).
δH (300 MHz, CDCl3): 1.50-1.80 (4H, m, H2 and H3), 2.82-2.88 (1H, m, H4), 2.98 (1H,
ddd, J=5.7, 3.3, 2.1 Hz, H5), 3.40-3.50 (2H, m, H1), 3.57 (3H, d, J=0.9 Hz, OCH3), 3.79
OTBSO 1
2
3
4
O
OOPMB
O
F3C Ph
MeO α1
2
3
45
6
172
(3H, s, ArOCH3), 4.19 (1H, dd, J=12.0, 6.0 Hz, H6a), 4.42 (2H, s, OCH2Ar), 4.51 (1H, dd,
J=12.0, 3.3 Hz, H6b), 6.88 (2H, dt, J=8.4, 2.4 Hz, 2 x ArCH), 7.25 (2H, dt, J=8.4, 2.4 Hz, 2
x ArCH), 7.36-7.44 (3H, m, 3 x PhCH), 7.50-7.58 (2H, m, 2 x PhCH).
δC (75 MHz, CDCl3): 25.9, 28.3 (t, C2 and C3), 54.5 (d, C4), 55.1 (q, ArOCH3), 55.4 (q,
OCH3), 56.2 (d, C5), 66.0 (t, C6), 69.0 (t, C1), 72.4 (t, OCH2Ar), 113.7 (d, 2 x ArCH),
127.2, 128.4(d, 3 x PhCH), 129.2 (d, 2 x ArCH), 129.6 (d, 2 x PhCH), 130.3 (s, ArC),
131.9 (s, PhC), 159.1 (s, ArC), 166.2 (s, C=O). αC and CF3 not seen due to fluorine
coupling.
7.3.2 Experimental for Chapter 3 (1S,7aS)-rel-1-[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]propyl]-5,7a-dihydro-1H,3H-
pyrrolo[1,2-c]oxazol-3-one (219).
The carbamate 218 (90 mg, 0.242 mmol), was dissolved in dry
THF (3 mL), then NaH (15 mg, 50 % suspension in parafin
wax, 0.313 mmol NaH), was added in one portion. The mixture
was stirred under N2 at R.T. for 2 d, then quenched with water
(50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried
(MgSO4) filtered and evaporated in vacuo to give an oil. The pure product was obtained by
column chromatography (increasing polarity form 15 % to 30 % EtOAc in pet. sp. as
elaunt), which gave the title compound (40 mg, 0.134 mmol, 55.6 %) as a clear oil.
MS (CI+) m/z 298 (39 %) (M+1), HRMS (CI+), found 298.1803, calc for C15H27NO3Si,
298.1838 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.56-1.80 (2H, m,
H2'), 1.80-1.94 (2H, m, H1'), 3.66 (2H, td, J=6.0, 1.8 Hz, H3'), 3.73-3.85 (1H, m, H5a),
4.26-4.45 (3H, m, H1, H7a and H5b), 5.82-5.90 (1H, m, H6), 5.96-6.04 (1H, m, H7).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 25.9 (q, (CH3)3CSi), 27.7 (t,
C2'), 31.9 (t, C1'), 54.5 (t, C5), 62.2 (t, C3'), 70.5 (d, C7a), 81.8 (d, C1), 128.6 (d, C6),
130.6 (d, C7), 162.7 (s, C3).
NO
OTBS
OH
H1
234
5
6 7
3'2'
7a 1'
173
1,1-Dimethylethyl (2S)-2-[(1S)-1,4-dihydroxybutyl]-1-pyrrolidinecarboxylate (221).
The O-TBS ether 220 (220 mg, 0.589 mmol) was dissolved in THF
(20 mL), then dry TBAF (372 mg, 1.177 mmol) was added. The
mixture was stirred at RT under N2 for 24 h, then silica gel (5 ml)
was added. The mixture was filtered and the solids washed with
CHCl3, before the filtrates were evaporated in vacuo to give an oil. The pure product was
obtained by column chromatography (5 % MeOH in DCM as eluant), which gave the title
compound (135 mg, 0.523 mmol, 88.7 %) as a clear oil.
[α]D20: -61 (c 1.0, CHCl3).
MS (CI+) m/z 260 (54 %) (M+1), HRMS (CI+) found 260.1823, calc for C13H25NO4
260.1862 (M+1).
δH (300 MHz, CDCl3): 1.44 (9H, s, (CH3)3C), 1.50-2.00 (8H, m, H3, H4, H2' and H3'),
2.17 (1/2H, br.s, OH), 3.25 (1H, ddd, J=11.1, 6.9, 6.3 Hz, H5a), 3.34 (1/2H, br.s, OH),
3.40-3.54 (2H, m, H5b and H1'), 3.55-3.70 (2H, m, H4'), 3.79 (1H, td, J=8.4, 4.5 Hz, H2),
5.55 (1H, br.s, OH).
δC (75 MHz, CDCl3): 24.0 (t, C4), 28.3 (q, (CH3)3C), 28.7, 29.0 (t, C2' and C3'), 31.9 (t,
C3), 47.3 (t, C5), 62.6 (d, C2), 62.7 (t, C4'), 75.7 (d, C1'), 80.6 (s, (CH3)3C), 158.0 (s, CO).
1,1-Dimethylethyl (2S)-2-[(2S)-tetrahydro-5-oxo-2-furanyl]-1-pyrrolidinecarboxylate
(222).151
The diol 221 (135 mg, 0.523 mmol) was dissolved in DCM (3 mL),
then 4Å molecular sieves (200 mg), N-methylmorpholine-N-oxide
(183 mg, 1.569 mmol) and finally TPAP (10 mg, 0.0285 mmol) were
added. The mixture was stirred at RT for 1 h then applied directly to a
short (6 cm) silica gel column and eluted with EtOAc (50 ml). Evaporation of the eluant in
vacuo gave an oil. The pure product was obtained by column chromatography (increasing
polarity from 2 % to 5 % MeOH in DCM as eluant), which gave the title compound (125
mg, 0.490 mmol, 93.6 %) as a clear oil that had spectral data identical to that reported in the
literature.151
[α]D21: -62 (c 0.77, CHCl3), lit.151 [α]D: -72 (c 3.20, CHCl3).
NOH
OHHBoc
H
4
52
3
11'
2'
3'
4'
ONH
Boc OH
4
5
3'
2
34'
5'1
2'
1'
174
MS (CI+) m/z 256 (56 %) (M+1), HRMS (CI+) found 256.1535, calc for C13H21NO4
256.1549 (M+1).
δH (300 MHz, CDCl3): 1.41 (9H, s, (CH3)3C), 1.70-2.60 (8H, m, H3, H4, H3' and H4'),
3.16-3.30 (1H, m, H5a), 3.30-3.60 (1H, m, H5b), 4.00-4.20 (1H, m, H2), 4.45-4.70 (1H, m,
H2').
δC (75 MHz, CDCl3): 23.0, 24.2 (br. t, C3 and C4), 28.2 (q, (CH3)3C), 28.3 (t, C3'), 46.8,
47.6 (br. t, C5 and C4'), 58.6, (d, C2), 79.7 (br.d, C2'), 83.2 (br. s, (CH3)3C), 155.0 (br. s,
CO), 177.0 (br. s, C5').
1,3-Dimethyl-5-[(2Z,4S)-7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-hydroxy-
2heptenyl]-5-(2-propenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (227) and 1,3-dimethyl-
5,5-bis[(2Z,4S)-7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-hydroxy-2heptenyl]-
2,4,6(1H,3H,5H)-pyrimidinetrione (228).
The allylamine 216 (240 mg, 0.818
mmol) was dissolved in DCM (2
mL) then N,N-dimethylbarbituric
acid (191 mg, 1.227 mmol) and
Pd(PPh3)4 (39.6 mg, 0.0341 mmol)
were added. The mixture was heated
in a sealed tube at 60 oC for 3 h, then
cooled, before it was diluted with EtOAc (50 mL), washed with sat NaHCO3 solution (3 x
30 mL), then dried (MgSO4), filtered and evaporated in vacuo to give an oil. The pure
products were obtained by column chromatography (increasing polarity from 1 % to 10 %
MeOH in DCM as eluant), which gave the title compound (75 mg, 0.172 mmol, 20.9 %)
and the dimer (55 mg, 0.0858 mmol, 21.0 %) as clear oils.
227:
MS (CI+) m/z 439 (2 %) (M+1) 421 (100 %) (M+1-H2O), HRMS (CI+) found 439.2617,
calc for C22H38N2O5Si 439.2628 (M+1).
δH (300 MHz, CDCl3): 0.01 (6H, s, (CH3)2Si), 0.84 (9H, s, (CH3)3CSi), 1.30-1.55 (4H, m,
H5' and H6'), 2.65 (4H, dd, J=7.2, 4.5 Hz, H1' and H1''), 2.91 (1H, br. d, J=3.6 Hz, OH),
NN
OH
OO
O
OTBS
H
NN
OH
OO
O
OH
OTBS OTBS
HH3'
2'
6
6'
5'
1'1''
2''
3''
4'3'
2'
1'
7'6'
5'
55
12 3
4 6
4'
7'
2 34
1
227 228
175
3.22 (6H, s, 2 x NCH3), 3.57 (2H, t, J=5.1 Hz, H7'), 3.90-4.00 (1H, m, H4'), 4.97-5.10 (2H,
m, H3''), 5.26-5.58 (3H, m, H3', H2' and H2'').
δC (75 MHz, CDCl3): -5.5 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 25.8 (q, (CH3)3CSi), 28.2 (q,
2 x NCH3), 28.5, 34.5 (t, C5' and C6'), 41.7 (t, C1'), 42.8 (t, C1''), 57.2 (s, C5), 63.1 (t, C7'),
71.3 (d, C4'), 120.4 (t, C3''), 122.0 (d, C2'), 130.7 (d, C2''), 139.4 (d, C3'), 150.9 (s, C2),
170.7 (s, C4), 170.7 (s, C6).
228:
MS (CI+) m/z 641 (1 %) (M+1) 623 (3 %), HRMS (CI+) found 623.3854, calc for
C32H60N2O7Si2 623.3912 (M+1-H2O).
δH (300 MHz, CDCl3): 0.03 (12H, s, (CH3)2Si), 0.86 (18H, s, (CH3)3CSi), 1.38-1.58 (8H,
m, H5' and H6'), 2.66 (4H, d, J=7.5 Hz, H1'), 2.99 (2H, br. d, J=3.9 Hz, 2 x OH), 3.24 (6H,
t, J=1.5 Hz, 2 x NCH3), 3.58 (4H, t, J=5.1 Hz, H7'), 3.92-4.00 (2H, m, H4'), 5.27-5.40 (2H,
m, H2'), 5.55 (2H, dd, J=15.0, 5.7 Hz, H3').
δC (75 MHz, CDCl3): -5.5 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 25.8 (q, (CH3)3CSi), 28.3 (q,
2 x NCH3), 28.6, 34.6 (C5' and C6'), 41.5 (t, C1'), 57.4 (s, C5), 63.2 (t, C7'), 71.4 (d, C4'),
122.0 (d, C2'), 139.4 (d, C3'), 151.0 (s, C2), 170.8 (s, C4 and C6).
7.3.3 Experimental for Chapter 4 1,1-Dimethylethyl (2S)-2,5-dihydro-2-[(1R)-4-[(4-methoxyphenyl)methoxy]-1-
[(phenylcarbonyl)oxy]butyl]-1H-pyrrole-1-carboxylate (232).
The alcohol 231 (380 mg, 1.007 mmol) was dissolved in DCM
(10 mL), and the mixture was cooled to 0 oC, before
benzoylchloride (341 mg, 2.00 mmol) and pyridine (316 mg,
4.00 mmol) were added. The mixture was stirred at 0 oC for 6h,
then left to stand at -20 oC for 3d. All solvents were removed in vacuo to give a semi-solid.
The pure product was obtained by column chromatography (increasing polarity from 10 %
to 20 % EtOAc in pet. sp. as eluant), which gave the title compound (470 mg, 0.976 mmol,
96.9 %) as a clear oil.
[α]D24: -122 (c 1.9, CHCl3).
MS (ES+) m/z 482.4 (64 %) (M+1), (CI+) m/z 480 (M-1) (100 %), HRMS (CI+) found
480.2366, calc for C28H34NO6 480.2386 (M-1).
NOPMB
BocOBzH
H
4
5
2'
1
2
3
3'4'
1'
176
δH (300 MHz, CDCl3): major rotamer 1.50 (9H, s, (CH3)3C), 1.65-1.85 (4H, m, H2' and
H3'), 3.42-3.56 (2H, m, H4'), 3.79 (3H, s, OCH3), 3.80-3.92 (1H, m, H5a), 4.16-4.24 (1H,
m, H5b), 4.43 (2H, s, OCH2Ar), 4.62-4.69 (1H, m, H2), 5.58-5.67 (1H, m, H1'), 5.85-6.03
(2H, m, H3 and H4), 6.87 (2H, d, J=8.7 Hz, 2 x ArCH), 7.24 (2H, d, J=8.7 Hz, 2 x ArCH),
7.35-7.60 (3H, m, OBz), 7.96 (2H, br t, J=8.1 Hz, OBz), minor rotamer inter alia 1.45 (9H,
s, (CH3)3C), 4.41 (2H, s, OCH2Ar), 4.74-4.79 (1H, m, H2), 5.67-5.75 (1H, m, H1'), 6.86
(2H, d, J=8.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): major rotamer 26.1, 28.1 (t, C2' and C3'), 28.4 (q, (CH3)3C), 53.6 (t,
C5), 55.2 (q, OCH3), 66.7 (d, C2), 69.3 (t, C4'), 72.5 (t, OCH2Ar), 73.5 (d, C1'), 80.1 (s,
(CH3)3C), 113.7 (d, 2 x ArCH), 125.0, 128.1 (d, C3 and C4), 128.2, 129.2, 129.5, 129.5 (d,
2 x ArCH, OBz), 130.0 (s, OBz), 130.6 (s, ArC), 153.8 (s, ArC), 159.1 (s, CO), 165.9 (s,
CO), minor rotamer inter alia 53.7 (t, C5), 66.9 (d, C2), 69.5 (t, C4'), 72.3 (t, OCH2Ar),
73.4 (d, C1'), 79.5 (s, (CH3)3C), 128.3, 127.8 (d, C3 and C4).
(1R,2S,8R,8aR)-Octahydro-1,2,8-indolizinetriol triacetate (239).39,53,155
(+)-1,2-Di-epi-swainsonine (31 mg, 0.179 mmol) was dissolved in
pyridine (1 mL) and then acetic anhydride (1 mL) was added. The
mixture was stirred at RT for 18 h, then diluted with DCM (25 mL) and
washed with cold sat. NaHCO3 solution (25 mL). The aqueous portion
was extracted with DCM (2 x 25 mL), then the combined organic extracts dried (MgSO4),
filtered and evaporated in vacuo to give a solid. The pure product was obtained by column
chromatography (increasing polarity from 30 % to 50 % EtOAc in pet. sp. as eluant), which
gave the title compound (50 mg, 0.167 mmol, 93.3 %) as a white solid that had spectral
data identical to that reported in the literature.39,53,155
m.p. 128-130 oC (EtOAc); lit.39 132-134 oC.
[α]D23: +57 (c 1.95, CHCl3); lit.39 [α]D
23: +61 (c 2.11, CHCl3).
MS (CI+) m/z 300 (46 %) (M+1), HRMS (CI+) found 300.143893, calc for C14H21NO6
300.144713 (M+1).
δH (300 MHz, CDCl3): 1.16-1.34 (1H, m, H7a), 1.50-1.74 (2H, m, H6), 1.96 (3H, s, OAc),
2.00 (6H, s, 2 x OAc), 2.00-2.10 (2H, m, H7b and H5a), 2.20-2.33 (2H, m, H3a and H8a),
OAcAcO
N
HOAc
12
3
4
56
7
8a 8
177
2.89 (1H, br.d, J=10.6 Hz, H5b), 3.53 (1H, dd, J=9.6, 6.6 Hz, H3b), 4.65 (1H, ddd, J=11.1,
9.3, 4.2 Hz, H8), 4.97 (1H, t, J=7.7 Hz H1), 5.16 (1H, dt, J=7.2, 6.0 Hz, H2).
δC (75 MHz, CDCl3): 20.4 (q, OAc), 20.7 (q, OAc), 21.0 (q, OAc), 23.6 (t, C6), 30.0 (t,
C7), 51.2 (t, C5), 58.4 (t, C3), 67.3 (d, C8a), 68.3 (d, C2), 72.8 (d, C8), 73.8 (d, C1), 168.9
(s, OAc), 169.6 (s, OAc), 169.8 (s, OAc).
1,1-Dimethylethyl (δR,2S)-2,5-dihydro-δ-[[(1,1-dimethylethyl)dimethysilyl]oxy)]-1H-
pyrrole-2-butanol-1-carboxylate (241).
The PMB ether 240 (235 mg, 0.551 mmol) was dissolved in DCM
(18 mL), then water (1 mL) and DDQ (144 mg, 0.634 mmol) were
added. The mixture was stirred at RT for 2.5 h, then diluted with
water (50 mL) and extracted with DCM (3 x 30 mL). The
combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an
oil. The pure product was obtained by column chromatography (increasing polarity from
15 % to 60 % EtOAc in pet. sp. as eluant), which gave the title compound (160 mg, 0.431
mmol, 78.1 %) as a clear oil.
[α]D20: -141 (c 1.55, CHCl3).
MS (CI+) m/z 372 (63 %) (M+1), HRMS (CI+) found 372.1454, calc for C19H38NO4Si
372.2570 (M+1).
δH (300 MHz, CDCl3): major rotamer -0.08 (3H, s, CH3Si), -0.03 (3H, s, CH3Si), 0.79 (9H,
s, (CH3)3CSi), 1.42 (9H, s, (CH3)3C-O), 1.40-1.75 (4H, m, H2' and H3'), 2.59 (1H, br. s,
OH), 3.50-3.66 (2H, m, H1'), 3.84-4.22 (3H, m, H2, H5a and H4'), 4.47 (1H, br.s, H5b),
5.64-5.82 (2H, m, H3 and H4), minor rotamer inter alia 1.44 (9H, s, (CH3)3C-O), 4.38 (1H,
br. s, H5b).
δC (75 MHz, CDCl3): major rotamer -5.0 (q, CH3Si), -4.4 (q, CH3Si), 17.9 (s, (CH3)3CSi),
25.8 (q, (CH3)3CSi), 28.5 (q, (CH3)3C-O), 29.0, 31.6 (t, C2' and C3'), 54.1 (t, C5), 62.4 (t,
C1'), 68.7, 70.8 (d, C2 and C4'), 79.3 (s, (CH3)3C-O), 125.9, 126.0 (d, C3 and C4), 154.2 (s,
CO), minor rotamer inter alia -4.9 (q, CH3Si), -4.6 (q, CH3Si), 25.7 (q, (CH3)3CSi), 28.6 (q,
(CH3)3C-O), 29.2, 31.9 (t, C2' and C3'), 53.9 (t, C5), 62.6 (t, C1'), 68.5, 72.1 (d, C2 and
C4'), 79.5 (s, (CH3)3C-O), 125.9, 126.0 (d, C3 and C4), 153.9 (s, CO).
NOH
Boc OTBSHH
4
5
3'
12
3
2'1'
4'
178
1,1-Dimethylethyl (2S)-2,5-dihydro-2-[(1R)-1-[[(1,1-dimethylethyl)dimethysilyl]oxy)]-
4-[[(4-methylphenyl)sulfonyl]oxy]butyl]-1H-pyrrole-1-carboxylate (242).
The alcohol 241 (155 mg, 0.417 mmol) was dissolved in pyridine
(0.35 mL), then the solution was cooled to 0 oC. para-
Toluenesulfonyl chloride (159 mg, 0.834 mmol) and CHCl3 (1
mL) were added, and the mixture stirred at 0 oC for 4 h, then at RT for 16 h. The reaction
was quenched with water (40 mL) and extracted with DCM (3 x 30 mL). The combined
organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. The
pure product was obtained by column chromatography (increasing polarity from 15 % to 35
% EtOAc in pet. sp.), which gave the title compound (154 mg, 0.293 mmol, 70.2 %) and
recovered starting material (40 mg, 0.108 mmol, 25.8 %) as clear oils.
[α]D20: -82 (c 1.55, CHCl3).
MS (ES+) m/z 526.3 (10 %) (M+1), 426.3 (100 %) (M-Boc+1), HRMS (ES+) found
451.2293, calc for C22H33NO5SSi 451.1848 (M-tBuO).
δH (300 MHz, CDCl3): major rotamer -0.09 (6H, s, (CH3)2Si), 0.77 (9H, s, (CH3)3CSi),
1.43 (9H, s, (CH3)3C-O), 1.30-1.84 (4H, m, H2' and H3'), 2.41 (3H, s, ArCH3), 3.84-4.20
(3H, m, H2, H5a and H1'), 4.36 (1H, br. s, H5b), 5.56-5.82 (2H, m, H3 and H4), 7.31 (2H,
d, J=8.4 Hz, 2 x ArCH), 7.75 (2H, d, J=8.4 Hz, 2 x ArCH), minor rotamer inter alia 4.29
(1H, br. s, H5b).
δC (75 MHz, CDCl3): major rotamer -5.0 (q, CH3Si), -4.5 (q, CH3Si), 17.9 (s, (CH3)3CSi),
21.6 (q, ArCH3), 25.7 (q, (CH3)3CSi), 25.7 (t, C2'), 28.5 (q, (CH3)3C-O), 31.1 (t, C3'), 54.1
(t, C5), 68.8, 70.5 (d, C2 and C1'), 70.6 (t, C4'), 79.2 (s, (CH3)3C-O), 125.4, 126.3 (d, C3
and C4), 127.6, 129.6 (d, 4 x ArCH), 132.9 (s, ArC), 144.4 (s, ArC), 154.0 (s, CO), minor
rotamer inter alia -4.9 (q, CH3Si), -4.6 (q, CH3Si), 28.6 (q, (CH3)3C-O), 31.3 (t, C3'), 53.9
(t, C5), 68.5, 71.6 (d, C2 and C1'), 70.3 (t, C4'), 79.4 (s, (CH3)3C-O), 125.2, 126.6 (d, C3
and C4), 133.0 (s, ArC), 144.6 (s, ArC), 153.7 (s, CO).
1,1-Dimethylethyl (2S)-2,5-dihydro-2-[(1R)-1-(2,2-dimethyl-1-oxypropoxy)-4-[(4-
methoxyphenyl)methoxy]butyl]-1H-pyrrole-1-carboxylate (243).
The alcohol 231 (426 mg, 1.261 mmol) was dissolved in THF
(20 mL), then triethylamine (0.72 mL, 5.044 mmol), pivolyl
NOTs
Boc OTBSHH
4
5
2'
1
2
3
3'4'
1'
NOPMB
Boc OPivHH
4
1'2'
12
3
3'4'
5
179
chloride (0.60 mL, 5.06 mmol), and DMAP (15 mg, 0.123 mmol) were added. The mixture
was heated in a sealed tube at 70 oC for 24 h then cooled, poured into sat. NaHCO3 solution
(50 mL), and extracted with DCM (3 x 40 mL). The combined organic extracts were dried
(MgSO4), filtered and evaporated in vacuo to give an oil. The pure product was obtained
by column chromatography (increasing polarity from 5 % to 30 % EtOAc in pet. sp. as
eluant), which gave the title compound (570 mg, 1.235 mmol, 97.9 %) as a clear oil.
[α]D24: -87 (c 0.97, CHCl3).
MS (CI+) m/z 462 (4 %) (M+1), HRMS (CI+) found 462.3161, calc for C26H39NO6
462.2855 (M+1).
δH (300 MHz, CDCl3): major rotamer 1.13 (9H, s, (CH3)3CCOO), 1.50 (9H, s, (CH3)3C-
O), 1.56-1.70 (4H, m, H2' and H3'), 3.40-3.52 (2H, m, H4'), 3.80 (3H, s, OCH3), 3.84-4.00
(1H, m, H5a), 4.05-4.24 (1H, m, H5b), 4.42 (2H, s, OCH2Ar), 4.51 (1H, br. s, H2), 5.38-
5.50 (1H, m, H1'), 5.74-5.94 (2H, m, H3 and H4), 6.87 (2H, d, J=8.4 Hz, 2 x ArCH), 7.25
(2H, d, J=8.4 Hz, 2 x ArCH), minor rotamer inter alia 1.14 (9H, s, (CH3)3CCOO), 1.46
(9H, s, (CH3)3C-O), 4.64 (1H, br. s, H2).
δC (75 MHz, CDCl3): major rotamer 26.1 (t, C2'), 27.2 (q, (CH3)3CCOO), 28.4 (q,
(CH3)3C-O), 28.6 (t, C3'), 38.7 (s, (CH3)3CCOO), 53.7 (t, C5), 55.2 (q, OCH3), 66.8 (d,
C2), 69.3 (t, C4'), 72.1 (d, C1'), 72.5 (t, OCH2Ar), 80.0 (s, (CH3)3C-O), 113.6 (d, 2 x
ArCH), 124.9, 127.3 (d, C3 and C4), 129.1 (d, 2 x ArCH), 130.3 (s, ArC), 153.6 (s, CO
Boc), 158.9 (s, ArC), 177.6 (s, CO Piv), minor rotamer inter alia 26.0 (t, C2'), 27.2 (q,
(CH3)3CCOO), 28.5 (q, (CH3)3C-O), 28.3 (t, C3'), 53.9 (t, C5), 66.9 (d, C2), 69.6 (t, C4'),
72.2 (d, C1'), 72.3 (t, OCH2Ar), 79.4 (s, (CH3)3C-O), 125.3, 127.1 (C3 and C4), 130.5 (s,
ArC), 153.7 (s, CO Boc), 158.9 (s, ArC), 177.5 (s, CO Piv).
(1R,2S,8R,8aR)-1,2-Octahydro-8-(phenylmethoxy)-indolizinediol-diacetate (258) and
(1S,2R,8R,8aR)-1,2-octahydro-8-(phenylmethoxy)-indolizinediol-diacetate (259).
The indolizidine 257 (77 mg, 0.336 mmol) was
dissolved in acetone (1.9 mL) then water (1.3 mL), N-
methylmorpholine-N-oxide (84 mg, 0.716 mmol) and
K2OsO4.2H2O (9 mg, 0.025 mmol) were added. The
mixture was stirred at RT for 2 d, then all volatiles
H
N
OAcAcO
OBnH
N
OAcAcO
OBn1
34
56
7
88a
21
3
4
56
7
88a
2
258 259
180
were removed in vacuo to give a mixture of diols. This was treated with pyridine (1 mL)
and acetic anhydride (1 mL), then the mixture stirred at RT for 1 d. The reaction was
quenched with cold sat. NaHCO3 solution (40 mL), and extracted with DCM (3 x 30 mL).
The combined organic extracts were dried (MgSO4) filtered and evaporated in vacuo to
give an oil. The pure products were obtained by column chromatography (increasing
polarity from 40 % to 100 % EtOAc in pet. sp. as eluant), which gave the title compounds
259 (43 mg, 0.124 mmol, 36.8 %) and 258 (20 mg, 0.576 mmol, 17.1 %) as clear oils.
259:
[α]D25: -108 (c 2.15, CHCl3).
MS (CI+) m/z 348 (69 %) (M+1), HRMS (CI+) found 348.1807, calc for C19H26NO5
348.1811 (M+1).
δH (300 MHz, CDCl3): 1.10-1.28 (1H, m, H7a), 1.50-1.80 (2H, m, H6), 1.90 (1H, td,
J=11.4, 3.0 Hz, H5a), 2.01 (6H, s, 2 x OAc), 2.07 (1H, dd, J=9.3, 4.2 Hz, H8a), 2.30 (1H,
ddd, J=11.4, 7.2, 3.3 Hz, H7b), 2.57 (1H, dd, J=11.4, 7.8 Hz, H3a), 2.97-3.10 (2H, m, H3b
and H5b), 3.63 (1H, ddd, J=11.1, 9.3, 4.8 Hz, H8), 4.50 (2H, AB system, J=11.7 Hz,
OCH2Ph), 5.29 (1H, ddd, J=8.4, 6.6, 2.1 Hz, H2), 5.56 (1H, dd, J=6.3, 4.2 Hz, H1), 7.20-
7.35 (5H, m, OCH2Ph).
δC (75 MHz, CDCl3): 20.6 (q, OAc), 20.8 (q, OAc), 23.3, 29.5 (t, C6 and C7), 52.1, 59.6 (t,
C3 and C5), 69.8, 70.0, (d, C8 and C8a), 70.5 (t, OCH2Ph), 71.1, 72.9 (d, C1 and C2),
127.5, 127.7, 128.2 (d, OCH2Ph), 138.0 (s, OCH2Ph), 169.8 (s, OAc), 169.8 (s, OAc).
258:
[α]D24: + 6 (c 1.0, CHCl3).
MS (CI+) m/z 348 (69 %) (M+1), HRMS (CI+) found 348.1808, calc for C19H26NO5
348.1811 (M+1).
δH (300 MHz, CDCl3): 1.16-1.32 (1H, m, H7a), 1.54 (1H, qt, J=13.0, 4.2 Hz, H6a), 1.74
(1H, br. d, J=12.6 Hz, H6b), 1.91 (3H, s, OAc), 2.02 (s, OAc), 2.08 (1H, td, J=11.7, 2.4 Hz,
H5a), 2.20-2.36 (3H, m, H3a, H7b and H8a), 2.91 (1H, br. d, J=10.8 Hz, H5b), 3.33 (1H,
ddd, 10.5, 9.0, 4.2 Hz, H8), 3.52 (1H, dd, J=9.6, 6.9 Hz, H3b), 4.50 (2H, AB system,
J=10.8 Hz, OCH2Ph), 5.10-5.25 (2H, m, H1 and H2), 7.21-7.35 (5H, m, OCH2Ph).
181
δC (75 MHz, CDCl3): 20.7 (q, OAc), 20.8 (q, OAc), 23.8, 30.0 (t, C6 and C7), 51.6, 58.3 (t,
C3 and C5), 68.3, 68.4 (d, C8 and C8a), 70.8 (t, OCH2Ph), 73.7, 79.0 (d, C1 and C2),
127.4, 127.7, 128.2 (d, OCH2Ph), 138.3 (s, OCH2Ph), 169.6 (s, OAc), 169.8 (s, OAc).
(3aR,9R,9aR,9bS)-Octahydro-2,3-dimethyl-9-(phenylmethoxy)-1,3-dioxolo[4,5-
a]indolizine (108).41
AD-mix-α (697 mg) and (DHQ)2PHAL (17 mg, 0.022 mmol) were
dissolved in water (2.7 mL) and tert-butanol (1.8 mL), then the mixture
was cooled to 0 oC. Methane sulfonamide (93 mg, 0.978 mmol), then the
didehydroindolizine 257 (91 mg, 0.397 mmol) dissolved in tert-butanol
(1.7 mL) were added, then the mixture was stirred at 4 oC for 7 d.
Sodium sulfite (1.2 g) was added and the mixture stirred at RT for 2 h. All volatiles were
removed in vacuo, then the residue was suspended in MeOH (10 mL) and filtered. The
solids were washed with MeOH (2 x 10 mL) and the combined filtrates evaporated in
vacuo to give the crude diol 260. This was dissolved in dry DCM (2 mL), then 2,2-
dimethoxypropane (0.25 mL, 2.03 mmol) and para-toluenesulfonic acid (105 mg, 0.610
mmol) were added and the mixture stirred at RT for 3 h. The reaction was quenched with
sat. NaHCO3 solution (30 mL) and extracted with CHCl3 (3 x 25 mL). The combined
organics were dried (MgSO4), filtered and evaporated in vacuo to give an oil. The pure
product was obtained by column chromatography (increasing polarity from 30 % to 60 %
Et2O in DCM as eluant), which gave the title compound (60 mg, 0.198 mmol, 49.8 %) as a
clear oil that had spectral data identical to that reported in the literature.41
[α]D25: -54 (c 0.6, CHCl3) (lit.41 [α]D
26 -59, c 0.27, CHCl3) (lit.40 [α]D23 -67, c 0.3, CHCl3).
MS (CI+) m/z 304 (100 %) (M+1), HRMS (ES+) found 304.1901, calc for C18H26NO3
304.1913 (M+1).
δH (300 MHz, CDCl3): 1.10-1.26 (1H, m, H8a), 1.34 (3H, s, CH3), 1.50 (3H, s, CH3), 1.56
(1H, dt, J=12.0, 4.1 Hz, H7a), 1.60-1.65 (2H, m, H7b and H9a), 1.82 (1H, td, J=10.5, 3.0
Hz, H6a), 2.08 (1H, dd, J=11.1, 4.8 Hz, H4a), 2.08-2.22 (1H, m, H8b), 2.96 (1H, br. d,
J=10.5 Hz, H6b), 3.11 (1H, d, J=10.5 Hz, H4b), 3.63 (1H, ddd, J=10.8, 8.7, 4.5 Hz, H9),
4.57 (1H, dd, J=6.3, 4.5 Hz, H3a), 4.67 (2H, s, OCH2Ph), 4.72 (1H, dd, J=5.7, 4.2 Hz,
H9b), 7.20-7.40 (5H, m, OCH2Ph).
HOBn
N
OO 13
4
5
67
8
9a
2
9
3a9b
182
δC (75 MHz, CDCl3): 24.0 (t, C7), 25.0 (q, CH3), 26.1 (q, CH3), 30.7 (t, C8), 51.7 (t, C6),
60.2 (t, C4), 71.4 (t, OCH2Ph)), 72.4, 74.2, 77.9, 79.4 (d, C3a, C9, C9a and C9b), 110.7 (s,
C2), 127.2, 127.6, 128.0 (d, OCH2Ph), 139.1 (s, OCH2Ph).
(4S,5R)-4-Ethenyl-5-[3-[(4-methoxyphenyl)methoxy]propyl]-3-(2-propenyl)-
oxazolidin-2-one (271).
The amino alcohol 229 (88 mg, 0.288 mmol) was dissolved in
DCM (2 mL), then triethylamine (88 mg, 0.870 mmol) was
added. The mixture was cooled to 0 oC, then triphosgene (44
mg, 0.284 mmol) dissolved in DCM (1 mL) was added via
syringe. The mixture was stirred at 0 oC for 2 h, then quenched
with water (50 mL) and extracted with DCM (3 x 25 mL). The combined organics were
dried (MgSO4), filtered and evaporated in vacuo to give an oil. The pure product was
obtained by column chromatography (increasing polarity from 20 % to 40 % EtOAc in pet.
sp. as eluant), which gave the title compound (72 mg, 0.217 mmol, 75.4 %) as a clear oil.
[α]D23: -29 (c 3.5, CHCl3).
MS (CI+) m/z 332 (23 %) (M+1), HRMS (CI+) found 332.1883, calc for C19H26NO4
332.1862 (M+1).
δH (300 MHz, CDCl3): 1.58-1.88 (4H, m, H1''' and H2'''), 3.36-3.46 (3H, m, H3''' and
H1'a), 3.79 (3H, s, OCH3), 4.08-4.22 (2H, m, H4 and H1'b), 4.41 (2H, s, OCH2Ar), 4.44-
4.56 (1H, m, H5), 5.12-5.22 (2H, m, H3'), 5.28 (1H, ddd, J=17.1, 1.5, 0.6 Hz, H2''a), 5.39
(1H, dd, J=10.2, 1.5 Hz, H2''b), 5.59-5.80 (2H, m, H1'' and H2'), 6.87 (2H, dt, J=8.4, 2.5
Hz, 2 x ArCH), 7.24 (2H, dt, J=8.4, 2.5 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 25.7, 27.2 (t, C1''' and C2'''), 44.3 (t, C1'), 55.1 (q, OCH3), 61.3 (d,
C4), 68.9, (t, C3'''), 72.3 (t, OCH2Ar), 77.1 (d, C5), 113.6 (d, 2 x ArCH), 118.1, 121.8 (t,
C2'' and C3'), 129.0 (d, 2 x ArCH), 130.3 (s, ArC), 131.3, 131.9 (d, C1'' and C2'), 157.3,
159.0 (s, ArC and C2).
δH (300 MHz, d6-benzene): 1.30-1.80 (4H, m, H1''' and H2'''), 3.16-3.35 (3H, m, H3''' and
H1'a), 3.38 (3H, s, OCH3), 3.56 (1H, t, J=9.0 Hz, H4), 4.06 (1H, ddd, J=9.0, 7.8, 4.2 Hz,
H5), 4.18 (1H, ddt, J=15.3, 4.5, 1.5 Hz, H1'b), 4.33 (2H, s, OCH2Ar), 4.80 (1H, ddd,
J=17.1, 1.5, 0.6 Hz, H2''a), 4.90 (1H, dd, J=10.2, 1.5 Hz, H2''b), 4.95-4.99 (1H, m, H3'a),
NO
OPMB
O
H
H
4 52'''12
3
3'''1'2'
3'1''
1'''
2''
183
4.99-5.04 (1H, m, H3'b), 5.19 (1H, ddd, J=17.1, 10.2, 9.0 Hz, H1''), 5.58 (1H, dddd,
J=17.1, 9.6, 7.5, 4.5 Hz, H2'), 6.85 (2H, dt, J=8.7, 2.7 Hz, 2 x ArCH), 7.25 (2H, dt, J=8.7,
2.7 Hz, 2 x ArCH).
δC (75 MHz, d6-benzene): 26.5, 27.6 (t, C1''' and C2''') 44.6 (t, C1'), 54.8 (q, OCH3), 61.4
(d, C4), 69.3 (t, C3'''), 72.7 (t, OCH2Ar), 76.9 (d, C5), 114.0 (d, 2 x ArCH), 117.5, 120.9 (t,
C2'' and C3'), 129.4 (d, 2 x ArCH), 131.1 (s, ArC), 132.3, 133.1 (d, C1'' and C2'), 157.1,
159.7 (s, ArC and C2).
(2R,3S,4R)-2-[(1R)-1-Hydroxy-4-[(4-methoxyphenyl)methoxy]butyl]-3,4-
bis(phenylmethoxy)pyrrolidine (275).
The oxazolidinone 274 (410 mg, 0.792 mmol) was dissolved
in MeOH (8 mL), NaOH (200 mg, 5.00 mmol) dissolved in
water (2 mL) was added. The mixture was placed in a teflon
tube with a 100 bar pressure cap, then heated in a microwave
reactor at 110 oC for 2 h. After cooling the mixture was poured into water (50 mL), then
extracted with DCM (3 x 30 mL). The combined organic extracts were dried (MgSO4),
filtered and evaporated in vacuo to give an oil. The pure product was obtained by column
chromatography (increasing polarity from 5 % to 15 % MeOH in DCM as eluant), which
gave the title compound (326 mg, 0.663 mmol, 83.7 %) as a clear oil.
[α]D24: -25 (c 3.26, CHCl3).
MS (CI+) m/z 492 (100 %) (M+1), HRMS (CI+) found 492.2769, calc for C30H38NO5
492.2750 (M+1).
δH (300 MHz, CDCl3): 1.40-1.54 (1H, m, H2'a), 1.60-1.90 (3H, m, H2'b and H3'), 2.70
(2H, br. s, NH and OH), 2.98 (1H, dd, J=6.3, 4.8 Hz, H2), 3.08 (1H, dd, J=11.1, 6.6 Hz,
H5a), 3.18 (1H, dd, J=11.1, 6.6 Hz, H5b), 3.40 (2H, m, H4'), 3.78 (3H, s, OCH3), 3.74-3.82
(1H, m, H1'), 4.00-4.10 (1H, m, H4), 4.15 (1H, t, J=4.2 Hz, H3), 4.43 (2H, s, OCH2Ar),
4.56 (2H, d, J=11.4 Hz, OCH2Ph), 4.62 (1H, d, J=12.0 Hz, OCH2Ph), 4.90 (1H, d, J=11.1
Hz, OCH2Ph), 6.87 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH), 7.22-7.38 (12H, m, 2 x ArCH and 2
x OCH2Ph).
δC (75 MHz, CDCl3): 26.0, 31.6 (t, C2' and C3'), 48.2 (t, C5), 55.1 (q, OCH3), 63.4 (d, C2),
69.9 (t, C4'), 71.1 (d, C1'), 71.9, 72.3, 73.4 (t, OCH2Ar and 2 x OCH2Ph), 79.4 (d, C3), 80.1
NH OH
OPMB
BnO OBn
HH1
2
34
5 1'2'
3'4'
184
(d, C4), 113.6 (d, 2 x ArCH), 127.4, 127.6, 127.8, 128.0, 128.3, 128.4 (d, 2 x OCH2Ph),
129.1 (d, 2 x ArCH), 130.4 (s, ArC), 137.8 (s, OCH2Ph), 137.9 (s, OCH2Ph), 159.0 (s,
ArC).
(δR,2S,3S,4R)-δ-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3,4-bis(phenylmethoxy)-2-
pyrrolidinebutanol (277).
The PMB ether 276 (484 mg, 0.663 mmol) was dissolved in
CH3CN (25 mL), then water (3.2 mL) and CAN (728 mg, 1.325
mmol) were added. The mixture was stirred at RT for 2h, then
more CAN (350 mg, 0.637 mmol) was added. The mixture was stirred at RT for 1 h, then
poured into sat. NaHCO3 solution (75 mL) and extracted with DCM (3 x 40 mL). The
combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an
oil. The pure product was obtained by column chromatography (increasing polarity from
7.5 % to 20 % MeOH in DCM as eluant), which gave the title compound (371 mg, 0.608
mmol, 91.8 %) as a white foam.
m.p. 38-40 oC
[α]D24: +12 (c 3.7, CHCl3).
MS (CI+) m/z 610 (83 %) (M+1), HRMS (CI+) found 610.3357, calc for C38H48NO4Si
610.3353 (M+1).
δH (300 MHz, CDCl3): 1.07 (9H, s, (CH3)3CSi), 1.20-1.64 (4H, m, C2' and C3'), 3.00-3.44
(7H, m, C2, C5, C1', NH and 2 x OH), 4.03 (1H, d, J=10.8 Hz, OCH2Ph), 4.10-4.20 (2H,
m, H3 and H4), 4.28 (1H, br. d, J=8.1 Hz, H4'), 4.56 (2H, s, OCH2Ph), 4.91 (1H, d, J=10.8
Hz, OCH2Ph), 7.10-7.44 (16H, m, 2 x OCH2Ph, Ph2Si), 7.65 (4H, d, J=6.9 Hz, Ph2Si).
δC (75 MHz, CDCl3): 19.3 (s, (CH3)3CSi), 26.0 (t, C2'), 27.0 (q, (CH3)3CSi), 29.9 (t, C3'),
47.7 (t, C5), 62.1 (t, C1'), 64.2 (d, C2), 70.0 (d, C4'), 72.4 (t, OCH2Ph), 72.5 (t, OCH2Ph),
76.7, 82.1 (C3 and C4), 127.1, 127.4, 127.4, 127.4, 127.5, 127.7, 128.0, 128.3, 129.5, 129.6
(d, Ph), 133.5, 124.3 (s, SiPh), 135.9, 136.0 (d, SiPh), 137.8, 138.8 (OCH2Ph).
NH OTBDPS
OH
BnO OBn
HH1
2
34
5 4'3'
2'1'
185
(1S,2R,8R,8aR)-Octahydro-8-hydroxy-1,2-bis(phenylmethoxy)indolizine (279).160
The indolizidine 278 (325 mg, 0.549 mmol) was dissolved in dry THF
(20 mL) then dry TBAF (300 mg, 1.147 mmol) was added. The
mixture was stirred at RT for 3 d, then TBAF (120 mg, 0.459 mmol)
was added. The mixture was stirred at RT for 2 d, then poured into
water (80 mL) and extracted with DCM (4 x 40 mL). The combined
organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. The
pure product was obtained by column chromatography (increasing polarity from 5 % to 15
% MeOH in DCM as eluant), which gave the title compound (147 mg, 0.416 mmol, 75.8
%) as a colourless solid that had spectral data identical to that reported in the literature.160
m.p. 78-80 oC; lit.41 101-104 oC.
[α]D23: -103 (c 1.0, CHCl3); lit.188 [α]D
26: 75 (c 1.54, MeOH).
MS (CI+) m/z 354 (100 %) (M+1), HRMS (CI+) found 354.2083, calc for C22H28NO3
354.2069 (M+1).
δH (300 MHz, CDCl3): 1.12 (1H, qd, J=12.6, 4.5 Hz, H7a), 1.50-1.76 (2H, m, H6), 1.80-
2.02 (3H, m, H5a, H7b and H8a), 2.12 (1H, br. s, OH), 2.42 (1H, dd, J=10.2, 7.2 Hz, H3a),
2.91 (1H, br. d, J=10.5 Hz, H5b), 3.20 (1H, dd, J=10.2, 3.0 Hz, H3b), 3.90 (1H, ddd,
J=11.1, 8.7, 4.5 Hz, H8), 4.00-4.12 (2H, m, H1 and H2), 4.49 (1H, d, J=12.0 Hz, OCH2Ph),
4.54 (1H, d, J=12.0 Hz, OCH2Ph), 4.59 (1H, d, J=12.0 Hz, OCH2Ph), 4.88 (1H, d, J=12.0
Hz, OCH2Ph), 7.22-7.40 (10H, m, 2 x OCH2Ph).
δC (75 MHz, CDCl3): 23.0 (t, C6), 32.3 (t, C7), 51.4 (t, C5), 57.8 (t, C3), 66.4 (d, C8), 71.7
(t, OCH2Ph), 72.0 (d, C8a), 73.3 (t, OCH2Ph), 76.7, 76.8 (d, C1 and C2), 127.3, 127.5,
127.6, 128.0, 128.1, 128.3 (d, OCH2Ph), 138.0, 138.52 (s, OCH2Ph).
7.3.4 Experimental for Chapter 5 (3R,3'S,4R,4'S)-rel-3,3'-Iminobis[8-[(4-methoxyphenyl)methoxy]-1-octen-4-ol] (281a)
and (3S,3'S,4S,4'S)-rel-3,3'-iminobis[8-[(4-methoxyphenyl)methoxy]-1-octen-4-ol]
(281b).
The rac-vinyl epoxide 208c (169 mg,
0.644 mmol) and the rac-amine 280 (180
mg, 0.644 mmol) were dissolved in
BnO OBn
H
NOH
12
345
6
7
88a
NH OHOH
PMBO OPMB
H H
1
23 4
56
78
186
CH3CN (1.2 mL), then LiOTf (100 mg, 0.641 mmol) was added. The mixture was placed
in a teflon tube with a 100 bar pressure cap, then heated at 120 oC for 1 h in a microwave
reactor. After cooling all volatiles were removed in vacuo to give a brown residue. The
pure product was obtained by column chromatography (increasing polarity from 5 % to 20
% MeOH in DCM as elaunt), which gave the title compound (227 mg, 0.419 mmol, 65.1
%) and recovered 208c (55 mg, 0.209 mmol, 32.5 %) as clear oils.
MS (CI+) m/z 542 (50 %) (M+1), HRMS (CI+) found 542.3484, calc for C32H48NO6
542.3482 (M+1).
δH (300 MHz, CDCl3): 1.22-1.70 (12H, m, H5, H6 and H7), 2.82 (3H, br. s, NH and 2 x
OH), 2.91 (1H, t, J=9.0 Hz, H3), 2.99 (1H, t, J=8.1 Hz, H3'), 3.30-3.50 (6H, m, H4 and
H8), 3.78 (6H, s, OCH3), 4.41 (4H, s, OCH2Ar), 5.06-5.26 (4H, m, H1), 5.44 (1H, ddd,
J=17.1, 10.2, 8.7 Hz, H2), 5.63 (1H, ddd, J=17.1, 10.5, 9.0 Hz, H2'), 6.86 (4H, d, J=8.4 Hz,
4 x ArCH), 7.24 (4H, d, J=8.4 Hz, 4 x ArCH).
δC (75 MHz, CDCl3): 22.3, 22.5 (t, C6 and C6'), 29.6 (t, C7 and C7'), 33.2, 33.5 (t, C5 and
C5'), 55.2 (q, OCH3), 63.5, 65.8 (d, C3 and C3'), 69.9 (t, C8 and C8'), 72.4 (t, OCH2Ar),
72.7, 73.1 (d, C4 and C4'), 113.6 (d, 4 x ArCH), 118.3, 119.2 (t, C1 and C1'), 129.1 (d, 4 x
ArCH), 130.4 (s, ArC), 136.7, 137.0 (d, C2 and C2'), 158.8 (s, ArC).
(3S,4S)-8-[(Methoxyphenyl)methoxy]-3-[[(1S,2S)-5-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]-1-ethenyl-2-hydroxypentyl]amino]-1-octen-4-ol
(282).
The vinyl epoxide 208a (190 mg, 0.784
mmol) and the amino alcohol 280 (260 mg,
0.931 mmol) were dissolved in CH3CN (2
mL), then LiOTf (180 mg, 1.176 mmol) was
added. The mixture was heated in a sealed tube at 130 oC for 3 d then cooled, before
volatiles were removed in vacuo to give an oil. The pure product was obtained by column
chromatography (increasing polarity from 5 % to 20 % MeOH in DCM as eluant), which
gave the title compound (395 mg, 0.757 mmol, 96.6 %) as a pale yellow oil. A 4:1 mixture
of diastereoisomers was estimated from analysis of the 1H NMR spectrum. Unreacted 280
was also recovered from the column but it required further purification.
NH OH
OTBSPMBO
OH HH
1
234
56
78
2''
1''1' 2'
3'4'
5'
187
MS (CI+) m/z 522 (42 %) (M+1), HRMS (ES+) found 522.3604, calc for C29H52NO5Si
522.3615 (M+1).
δH (300 MHz, CDCl3): major isomer 0.04 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.20-
1.80 (10H, m, H5, H6, H7, H3' and H4'), 2.84-3.14 (2H, m, H3 and H1'), 3.25-3.50 (4H, m,
H4, H2' and H8), 3.50-3.70 (2H, m, H5'), 3.77 (3H, s, OCH3), 3.95 (3H, br. s, NH and 2 x
OH), 4.39 (2H, s, OCH2Ar), 5.05-5.30 (4H, m, H1 and H2''), 5.40-5.80 (2H, m, H2 and
H1''), 6.84 (2H, d, J=8.4 Hz, 2 x ArCH), 7.23 (2H, d, J=8.4 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): major isomer -5.3 (CH3Si), -5.3 (CH3Si), 18.3 (s, (CH3)3CSi), 22.4
(t, C6), 25.9 (q, (CH3)3CSi), 28.9, 29.7, 31.2, 33.4 (t, C5, C7, C3' and C4'), 55.2 (q, OCH3),
63.3, 63.5 (d, C3 and C1'), 63.5 (t, C5'), 70.0 (t, C8), 72.4 (t, OCH2Ar), 72.4, 72.8 (d, C4
and C2'), 113.6 (d, 2 x ArCH), 118.5, 118.8 (t, C1 and C2''), 129.1 (d, 2 x ArCH), 130.5 (s,
ArC), 137.0, 137.6 (d, C2 and C1''), 158.8 (s, ArC).
1,1-Dimethylethyl N-[(1S,2S)-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-ethenyl-2-
hydroxypentyl]-N-[(1S,2S)-1-ethenyl-2-hydroxy-6-[(methoxyphenyl)methoxy]hexyl]-
carbamate (283).
The amine 282 (221 mg, 0.424 mmol) was
dissolved in CH3CN (10 mL) then di-tert-
butyldicarbonate (164 mg, 0.788 mmol),
triethylamine (76 mg, 0.788 mmol) and
DMAP (5 mg, 0.041 mmol) were added. The mixture was stirred at RT for 40 h then di-
tert-butyldicarbonate (164 mg, 0.788 mmol) triethylamine (76 mg, 0.788 mmol) and
DMAP (10 mg, 0.082 mmol) were added. The mixture was stirred at RT for 6 h then all
volatiles were removed in vacuo. The pure product was obtained by column
chromatography (increasing polarity from 10 % to 40 % EtOAc in pet. sp. as eluant), which
gave the title compound (125 mg, 0.201 mmol 47.4 %) as a clear oil.
MS (CI+) m/z 548 (12 %) (M-C4H9O), 620 (0.5 %) (M+1), HRMS (ES+) found 548.3391,
calc for C30H50NO6Si 548.3407 (M-C4H9O).
δH (300 MHz, CDCl3): 0.02 (6H, s, (CH3)2Si), 0.86 (9H, s, (CH3)3CSi), 1.46 (9H, s,
(CH3)3C-O), 1.40-1.80 (12H, m, H3, H4, H5, H3', H4' and 2 x OH), 3.35-3.44 (2H, m, H6),
3.53-3.65 (2H, m, H5'), 3.78 (3H, m, OCH3), 3.70-4.16 (4H, m, H1, H2, H1' and H2'), 4.39
NOH
OTBSPMBO
OHBoc
H H
123
45
6 1' 2'3'
4'5'
188
(2H, s, OCH2Ar), 5.00-5.44 (4H, m, 2 x CH=CH2), 5.60-6.08 (2H, m, 2 x CH=CH2), 6.85
(2H, d, J=8.4 Hz, 2 x ArCH), 7.22 (2H, d, J=8.4 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): major rotamer inter alia -5.3 (q, (CH3)2Si), 18.3 (s, (CH3)3CSi), 21.5
(t, C4), 25.9 (q, (CH3)3CSi), 27.8 (q, (CH3)3C-O), 28.5, 29.3, 31.4, 33.3 (t, C3, C5, C3' and
C4'), 55.2 (q, OCH3), 60.7, 65.2 (d, C1 and C1'), 62.1 (t, 5'), 69.5 (t, C6), 72.4 (t,
OCH2Ar), 75.0, 78.9 (d, C2 and C2'), 81.9 (s, (CH3)3C-O), 113.6 (d, 2 x ArCH), 120.0,
120.7 (t, 2 xCH=CH2), 129.1 (d, 2 x ArCH), 130.5, 136.1 (d, 2 x CH=CH2), 131.6 (s,
ArC), 152.9 (s, CO), 158.9 (s, ArC), minor rotamer inter alia 21.4 (t, C4), 28.3, 29.4, 31.7,
33.2 (t, C3, C5, C3' and C4'), 60.8, 66.6 (d, C1 and C1'), 62.4 (t, C5'), 69.6 (t, C6), 72.5 (t,
OCH2Ar), 74.8, 79.0 (d, C2 and C2'), 120.3, 121.1 (t, 2 x CH=CH2), 130.5, 135.4 (d, 2 x
CH=CH2), 131.3 (s, ArC).
(4S,5S)-4-Ethenyl-5-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]propyl]-3-[(1S,2S)-1-
ethenyl-2-hydroxy-6-[(methoxyphenyl)methoxy]hexyl]-oxazolidin-2-one (284a) and
(4S,5S)-4-ethenyl-5-[4-[(methoxyphenyl)methoxy]butyl]-3-[(1S,2S)-1-ethenyl-2-
hydroxy-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]pentyl]-oxazolidin-2-one (284b).
The amino diol 282 (60 mg, 0.115 mmol) was dissolved in
DCM (2 mL), then the solution was cooled to 0 oC.
Triethylamine (60 mg, 0.588 mmol) was added then a
solution of triphosgene (24 mg, 0.153 mmol) in DCM (1
mL) was added dropwise via syringe. The mixture was
stirred at 0 oC for 2 h, then poured into water (30 mL) and
extracted with DCM (3 x 20 mL). The combined organic extracts were dried (MgSO4),
filtered and evaporated in vacuo to give an oil. The pure product was obtained by column
chromatography (increasing polarity from 30 % to 50 % EtOAc in pet. sp. as eluant), which
gave the title compounds (31 mg, 0.058 mmol, 50.4 %) as clear oil, and as an inseparable
mixture of regioisomers.
MS (CI+) m/z 548 (57 %) (M+1), HRMS (EI+) found 547.3304, calc for C30H49NO6Si
547.3329 (M).
δH (300 MHz, CDCl3): 0.03 (3H, s, CH3Si), 0.05 (3H, s, CH3Si), 0.87 (9H, s, (CH3)3CSi),
1.00-1.80 (11H, m, H3', H4', H5', H1'', H2'' and OH), 3.38-3.50 (3H, m, H2' and
OH NO
O
H H
H
R R'1
2
3 4 51''
2''
3''
1'2'3'
4'
5'
284a R=CH2OPMB, R'=OTBS284b R=OTBS, R'=CH2OPMB
189
CH2OPMB), 3.50-3.70 (3H, m, CH2OTBS and H1'), 3.79 (3H, s, OCH3), 3.80-3.90 (1H, m,
H4), 4.10-4.24 (1H, m, H5), 4.41 (2H, s, OCH2Ar), 5.04-5.40 (4H, m, 2 x CH=CH2), 5.56-
5.80 (1H, m, CH=CH2), 5.82-6.00 (1H, m, CH=CH2), 6.87 (2H, d, J=8.7 Hz, 2 x ArCH),
7.24 (2H, J=8.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 21.8/22.5 (t, C4'), 25.9/25.9
(q, (CH3)3CSi), 29.0/27.9, 29.3/29.6, 31.4/29.8, 33.2/34.4 (t, C3', C5', C1'' and C2''), 55.2
(q, OCH3), 62.7/62.1 (t, CH2OTBS), 63.0/62.7, 65.9/66.2 (d, C4 and C1'), 69.5/70.0 (t,
CH2OPMB), 71.1/71.6 (d, C2'), 72.5/72.5 (t, OCH2Ar), 79.8/79.9 (d, C5), 113.7/113.7 (d, 2
x ArCH), 118.6, 121.8/122.3 (t, 2 x CH=CH2), 129.2 (d, 2 x ArCH), 130.4 (s, ArC),
132.2/132.9, 135.4/135.0 (d, 2 x CH=CH2), 156.0 (s, C2), 159.1 (s, ArC).
1,1-Dimethylethyl (2S,5S)-2,5-dihydro-5-[(1S)-1-hydroxy-4-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]butyl]-2-[(1S)-1-hydroxy-5-[(4-
methoxyphenyl)methoxy]pentyl]-1H-pyrrole-1-carboxylate (285).
The diene 283 (85 mg, 0.137 mmol) was
dissolved in dry DCM, then Grubbs' catalyst
(30 mg, 0.036 mmol) was addded. The
mixture was heated at reflux under N2 for 20
h, then Grubbs' catalyst (62 mg, 0.075 mmol) was added. The mixture was heated to reflux
for 3 d, then all volatiles were removed in vacuo to give a black oil. The pure product was
obtained by column chromatography (increasing polarity from 15 % to 50 % EtOAc in pet.
sp. as eluant), which gave the title compound (44 mg, 0.0741 mmol, 57.1 %) as a pale gray
oil.
MS (ES+) m/z 593.5 (40 %) (M+1), HRMS (ES+) found 520.3263, calc for C32H56NO7Si
520.3094 (M+1).
δH (300 MHz, CDCl3): 0.04 (6H, s, (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.46 (9H, s,
(CH3)3C-O), 1.30-1.95 (14H, m, H2', H3', H4', H2'', H3'' and 2 x OH), 3.32-3.49 (2H, m,
H5'), 3.52-3.80 (2H, m, H4''), 3.78 (3H, s, OCH3), 4.20-4.42 (2H, m, H2 and H5), 4.40 (2H,
s, OCH2Ar), 4.50-4.80 (2H, m, H1' and H1''), 5.78-5.98 (2H, m, H3 and H4), 6.84 (2H, d,
J=8.4 Hz, 2 x ArCH), 7.23 (2H, d, J=8.4 Hz, 2 x ArCH),.
NOH
OTBSPMBO
OHBoc
HH1
2
3 4
5 1''2''
3''4''
1'2'
3'4'
5'
190
δC (75 MHz, CDCl3): -5.2 (q, (CH3)2Si), 18.4 (s, (CH3)3CSi), 22.2/21.6 (t, C3'), 26.0 (q,
(CH3)3CSi), 27.7 (q, (CH3)3C-Oi), 27.9/28.1, 28.6/29.4, 29.4/31.5, 32.0/35.2 (t, C2', C4',
C2'' and C3''), 55.2 (q, OCH3), 62.3/62.6 (t, C4''), 69.4/69.7 (t, C5'), 69.6/69.6, 70.4 (d, C2
and C5), 72.4/72.6 (t, OCH2Ar), 76.6, 81.9 (d, C1' and C1''), 81.9 (s, (CH3)3C-O),
113.6/113.7 (d, 2 x ArCH), 129.0/129.1 (d, 2 x ArCH), 130.2, 130.8 (C3 and C4),
130.4/130.6 (s, ArC), 159.0/158.9 (s, ArC), 153.1/162.0 (s, CO).
1,1-Dimethylethyl (2S,5S)-2,5-dihydro-5-[(1S)-1,4-bishydroxybutyl]-2-[(1S)-1-
hydroxy-5-[(4-methoxyphenyl)methoxy]pentyl]- 1H-pyrrole-1-carboxylate (286).
The silyl ether 285 (44 mg, 0.0741 mmol) was
dissolved in THF (2.5 mL), then TBAF.H2O (47
mg, 0.156 mmol) was added. The mixture was
stirred at RT for 20 h, then silica gel (3 mL) was added, and the slurry filtered. The solids
were washed with CHCl3 (2 x 10 mL), before the combined filtrates were evaporated in
vacuo to give an orange gum. The pure product was obtained by column chromatography
(increasing polarity from 5 % to 10 % MeOH in DCM as eluant), which gave the title
compound (24 mg, 0.050 mmol, 67.5 %) as an amber oil.
MS (CI+) m/z 480 (13 %) (M+1).
δH (300 MHz, CDCl3): 1.43 (9H, s, (CH3)3C), 1.40-1.96 (15H, m, H2', H3', H4', H2'', H3''
and 3 x OH), 3.40 (2H, m, H5'), 3.62-3.74 (2H, m, H4''), 3.80 (3H, s, OCH3), 4.26-4.40
(2H, m, H2 and H5), 4.42 (2H, s, OCH2Ar), 4.55-4.82 (1H, m, H1' and H1''), 5.86-5.94
(2H, m, H3 and H4), 6.86 (2H, d, J=8.4 Hz, 2 x ArCH), 7.25 (2H, d, J=8.4 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 21.7/22.2 (t, C3'), 27.8 (q, (CH3)3C), 28.2/28.5, 29.4, 31.5/32.0, 35.1
(t, C2', C4', C2'' and C3''), 55.3 (q, OCH3), 62.0/62.3 (t, C4''), 69.4/69.5 (t, C5'), 69.7/69.7,
70.5/70.5 (d, C2 and C5), 72.4/72.6 (t, OCH2Ar), 76.4, 81.8/82.2 (d, C1' and C1''),
82.0/82.1 (s, (CH3)3C), 113.6/113.7 (d, 2 x ArCH), 129.1/129.1 (d, 2 x ArCH), 130.2/130.4,
130.9/130.7 (d, C3 and C4), 130.6 (s, ArC), 153.2/162.2 (s, CO), 159.0 (s, ArC).
Ethyl N,N-di-(2-propenyl)-carbamate (290).189
Diethylpyrocarbonate (508 mg, 3.132 mmol) was dissolved in DCM
(20 mL) then the solution was cooled to 0 oC. Diallylamine (377 mg,
NOH
OHPMBO
OHBoc
H H1
2
3 4
5 1''2''
3''4''
1'3'4'
5'2'
NO
O
1'2'3'
1
191
3.881 mmol) was added, then the mixture was stirred at 0 oC for 10 min, then at RT for 2 h.
Solvent and excess amine were removed in vacuo to give the volatile title compound (410
mg, 2.423 mmol, 77.4 %) as a clear oil that had spectral data identical to that reported in the
literature.189
MS (CI+) m/z 170 (100 %) (M+1), HRMS (EI+) found 169.1101, calc for C9H15NO2
169.1103 (M+1).
δH (300 MHz, CDCl3): 1.20 (3H, t, J=6.9 Hz, OCH2CH3), 3.79 (4H, br. s, H1'), 4.09 (2H,
q, J=7.2 Hz, OCH2CH3), 5.00-5.12 (4H, m, H3'), 5.63-5.78 (2H, m, H2').
δC (75 MHz, CDCl3): 14.5 (q, OCH2CH3), 48.3 (br. t, C1'), 61.2 (t, OCH2CH3), 116.4 (br.
t, C3'), 133.5 (d, C2'), 156.1 (s, C1).
Ethyl 2,5-dihydro-2-[(1-hydroxy-1-phenyl)methyl]-2-[(2,5-dihydro-1H-pyrrol-1-
yl)carbonyl]-1H-pyrrole-1-carboxylate (292).
Diisopropylamine (607 mg, 5.873 mmol) was dissolved in THF (45
mL) at -78 oC, then n-butyllithium (3.8 mL, 4.56- mmol, 1.2 M)
was added. After stirring for 10 min under N2, the 2,5-
dihydropyrrole 291 (550 mg, 3.929 mmol) was added via cannula.
The mixture was stirred for 3 min, then benzaldehyde (542 mg,
5.108 mmol) was added. The mixture was stirred at -78 oC for 30 min, then sat. NH4Cl
(aq) (20 mL) was added, before the mixture was allowed to warm to RT. The mixture was
extracted with Et2O (3 x 30 mL), then the combined organic extracts were dried (MgSO4),
filtered and evaporated in vacuo to give an oil. The pure products were obtained by column
chromatography (increasing polarity form 20 % to 100 % EtOAc in pet. sp. as eluant),
which gave the title compound (220 mg, 0.643 mmol, 32.7 %) and the diastereoisomer (48
mg, 0.140 mmol, 7.1 %) as pale yellow solids.
Major diastereomer:
MS (CI+) m/z 343 (100 %) (M+1), HRMS (CI+) found 343.1655, calc for C19H23N2O4
343.1658 (M+1).
δH (300 MHz, CDCl3): major rotamer inter alia 1.21 (3H, t, J=6.9 Hz, OCH2CH3), 2.85
(1H, dt, J=15.9, 1.8 Hz, H2'a), 3.66-4.44 (8H, m, H5a, H1'', H2'b, H5', OCH2CH3 and OH),
5.09 (1H, dd, J=5.4, 2.1 Hz, H5b), 5.60-5.88 (4H, m, H3, H3', H4 and H4'), 7.10-7.22 (5H,
N
N
OH
O
OO
Ph
12
3 4
2'
1'' 5
3'
1'
4'
5'
192
m, Ph), minor rotamer inter alia 1.19(3H, t, J=6.9 Hz, OCH2CH3), 2.81 (1H, dt, J=15.9, 1.8
Hz, H2').
δC (75 MHz, CDCl3): major rotamer inter alia 14.6 (q, OCH2CH3), 51.3, 54.1, 55.3 (t, C5,
C2' and C5'), 61.4 (t, OCH2CH3), 75.2 (d, C1'') 76.9 (s, C2), 124.4, 124.6, 125.2 (d, C3, C4,
C3'), 126.8, 127.1, 127.7 (d, Ph), 129.9 (d, C4'), 137.6 (s, Ph), 152.9 (s, CO), 169.5 (s, CO),
minor rotamer inter alia 14.7 (q, OCH2CH3), 51.4, 53.6, 55.3 (t, C5, C2' C5'), 61.3 (t,
OCH2CH3), 74.3 (d, C1'') 77.3 (s, C2), 124.3, 124.7, 125.0 (d, C3, C4, C3'), 126.6, 127.2,
127.8 (d, Ph), 129.9 (d, C4'), 137.8 (s, Ph), 153.0 (s, CO), 169.2 (s, CO).
(3S,4S)-3-[[(1S,2S)-2,5-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-ethenyl-
pentyl]amino]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-8-[(methoxyphenyl)methoxy]-
1-octene (296).
The diol 282 (200 mg, 0.383 mmol) was
dissolved in CH3CN (3 mL) then imidazole
(160 mg, 2.30 mmol) and TBSCl (284 mg,
1.917 mmol) were added. The mixture was heated in a sealed tube at 70 oC for 20 h then
cooled, before it was poured into sat. Na2CO3 solution (30 mL) and extracted with CHCl3
(3 x 30 mL). The combined organic extracts were dried (MgSO4) filtered and evaporated in
vacuo to give an oil. The pure product was obtained by column chromatography
(increasing polarity from 4 % to 15 % Et2O in pet. sp. as eluant), which gave the title
compound (252 mg, 0.336 mmol, 87.7 %) as a clear oil. The two diastereoisomers could be
partially separated using this method.
MS(ES+) m/z 750.9 (100 %) (M+1), HRMS (ES+) found 750.5334, calc for C41H80NO5Si3
750.5344 (M+1).
major isomer:
[α]D28: -20 (c 1.65, CHCl3).
δH (300 MHz, CDCl3): 0.04 (6H, s, (CH3)2Si), 0.05 (3H, s, CH3Si), 0.06 (6H, s, (CH3)2Si),
0.07 (3H, s, CH3Si), 0.89 (27H, s, 3 x (CH3)3CSi), 1.00-1.80 (11H, m, H5, H6, H7, H3', H4'
and NH), 3.10 (2H, t, J=6.6 Hz, H3 and H1'), 3.42 (2H, t, J=6.6 Hz, H8), 3.52-3.64 (4H, m,
H4, H2' and H5'), 3.80 (3H, s, OCH3), 4.42 (2H, s, OCH2Ar), 5.04-5.18 (4H, m, H1 and
NH OTBS
OTBSTBSO
PMBO
HH
12
345
67
8
2''1''
1' 2'3'
4'5'
193
H2''), 5.50-5.68 (2H, m, H2 and H1''), 6.87 (2H, d, J=8.4 Hz, 2 x ArCH), 7.25 (2H, d, J=8.4
Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -5.1 (q, (CH3)2Si), -4.3 (q, CH3Si), -4.2 (q, CH3Si), -4.1 (q, CH3Si),
-4.0 (q, CH3Si), 18.2 (s, 2 x (CH3)3CSi), 18.5 (s, (CH3)3CSi), 21.6 (t, C6), 26.1 (q, 3 x
(CH3)3CSi), 28.0, 29.8, 30.1, 33.1 (t, C5, C7, C3' and C4'), 55.3 (q, OCH3), 61.4, 61.6 (d,
C3 and C1'), 63.6 (t, C5'), 70.2 (t, C8), 72.5 (t, OCH2Ar), 75.2, 75.5 (d, C4 and C2'), 113.6
(d, 2 x ArCH), 116.5, 116.9 (t, C1 and C2''), 129.0 (d, 2 x ArCH), 130.7 (s, ArC), 138.5,
138.5 (d, C2 and C1''), 158.9 (s, ArC).
minor isomer:
δH (300 MHz, CDCl3): 0.04 (6H, s, (CH3)2Si), 0.05 (6H, s, (CH3)2Si), 0.06 (6H, s,
(CH3)2Si), 0.89 (27H, s, 3 x (CH3)3CSi), 1.00-1.80 (11H, m, H5, H6, H7, H3', H4' and NH),
3.14-3.22 (2H, m, H3 and H1'), 3.44 (2H, t, J=6.6 Hz, H8), 3.54-3.70 (4H, m, H4, H2' and
H5'), 3.80 (3H, s, OCH3), 4.43 (2H, s, OCH2Ar), 5.05-5.24 (4H, m, H1 and H2''), 5.70-5.82
(2H, m, H2 and H1''), 6.87 (2H, d, J=8.4 Hz, 2 x ArCH), 7.26 (2H, d, J=8.4 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -5.1 (q, (CH3)2Si), -4.3 (q, CH3Si), -4.2 (q, CH3Si), -4.1 (q, CH3Si),
-4.1 (q, CH3Si), 18.2 (s, 2 x (CH3)3CSi), 18.4 (s, (CH3)3CSi), 22.6 (t, C6), 26.0 (q, 3 x
(CH3)3CSi), 29.0, 29.1, 30.1, 32.0 (t, C5, C7, C3' and C4'), 55.3 (q, OCH3), 61.2, 61.7 (d,
C3 and C1'), 63.5 (t, C5'), 70.2 (t, C8), 72.5 (t, OCH2Ar), 73.9, 74.3 (d, C4 and C2'), 113.6
(d, 2 x ArCH), 115.2, 115.8 (t, C1 and C2''), 129.0 (d, 2 x ArCH), 130.7 (s, ArC), 138.6,
138.7 (d, C2 and C1''), 158.9 (s, ArC).
Ethyl N-[(1S,2S)-1-ethenyl-2,5-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]pentyl]-N-
[(1S,2S)-1-ethenyl-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-
[(methoxyphenyl)methoxy]hexyl]-carbamate (297).
The amine 296 (343 mg, 0.457 mmol) was
dissolved in DCM (2 mL) then
diethylpyrocarbonate (296 mg, 1.828 mmol)
was added. The mixture was heated in a
sealed tube at 160 oC for 4 d then cooled. After careful release of pressure (CO2) all
volatiles were removed in vacuo to give an oil. The pure product was obtained by column
NOTBS
OTBSTBSO
PMBO
COOEtH H
65
43
2 1 1' 2'3'
4'5'
194
chromatography (increasing polarity from 5 % to 15 % EtOAc in pet. sp. as eluant), which
gave the title compound (355 mg, 0.432 mmol, 94.5 %) as a clear oil.
MS (ES+) m/z 823.0 (100 %) (M+1), HRMS (ES+) found 822.5541, calc for C44H83NO7Si3
822.5556 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.04 (3H, s, CH3Si), 0.04 (3H, s, CH3Si),
0.06 (3H, s, CH3Si), 0.07 (3H, s, CH3Si), 0.88 (27H, s, (CH3)3CSi), 1.25 (3H, t, J=6.9 Hz,
CH3CH2O), 1.30-1.80 (10H, m, H3, H4, H5, H3' and H4'), 3.42 (2H, t, J=6.6 Hz, H6), 3.48-
3.64 (2H, m, H5'), 3.79 (3H, s, OCH3), 3.98-4.32 (6H, m, H1, H2, H1', H2' CH3CH2O),
4.42 (2H, s, OCH2Ar), 5.02-5.20 (4H, m, 2 x CH=CH2), 6.02-6.18 (2H, m, 2 x CH=CH2),
6.86 (2H, dt, J=9.0, 2.7 Hz, 2 x ArCH), 7.25 (2H, dt, J=9.0, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), -5.1 (q, CH3Si), -5.0 (q, CH3Si), -4.1 (q, CH3Si), -
4.1 (q, CH3Si), 14.6 (q, CH3CH2O), 18.1 (s, 3 x (CH3)3CSi), 21.1 (t, C4), 25.9 (q,
(CH3)3CSi), 26.0 (q, 2 x (CH3)3CSi), 27.2, 29.8, 30.0, 33.0 (t, C3, C5, C3' and C4'), 55.2 (q,
OCH3), 60.7 (t, CH3CH2O), 63.3 (t, C5'), 66.0, 66.3 (d, C1 and C1'), 70.1 (t, C6), 72.4 (t,
OCH2Ar), 73.0, 73.0 (d, C2 and C2'), 113.6 (d, 2 x ArCH), 118.0, 118.2 (t, 2 x CH=CH2),
129.0 (d, 2 x ArCH), 130.7 (s, ArC), 135.2, 135.6 (d, 2 x CH=CH2), 155.4 (s, CO), 159.0
(s, ArC).
(3S,4S)-3-Acetyloxy-8-[(methoxyphenyl)methoxy]-3-[[(1S,2S)-5-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]-1-ethenyl-2-acetyloxy-pentyl]amino]-1-octene (298).
The amino diol 282 (200 mg, 0.380 mmol)
was dissolved in pyridine (0.5 mL) and acetic
anhydride (0.5 mL), then the mixture was
stirred at RT for 24 h. All volatiles were
removed in vacuo to give an oil. The pure product was obtained by column
chromatography (increasing polarity from 10 % to 40 % EtOAc in pet. sp. as eluant), which
gave the title compound (120 mg, 0.198 mmol, 51.7 %) as a clear oil.
MS (CI+) m/z 606 (79 %) (M+1), HRMS (EI+), found 605.3707, calc for C33H55NO7Si
605.3694 (M).
δH (300 MHz, CDCl3): 0.03 (6H, s (CH3)2Si), 0.87 (9H, s, (CH3)3CSi), 1.10-1.80 (11H, m,
H5, H6, H7, H3', H4' and NH), 2.03 (3H, s, OAc), 2.04 (3H, s, OAc), 3.15 (2H, ddd, J=8.1,
NH OAc
OTBSAcO
PMBO
HH
1
234
56
78
2''
1''1' 2'
3'4'
5'
195
6.3, 3.3 Hz, H3 and H1'), 3.40 (2H, t, J=6.6 Hz, H8), 3.57 (2H, t, J=6.0 Hz, H5'), 3.79 (3H,
s, OCH3), 4.40 (2H, s, OCH2Ar), 4.75-4.86 (2H, m, H4 and H2'), 5.05-5.30 (4H, m, H1 and
H2''), 5.48 (2H, ddd, J=17.4, 10.5, 8.4 Hz, H2 and H1''), 6.86 (2H, d, J=8.4 Hz, 2 x ArCH),
7.24 (2H, d, J=8.4 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -5.2 (q, (CH3)2Si), 18.4 (s, (CH3)3CSi), 21.1 (q, 2 x OAc), 22.1 (t,
C6), 26.0 (q, (CH3)2CSi), 27.2, 28.6, 29.6, 30.5 (t, C5, C7, C3' and C4'), 55.2 (q, OCH3),
60.2, 60.3 (d, C3 and C1'), 62.7 (t, C5'), 69.8 (t, C8), 72.4 (t, OCH2Ar), 75.9, 76.1 (d, C4
and C2'), 113.6 (d, 2 x ArCH), 117.9, 118.0 (t, C1 and C2''), 129.0 (d, 2 x ArCH), 130.6 (s,
ArC), 136.8, 136.9 (d, C2 and C1''), 158.9 (s, ArC), 170.6 (s, 2 x OAc).
Ethyl N-[(1S,2S)-1-ethenyl-2-acetyloxy-5-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]pentyl]-N-[(1S,2S)-1-ethenyl-2-acetyloxy-6-
[(methoxyphenyl)methoxy]hexyl] carbamate (299).
The amine 298 (51 mg, 0.0842 mmol) was
dissolved in DCM (2 mL) then
diethylpyrocarbonate (130 mg, 0.803 mmol)
was added. The mixture was heated in a
sealed tube at 130 oC for 2 d, then diethylpyrocarbonate (130 mg, 0.803 mmol) was added.
The mixture was heated to 130 oC for 2 d then cooled. The pure product was obtained by
column chomatography (increasing polarity from 20 % to 50 % EtOAc in pet. sp. as
eluant), which gave the title compound (23 mg, 0.0339 mmol, 40.3 %) and recovered
starting material (16 mg, 0.0264 mmol, 31.4 %) as clear oils.
MS (ES+) m/z 678 (35 %) (M+1), HRMS (CI+) found 678.4016, calc for C36H60NO9Si
678.4038 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.88 (9H, s, (CH3)3CSi), 1.27 (3H, t, J=7.2
Hz, CH3CH2O), 1.25-1.78 (10H, m, H3, H4, H5, H3' and H4'), 1.98 (3H, s, OAc), 1.99 (3H,
s, OAc), 3.40 (2H, t, J=6.3 Hz, H6), 3.56 (2H, t, J=6.0 Hz, H5'), 3.58-3.68 (2H, m, H1 and
H1'), 3.80 (3H, s, OCH3), 4.00-4.20 (2H, m, CH3CH2O), 4.40 (2H, s, OCH2Ar), 5.13-5.25
(4H, m, 2 x CH=CH2), 5.40-5.55 (2H, m, 2 x CH=CH2), 6.00-6.30 (2H, m, H2 and H2'),
6.85 (2H, dt, J=8.4, 2.1 Hz, 2 x ArCH), 7.23 (2H, dt, J=8.4, 2.1 Hz, 2 x ArCH).
NOAc
OTBSAcO
PMBO
COOEtH H
65
43
2 1 1' 2'3'
4'5'
196
δC (75 MHz, CDCl3): -5.2 (q, (CH3)2Si), 14.5 (q, CH3CH2O), 18.3 (CH3)3CSi), 21.7 (q,
OAc), 21.8 (q, OAc), 22.2 (br. t, C4), 26.0 (q, (CH3)3CSi), 27.2, 28.3, 29.6, 32.0 (t, C3, C5,
C3' and C4'), 53.5 (t, CH3CH2O), 55.3 (qOCH3), 61.3 (d, C1), 62.3 (t, C5'), 69.8 (t, C6),
70.5 (br. d, C1'), 72.5 (t, OCH2Ar), 72.5, 74.0 (d, C2 and C2'), 113.6 (d, 2 x ArCH), 118.9,
119.0 (t, 2 x CH=CH2), 129.1 (d, 2 x ArCH), 130.6 (s, ArC), 134.5, 134.5 (d, 2 x
CH=CH2), 159.0 (s, ArC), 155.3 (s, CO), 170.0 (s, 2 x OAc).
Ethyl (2S,5S)-2,5-dihydro-2-[(1S)-1-acetyloxy-5-[(4-methoxyphenyl)methoxy]pentyl]-
[(1S)-1-acetyloxy-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butyl]-1H-pyrrole-1-
carboxylate (300).
The diene 299 (23 mg, 0.034 mmol) was
dissolved in dry DCM (10 mL) then
Grubbs' catalyst (28 mg, 0.034 mmol) was
added. The mixture was heated at reflux
under N2 for 2 d, then all volatiles were removed in vacuo to give an oil. The pure product
was obtained by column chromatography (increasing polarity from 20 % to 40 % EtOAc in
pet. sp. as eluant), which gave the title compound (15 mg, 0.0231 mmol 67.9 %) as a pale
grey oil.
MS (CI+) m/z 650 (14 %) (M+1), HRMS (CI+) found 650.3732, calc for C34H56NO9Si
650.3724 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.88 (9H, s, (CH3)3CSi), 1.15-1.75 (13H, m,
H2', H3', H4', H2'', H3'' and CH3CH2O), 2.06 (3H, s, OAc), 2.07 (3H, s, OAc), 3.38 (2H, t,
J=6.3 Hz, H5'), 3.54 (2H, t, J=5.4 Hz, H4''), 3.80 (3H, s, OCH3), 4.04-4.32 (2H, m,
CH3CH2O), 4.39 (2H, s, OCH2Ar), 4.60-4.76 (2H, m, H2 and H5), 5.50-5.60 (1H, m, H1''),
5.70-5.90 (3H, m, H3, H4 and H1'), 6.86 (2H, d, J=8.4 Hz, 2 x ArCH), 7.22 (2H, d, J=8.4
Hz, 2 x ArCH).
δC (75 MHz, CDCl3): Not obtained.
NOAc
OTBSAcO
PMBO
COOEtH H
12
3 4
5 1''2''
3''4''
1'2'
3'5'4'
197
(3S,4S)-8-[(Methoxyphenyl)methoxy]-3-[N-[(1S,2S)-5-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]-1-ethenyl-2-hydroxypentyl]-N-phenylmethyl-amino]-
1-octen-4-ol (303).
The vinyl epoxide 208a (135 mg, 0.558
mmol) and the amine 302 (268 mg, 0.725
mmol) were dissolved in CH3CN (1 mL) then
LiOTf (130 mg, 0.837 mmol) was added. The
mixture was heated in a sealed tube at 135 oC for 3d, then LiOTf (205 mg, 1.255 mmol)
was added. The mixture was heated to 140 oC for 2d then cooled, before all volatiles were
removed in vacuo. The pure product was obtained by column chromatography (increasing
polarity from 2 % to 10 % MeOH in DCM as eluant), which gave the title compound (246
mg, 0.402 mmol, 72.0 %) as a 4:1 diastereoisomeric mixture. A pure sample of the major
isomer was obtained by column chromatography (increasing polarity from 10 % to 50 %
EtOAc in pet. sp. as eluant), giving a clear oil.
major isomer:
[α]D22: -23 (c 0.68, CHCl3).
MS (CI+) m/z 612 (72 %) (M+1), HRMS (CI+), found 612.4086, calc for C36H58NO5Si
612.4084 (M+1).
δH (300 MHz, CDCl3): 0.04 (6H, s, (CH3)2Si), 0.88 (9H, s, (CH3)3CSi), 1.06-1.74 (11H, m,
H5, H6, H7, H3', H4' and OH), 3.00 (1H, t, J=9.6 Hz, H3), 3.10 (1H, t, J=9.6 Hz, H1'),
3.30-3.72 (7H, m, H4, H8, H2', H5' and NCH2Ph), 3.79 (3H, s, OCH3), 3.95 (1H, d, J=14.1
Hz, NCH2Ph), 4.10 (1H, br. s, OH), 4.40 (2H, s, OCH2Ar), 5.00-5.30 (4H, m, H1 and H2''),
5.66-5.84 (2H, m, H2 and H1''), 6.86 (2H, dt, J=9.0, 2.1 Hz, 2 x ArCH), 7.18-7.42 (7H, m,
2 x ArCH and NCH2Ph).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.2 (s, (CH3)3CSi), 22.5 (t, C6), 25.9 (q,
(CH3)3CSi), 29.0, 29.7, 31.4, 33.8 (t, C5, C7, C3' and C4'), 50.2 (t, NCH2Ph), 55.2 (q,
OCH3), 63.3 (t, C5'), 66.3, 66.8 (d, C3 and C1'), 69.3, 69.6 (d, C4 and C2'), 70.1 (t, C8),
72.4 (t, OCH2Ar), 113.6 (d, 2 x ArCH), 119.2, 119.2 (t, C1 and C2''), 126.9, 128.4, 128.8
(d, NCH2Ph), 129.1 (d, 2 x ArCH), 130.7 (s, ArC), 135.0, 135.3 (d, C2 and C1''), 139.7 (s,
NCH2Ph), 159.0 (s, ArC).
NOH
OTBSPMBO
BnOH HH
12
345
67
8
2''1''
1' 2'3'
4'5'
198
Phenylmethyl N-[(1S,2S)-1-ethenyl-2-hydroxy-5-[(4-methoxyphenyl)methoxy]pentyl]-
N-(2-propenyl) carbamate (304).
The amino alcohol 224 (64 mg, 0.200 mmol) was dissolved
in THF (0.7 mL) then sat. Na2CO3 solution (0.7 mL), and
benzylchloroformate (146 mg, 0.856 mmol), were added.
The mixture was stirred at RT for 2 h then diluted with water
(25 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were dried
(MgSO4) filtered and evaporated in vacuo to give an oil. The pure product was obtained by
column chromatography (increasing polarity from 20 % to 50 % EtOAc in pet. sp. as
eluant), which gave the title compound (76 mg, 0.168 mmol, 83.8 %) as a clear oil.
[α]D23: -12 (c 1.0, CHCl3).
MS (CI+) m/z 454 (35 %) (M+1), HRMS (CI+) found 454.2585, calc for C27H36NO5
454.5293 (M+1).
δH (300 MHz, CDCl3): 0.80-1.00 (1H, m, H4a), 1.10-1.70 (5H, m, H3, H4b and H5), 2.05
(1/2H, br.s, free OH), 3.20 (1/2H, br.s, H-bonded OH), 3.44 (2H, t, J=6.0 Hz, H6), 3.78
(3H, s, OCH3), 3.74-4.10 (4H, m, H1, H2 and H1'), 4.42 (2H, s, OCH2Ar), 5.06-5.30 (6H,
m, H2'', H3' and OCH2Ph), 5.72-6.02 (2H, m, H1'' and H2'), 6.87 (2H, dt, J=8.4, 1.8 Hz, 2 x
ArCH), 7.26 (2H, dt, J=8.4, 1.8 Hz, 2 x ArCH), 7.28-7.38 (5H, m, OCH2Ph).
δC (75 MHz, CDCl3): major rotamer inter alia 22.3 (t, C4), 29.5 (t, C5), 34.0 (br. t, C3),
49.8 (br. t, C1'), 55.1 (q, OCH3), 65.9 (br. d, C1), 67.2 (t, OCH2Ph), 69.9 (t, C6), 71.7 (br.d,
C2), 72.4 (t, OCH2Ar), 113.6 (d, 2 x ArCH), 117.1 (t, C3'), 118.5 (br.t, C2''), 127.6, 127.9,
128.3 (d, OCH2Ph), 129.1 (d, 2 x ArCH), 130.5 (s, ArC), 134.0 (d, C2'), 134.7 (br. d, C1''),
136.4 (s, OCH2Ph), 156.5 (s, CO), 159.0 (s, ArC), minor rotamer inter alia 15.3 (t, C4),
29.4 (t, C5), 69.6 (br.d, C1).
(4S,5S)-4-Ethenyl-5-[4-[(4-methoxyphenyl)methoxy]butyl]-3-(2-propenyl)-oxazolidin-
2-one (311).
Method A
The amino alcohol 224 (100 mg, 0.313 mmol) was dissolved
in DCM (2 mL) and the solution was cooled to 0 oC.
Triethylamine (100 mg, 0.988 mmol) and then triphosgene
NOHH
H
OPMB
Cbz
3'3
4
2''
1''1
5
61'2'
2
NO
O
OPMBH
H123
4 5 2'''3'''
4'''1'
2'
3'
1''1'''
2''
199
(50 mg, 0.168 mmol) in DCM (1 mL) were added. The mixture was stirred at 0 oC for 1 h,
then the mixture was poured into water (50 mL) and extracted with DCM (3 x 25 mL). The
combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an
oil. The pure product was obtained by column chromatography (increasing polarity from
30 % to 50 % EtOAc in pet. sp. as eluant), which gave the title compound (58 mg, 0.168
mmol, 53.6 %) as a clear oil.
Method B
The carbamate 262 (209 mg, 0.498 mmol) was disolved in THF (20 mL), then sodium
hydride (37 mg, 0.771 mmol, 50 % dispersion in paraffin wax) was added. The mixture
was stirred under N2 at RT for 2 h, then poured into water (50 mL) and extracted with
DCM (3 x 25 mL). The combined organic extracts were dried (MgSO4), filtered and
evaporated in vacuo to give an oil. The pure product was obtained by column
chromatography(increasing polarity from 30 % to 50 % EtOAc in pet. sp. as eluant), which
gave the title compound (165 mg, 0.478 mmol, 95.9 %) as a clear oil.
[α]D29: -61 (c 1.65, CHCl3).
MS (CI+) m/z 346 (20 %) (M+1), 344 (16 %) (M-1), HRMS (CI+) found 344.1862, calc
for C20H26NO4 344.1862 (M-1).
δH (300 MHz, CDCl3): 1.35-1.80 (6H, m, H1''', H2''' and H3'''), 3.40 (2H, t, J=5.4 Hz,
H4'''), 3.46 (1H, dd, J=15.6, 7.8 Hz, H1'a), 3.76 (3H, s, OCH3), 3.70-3.82 (1H, m, H4),
3.98-4.12 (2H, m, H5 and H1'b), 4.38 (2H, s, OCH2Ar), 5.08-5.35 (4H, m, H2'' and H3'),
5.53-5.76 (2H, m, H1'' and H2'), 6.83 (2H, d, J=8.4 Hz, 2 x ArCH), 7.21 (2H, J=8.4 Hz, 2 x
ArCH).
δC (75 MHz, CDCl3): 21.7 (t, C2'''), 29.2, 33.4 (t, C1''' and C3'''), 44.4 (t, C1'), 55.1 (q,
OCH3), 64.2 (d, C4), 69.4 (t, C4'''), 72.4 (t, OCH2Ar), 79.0 (d, C5), 113.5 (d, 2 x ArCH),
118.2, 121.1 (t, C2'' and C3'), 128.9 (d, 2 x ArCH), 130.3 (s, ArC), 131.4, 134.5 (d, C1'' and
C2'), 157.0 (s, C2), 158.8 (s, ArC).
200
(1S,5S,7aS)-1-[3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]propyl]-5,7a-dihydro-5-[(1S)-
1-hydroxy-5-[(methoxyphenyl)methoxy]-pentyl]-1H,3H-pyrrolo[1,2-c]oxazol-3-one
(313a) and (1S,5S,7aS)-1-[4-[(methoxyphenyl)methoxy]butyl]-5,7a-dihydro-5-[(1S)-1-
hydroxy-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butyl]-1H,3H-pyrrolo[1,2-c]oxazol-
3-one (313b).
The mixture of dienes 284a and 284b (31 mg, 0.058
mmol) was dissolved in dry DCM (20 mL) then Grubbs'
catalyst (20 mg, 0.024 mmol) was added. The mixture
was heated at reflux under N2 for 2 d, then cooled before
all volatiles were removed in vacuo to give an oil. The
pure product was obtained by column chromatography
(increasing polarity from 40 % to 60 % EtOAc in pet. sp. as eluant), which gave a 1:1
mixture of the title compounds (16 mg, 0.032 mmol, 54.5 %) as a pale grey oil.
MS (CI+) m/z 520 (36 %) (M+1), HRMS (EI+) found 519.2976, calc for C28H45NO6Si
519.3016 (M).
δH (300 MHz, CDCl3): 0.05 (3H, s, CH3Si), 0.06 (3H, s, CH3Si), 0.89 (9H, s, (CH3)3CSi),
1.20-1.98 (10H, m, H2', H3', H4', H1'' and H2''), 2.94 (1H, br. s, OH), 3.42-3.64 (5H, m,
H1', CH2OTBS and CH2OPMB), 3.80 (3H, s, OCH3), 4.28-4.50 (3H, m, H1, H5 and H7a),
4.43 (2H, s, OCH2Ar), 5.90-6.02 (2H, m, H6 and H7), 6.87 (2H, d, J=8.7 Hz, 2 x ArCH),
7.25 (2H, d, J=8.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), 18.3 (s, (CH3)3CSi), 21.5/22.3 (t, C3'), 25.9 (q,
(CH3)3CSi), 28.8/27.8, 31.2/29.3, 31.9/29.5, 33.6/34.8 (t, C2', C4', C1'' and C2''), 55.2 (q,
OCH3), 62.3/63.4 (t, CH2OTBS), 69.4/69.9 (d, C7a), 70.7/70.9 (t, CH2OPMB), 71.9/72.1
(d, C5), 72.4/72.5 (d, C1'), 72.6/72.7 (t, OCH2Ar), 82.4 (d, C1), 113.7 (d, 2 x ArCH), 129.2
(d, 2 x ArCH), 129.7/130.1, 131.6/131.3 (d, C6 and C7), 130.4 (s, ArC), 159.1 (s, ArC),
162.4 (s, C3).
(1S,7aS)-1-(4-Chlorobutyl)-tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (315).
The alcohol 314 (46 mg, 0.231 mmol) was dissolved in dry CCl4
(4 mL) and CH2Cl2 (1 mL). Solid K2CO3 (68 mg, 0.492 mmol)
and then PPh3 (160 mg, 0.610 mmol) were added. The mixture
ROH N
OO
R'H
H
H
1
23
4
5
6
1''2''
3''1'2'
3'4' 7
7a
313a R=CH2OPMB, R'=OTBS313b R=OTBS, R'=CH2OPMB
NO
O
ClH
H1
23
4
5
6 7
2'3'
4'7a1'
201
was stirred at RT for 24 h, then heated at reflux (70 oC) for 24 h. After cooling the mixture
was poured into water (30 mL) and extracted with DCM (3 x 20 mL). The combined
organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give a semi-solid.
The pure product was obtained by column chromatography (increasing polarity from 2 % to
10 % MeOH in DCM as eluant), which gave the title compound (21 mg, 0.0965 mmol, 41.8
%) and recovered starting material (12 mg, 0.060 mmol, 26.1 %) as clear oils.
[α]D27: -50 (c 1.05, CHCl3).
MS (CI+) m/z 218 (100 %) (M-1), 220 (34 %) (M+1), HRMS (CI+) found 218.0946, calc
for C10H18NO3 218.0948 (M+1).
δH (300 MHz, CDCl3): 1.40-2.12 (10 H, m, H6, H7, H1', H2' and H3'), 3.14 (1H, ddd,
J=11.4, 8.7, 4.5 Hz, H5a), 3.48-3.66 (2H, m, H7a and H5b), 3.54 (2H, t, J=6.3 Hz, H4'),
4.27 (1H, dt, J=7.5, 4.8 Hz, H1).
δC (75 MHz, CDCl3): 22.1 (t, C2'), 25.8, 30.8, 32.0, 34.5 (t, C6, C7, C1' and C3'), 44.6,
45.5 (t, C5 and C4'), 64.6 (d, C7a), 80.4 (d, C1), 161.0 (s, C3).
(3S,4S)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[[(1S,2S)-5-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]-1-ethenyl-2-hydroxypentyl]amino]-8-
[(methoxyphenyl)methoxy]-1-octene (318).
The vinyl epoxide 208a (400 mg, 1.649
mmol) and the amine 226 (844 mg, 2.144
mmol) were dissolved in CH3CN (3 mL), then
LiOTf (650 mg, 4.123 mmol) was added. The
mixture was heated in a sealed tube at 135-140 oC for 3d, then cooled, before all volatiles
were removed in vacuo to give a semi solid. The pure products were obtained by column
chromatography (increasing polarity from 5 % to 25 % Et2O in 1:1 pet. sp:DCM as eluant),
which gave the title compound 318 (819 mg, 1.288 mmol, 78.1 %) and 319 (182 mg, 0.286
mmol, 17.3 %) as clear oils. Excess 226 was also recovered by increasing the eluant
polarity to 10 % MeOH in DCM, but it required further purification.
Major isomer:
[α]D22: + 1 (c 0.49, CHCl3).
NH OH
OTBSTBSO
PMBO
HH
1
234
56
78
2''
1''1' 2'
3'4'
5'
202
MS (ES+) m/z 636.5 (100 %) (M+1), HRMS (EI+) found 635.4391, calc for C35H65NO5Si2
635.4401 (M).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.06 (3H, s, CH3Si), 0.08 (3H, s, CH3Si),
0.88 (9H, s, (CH3)3CSi), 0.89 (9H, s, (CH3)3CSi), 1.20-1.80 (12H, m, H5, H6, H7, H3', H4',
NH and OH), 2.82 (1H, t, J=8.7 Hz, H1'), 3.12 (1H, t, J=8.1 Hz, H3), 3.20 (1H, t, J=8.7 Hz,
H2'), 3.41 (2H, t, J=6.3 Hz, H8), 3.50-3.68 (3H, m, H4 and H5'), 3.79 (3H, s, OCH3), 4.41
(2H, s, OCH2Ar), 5.00-5.24 (4H, m, H1 and H2''), 5.32-5.54 (2H, m, H2 and H1''), 6.86
(2H, d, J=7.8 Hz, 2 x ArCH), 7.24 (2H, d, J=7.8 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -5.3 (q, (CH3)2Si), -4.6 (q, CH3Si), -4.1 (q, CH3Si), 18.1 (s,
(CH3)3CSi), 18.3 (s, (CH3)3CSi), 20.5 (t, C6), 25.9 (q, (CH3)3CSi), 25.9 (q, (CH3)3CSi),
28.9, 29.9, 30.0, 33.5 (t, C5, C7, C3' and C4'), 55.2 (q, OCH3), 61.8 (d, C3), 63.2 (d, C1'),
63.2 (t, C5'), 70.0 (t, C8), 72.4 (t, OCH2Ar), 72.8 (d, C2'), 74.6 (d, C4), 113.7 (d, 2 x
ArCH), 118.0, 118.7 (t, C1 and C2''), 129.1 (d, 2 x ArCH), 130.7 (s, ArC), 137.1, 138.0 (d,
C2 and C1''), 159.0 (s, ArC).
(4S,5S)-3-[(1S,2S)-2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1-ethenyl-6-
[(methoxyphenyl)methoxy]hexyl]-5-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]propyl]-
4-ethenyl-2-oxazolidinone (320) and (2R,3S)-1-[(1S,2S)-2-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]-1-ethenyl-6-[(methoxyphenyl)methoxy]hexyl]-3-[3-
[[(1,1-dimethylethyl)dimethylsilyl]oxy]propyl]-2-ethenyl-aziridine (321).
TBSO NO
O
PMBO OTBS
H H
H
TBSO
PMBO
N
OTBS
H
H
H1
2
3 4 51''
2'' 3''1'2'3'
4'6'5'
1
2
3
1''2'' 3''
1'2'3'
4'5'
6'
320 321 The amino alcohol 318 (1.320 g, 2.072) was dissolved in dry DCM (60 mL) then the
solution was cooled to -40 oC. Triethylamine (1.189 g, 11.64 mmol) was added, then a
solution of triphosgene (324 mg, 1.088 mmol) in DCM (4 mL) was added dropwise via
syringe. The mixture was stirred at -40 oC for 2 h, then poured into water (75 mL) and
extracted with DCM (3 x 30 mL). The combined organic extracts were dried (MgSO4),
filtered and evaporated to dryness in vacuo to give an oil. The pure products were obtained
by column chromatography (increasing polarity from 5 % to 20 % EtOAc in pet. sp. as
203
eluant), which gave 320 (1.155 g, 1.745 mmol, 84.2 %) and 321 (184 mg, 0.298 mmol,
14.3 %) as colourless oils.
320:
[α]D26: -19 (c 0.3, CHCl3).
MS (ES+) m/z 662.5 (100 %) (M+1), HRMS (EI+) found 661.4215, calc for C36H63NO6Si2
661.4221 (M).
δH (300 MHz, CDCl3): 0.04 (6H, s, (CH3)2Si), 0.05 (3H, s, CH3Si), 0.07 (3H, s, CH3Si),
0.88 (9H, s, (CH3)3CSi), 0.89 (9H, s, (CH3)3CSi), 1.10-1.82 (10H, m, H3', H4', H5', H1''
and H2''), 3.41 (2H, t, J=6.3 Hz, H6'), 3.54-3.67 (3H, m, H3'' and H1'), 3.79 (3H, s, OCH3),
3.87 (1H, t, J=8.4 Hz, H4), 4.02-4.10 (1H, m, H5), 4.40 (2H, s, OCH2Ar), 4.36-4.45 (1H,
m, H2'), 5.08-5.20 (2H, m, CH=CH2), 5.24-5.34 (2H, m, CH=CH2), 5.74 (1H, ddd, J=17.7,
9.6, 8.7 Hz, CH=CH2), 6.02 (1H, dt, J=16.8, 10.2 Hz, CH=CH2), 6.86 (2H, dt, J=8.7, 2.1
Hz, 2 x ArCH), 7.24 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -5.4 (q, CH3Si), -5.4 (q, CH3Si), -4.8 (q, CH3Si), -4.2 (CH3Si), 18.1
(s, (CH3)3CSi), 18.1 (s, (CH3)3CSi), 19.7 (t, C4'), 25.9 (q, (CH3)3CSi), 26.0 (q, (CH3)3CSi),
28.2, 29.8, 29.9, 34.3 (t, C3', C5', C1'' and C2''), 55.2 (q, OCH3), 62.1 (d, C1'), 62.2 (t, C1''),
66.0 (d, C4), 69.9 (t, C6'), 70.8 (d, C2'), 72.4 (t, OCH2Ar), 79.2 (d, C5), 113.7 (d, 2 x
ArCH), 118.8, 120.5 (t, 2 x CH=CH2), 129.1 (d, 2 x ArCH), 130.7 (s, ArC), 133.3, 136.2
(d, CH=CH2), 157.0 (s, C2), 159.0 (s, ArC).
321:
[α]D24: -15 (c 1.0, CHCl3).
MS (ES+) m/z 618.4 (100 %) (M+1), HRMS (ES+) found 618.4354, calc for C35H64NO4Si2
618.4374 (M+1).
δH (300 MHz, CDCl3): 0.04 (9H, s, CH3Si and (CH3)2Si), 0.05 (3H, s, CH3Si), 0.88 (9H, s,
(CH3)3CSi), 0.89 (9H, s, (CH3)3CSi), 1.10-1.86 (11H, m, H3, H3', H4', H5', H1'' and H2''),
1.96 (1H, t, J=6.3 Hz, H2), 2.05 (1H, dd, J=4.8, 3.0 Hz, H1'), 3.43 (2H, t, J=6.3 Hz, H6'),
3.59 (2H, t, J=6.3 Hz, H3''), 3.63-3.72 (1H, m, H2'), 3.80 (3H, s, OCH3), 4.42 (2H, s,
OCH2Ar), 5.10-5.34 (4H, m, 2 x CH=CH2), 5.66 (1H, ddd, J=17.4, 10.5, 6.9 Hz, CH=CH2),
5.89 (1H, ddd, J=17.4, 10.8, 6.6 Hz, CH=CH2), 6.87 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH),
7.25 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH).
204
δC (75 MHz, CDCl3): -5.3 (q, (CH3)2Si), -4.5 (q, CH3Si), -4.2 (q, CH3Si), 18.0 (s,
(CH3)3CSi), 18.3 (s, (CH3)3CSi), 22.9, 24.9, 29.7, 30.6, 31.7 (t, C3', C4', C5', C1'' and C2''),
25.9 (q, (CH3)3CSi), 25.9 (q, (CH3)3CSi), 45.0, 45.2 (d, C2 and C3), 55.2 (q, OCH3), 70.2
(t, C6'), 72.4 (t, OCH2Ar), 73.9 (d, C2'), 77.9 (d, C1'), 113.7 (d, 2 x ArCH), 116.9, 117.0 (t,
2 x CH=CH2), 129.1 (d, 2 x ArCH), 130.9 (s, ArC), 135.1, 135.8 (d, 2 x CH=CH2), 159.0
(s, ArC).
(1S,5S,7aS)-5-[(1S)-1-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-
[(methoxyphenyl)methoxy]pentyl]-1-[3-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]propyl]-5,7a-dihydro-1H,3H-pyrrolo[1,2-c]oxazol-3-
one (322).
The diene 320 (547mg, 0.826 mmol) was
dissolved in dry DCM (95 mL), then Grubbs'
catalyst (338 mg, 0.413 mmol) was added.
The mixture was heated at reflux under N2 for
7d then cooled, before all volatiles were removed in vacuo to give a black oil. The pure
product was obtained by column chromatography (increasing polarity from 10 % to 40 %
EtOAc in pet. sp. as eluant), which gave a black oil. This was dissolved in EtOAc (30 mL)
and stirred with activated charcoal for 20 min to remove residual ruthenium, then filtered
through celite. Evaporation of the filtrate afforded the title compound (485 mg, 0.785
mmol, 92.6 %) as a colourless oil.
[α]D26: -86 (c 1.0, CHCl3).
MS (ES+) m/z 634.5 (100 %) (M+1), HRMS (ES+) found 634.3975, calc for C34H59NO6Si2
634.3959 (M+1).
δH (300 MHz, CDCl3): 0.04 (6H, s, (CH3)2Si), 0.05 (6H, s, (CH3)2Si), 0.86 (9H, s,
(CH3)3CSi), 0.89 (9H, s, (CH3)3CSi), 1.34-1.96 (10H, m, H2', H3', H4', H1'' and H2''), 3.44
(2H, t, J=6.6 Hz, H5'), 3.62-3.74 (3H, m, H1' and H3''), 3.79 (3H, s, OCH3), 4.24-4.30 (1H,
m, H7a), 4.35 (1H, q, J=6.0 Hz, H1), 4.42 (2H, s, OCH2Ar), 4.54 (1H, app. t, J=3.9 Hz,
H5), 5.85-5.92 (2H, m, H6 and H7), 6.86 (2H, d, J=8.7 Hz, 2 x ArCH), 7.25 (2H, d, J=8.7
Hz, 2 x ArCH).
PMBO
TBSO NO
OTBS
O
H
H
H1
23
4
5
6 7
7a1'2'
3'4'
5' 1''2''
3''
205
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), -4.6 (q, CH3Si), -4.4 (q, CH3Si), 18.0 (s,
(CH3)3CSi), 18.3 (s, (CH3)3CSi), 22.2 (t, C3'), 25.8 (q, (CH3)3CSi), 25.9 (q, (CH3)3CSi),
27.9, 29.9, 31.9, 33.6 (t, C2', C4', C1'' and C2''), 55.2 (q, OCH3), 62.3 (t, C3''), 70.0 (t, C5''),
70.6 (d, C7a), 71.0 (d, C5), 72.5 (t, OCH2Ar), 73.3 (d, C1'), 82.0 (d, C1), 113.7 (d, 2 x
ArCH), 129.2 (d, 2 x ArCH), 129.6, 132.2 (d, C6 and C7), 130.8 (s, ArC), 159.0 (s, ArC),
162.4 (s, C3).
(1S,5S,7aS)-5-[(1S)-1-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-
[(methoxyphenyl)methoxy]pentyl]-1-[3-[[(1,1-
dimethylethyl)dimethylsilyl]oxy]propyl]-tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one
(323).
The 2,5-dihydropyrrole 322 (160 mg, 0.252
mmol) was dissolved in EtOAc (70mL) then
Pd/C (30 mg, 10 % Pd w/w) was added. The
mixture was stirred under an atmosphere of H2
for 1h, then the flask flushed with N2, prior to filtration of the mixture through celite. The
solids were washed with EtOAc, then the combined filtrates evaporated in vacuo to give an
oil. The pure product was obtained by column chromatography (increasing polarity from
10 % to 40 % EtOAc in pet. sp. as eluant), which gave the title compound (152 mg, 0.239
mmol, 94.7 %) as a clear oil.
[α]D25: -28 (c 1.0, CHCl3).
MS (ES+) m/z 636.5 (100 %) (M+1), HRMS (ES+) found 636.4106, calc for C34H62NO6Si2
636.4116 (M+1).
δH (300 MHz, CDCl3): 0.04 (6H, s, (CH3)2Si), 0.06 (6H, s, (CH3)2Si), 0.88 (9H, s,
(CH3)3CSi), 0.89 (9H, s, (CH3)3CSi), 1.30-2.10 (14H, m, H6, H7, H2', H3', H4', H1'' and
H2''), 3.38-3.50 (2H, m, H5'), 3.50-3.70 (4H, m, H5, H3'' and H1'), 3.80 (3H, s, OCH3),
3.92 (1H, td, J=7.5, 3.0 Hz, H7a), 4.23-4.32 (1H, m, H1), 4.42 (2H, s, OCH2Ar), 6.87 (2H,
dt, J=8.7, 2.1 Hz, 2 x ArCH), 7.26 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), -4.6 (q, CH3Si), -4.3 (q, CH3Si), 17.9 (s,
(CH3)3CSi), 18.3 (s, (CH3)3CSi), 21.8 (t, C3'), 25.8 (q, (CH3)3CSi), 25.9 (q, (CH3)3CSi),
27.7, 27.8, 29.9, 31.4, 32.1, 33.8 (t, C6, C7, C2', C4', C1'' and C2''), 55.2 (q, OCH3), 61.0
TBSO NO
OTBS
O
PMBO
H H
H
1
234
5
6 7
2''3''1'
2'3'
4'5' 1''
7a
206
(d, C7a), 62.4 (t, C3''), 65.1 (d, C5), 70.1 (t, C5'), 72.5 (t, OCH2Ar), 74.4 (d, C1'), 80.1 (d,
C1), 113.7 (d, 2 x ArCH), 129.2 (d, 2 x ArCH), 130.7 (s, ArC), 159.0 (s, ArC), 161.3 (s,
C3).
(1S,5S,7aS)-5-[(1S)-1-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-hydroxypentyl]-1-(3-
[[(1,1-dimethylethyl)dimethylsilyl]oxy]propyl)-tetrahydro-1H,3H-pyrrolo[1,2-
c]oxazol-3-one (324).
The PMB ether 323 (62 mg, 0.0975 mmol) was
dissolved in DCM (10 mL), then water (1 mL)
and DDQ (24 mg, 0.106 mmol) were added. The
mixture was stirred at RT for 90 min, then diluted
with water (30 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts
were dried (MgSO4), filtered and evaporated in vacuo to give an oil. The pure product was
obtained by column chromatography (increasing polarity from 40 % to 70 % EtOAc in pet.
sp. as eluant), which gave the title compound (49 mg, 0.095 mmol, 97.5 %) as a clear oil.
[α]D28: -23 (c 0.47, CHCl3).
MS (CI+) m/z 516 (100 %) (M+1), HRMS (CI+), found 516.3559, calc for C26H54NO5Si2
516.3541 (M+1).
δH (300 MHz, CDCl3): 0.02 (6H, s, (CH3)2Si), 0.04 (3H, CH3Si), 0.05 (3H, s, CH3Si), 0.86
(18H, s, 2 x (CH3)3CSi), 1.05-2.13 (14H, m, H6, H7, H2', H3', H4', H1'' and H1''), 2.50 (1H,
br. s. OH), 3.51-3.70 (6H, m, H5, H1', H5' and H3''), 3.94 (1H, td, J=7.5, 2.4 Hz, H7a),
4.28 (1H, ddd, J=6.6, 5.4, 3.0 Hz, H1).
δC (75 MHz, CDCl3): -5.4 (q, (CH3)2Si), -4.7 (q, CH3Si), -4.2 (q, CH3Si), 17.9 (s,
(CH3)3CSi), 18.2 (s, (CH3)3CSi), 20.6 (t, C3'), 25.8 (q, (CH3)3CSi), 25.9 (q, (CH3)3CSi),
27.7, 27.9, 31.5, 32.1, 32.3, 33.6 (t, C6, C7, C2', C4', C1'' and C2''), 60.5 (d, C7a), 61.3 (t,
C5'), 62.4 (t, C3''), 65.3 (d, C5), 74.5 (d, C1' ), 80.3 (d, C1), 161.5 (s, C3).
(1S,5S,7aS)-5-[(1S)-1-Hydroxy-5-[(methoxyphenyl)methoxy]pentyl]-1-(3-
hydroxypropyl)-tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (326).
The di-O-silyl ether 323 (78 mg, 0.123 mmol)
was dissolved in THF (5 mL), then dry TBAF
TBSO NO
OTBS
O
OH
H
H
H
1
234
5
6 7
2''3''1'
2'3'
4'5' 1''7a
OH NO
OH
O
PMBO
H
H
H
1
234
5
6 7
2''3''1'
2'3'
4'5' 1''
7a
207
(194 mg, 0.615 mmol) was added. The mixture was stirred at RT for 4d, then silica gel (3
mL) was added. After stirring for a further 20 min the slurry was filtered, then the solids
were washed with MeOH. The combined filtrates were evaporated in vacuo to give an oil.
The pure product was obtained by column chromatography (increasing polarity from 2.5 %
to 20 % MeOH in DCM as eluant), which gave the title compound (50 mg, 0.123 mmol,
99.8 %) as a clear gum.
[α]D24: -59 (c 0.5, CHCl3).
MS (CI+) m/z 408 (2 %) (M+1), HRMS (ES+) found 408.2388, calc for C22H34NO6
408.2386 (M+1).
δH (300 MHz, CDCl3): 1.30-2.20 (14H, m, H6, H7, H2', H3', H4', H1'' and H2''), 2.32 (1H,
br. s, OH), 3.00 (1H, br. s, OH), 3.33-3.42 (1H, m, H1'), 3.44 (2H, t, J=6.0 Hz, H5'), 3.56-
3.70 (4H, m, H7a, H5 and H3''), 3.78 (3H, s, OCH3), 4.30-4.38 (1H, m, H1), 4.40 (2H, s,
OCH2Ar), 6.85 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH), 7.24 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 22.0 (t, C3'), 27.6, 29.5, 29.6, 31.6, 31.7, 33.7 (t, C6, C7, C2', C4',
C1'' and C2''), 55.2 (q, OCH3), 61.8 (t, C3''), 63.8, 65.0 (d, C7a and C5), 69.9 (t, C5'), 72.4
(t, OCH2Ar), 74.1 (d, C1'), 81.2 (d, C1), 113.7 (d, 2 x ArCH), 129.2 (d, 2 x ArCH), 130.5
(s, ArC), 159.0 (s, ArC), 162.1 (s, C3).
(δS,2S,5S)-2-[(1S)-1-Hydroxy-5-[(methoxyphenyl)methoxy]pentyl]-δ-hydroxy-5-
pyrrolidinebutanol (327).
The oxazolidinone 326 (543 mg, 1.332 mmol)
was dissolved in MeOH (35 mL) then NaOH
(530 mg, 13.25 mmol) in water (5 mL) was
added. The mixture was placed in a teflon tube with a 100 bar pressure cap, then heated at
100 oC for 90 min in microwave reactor. After cooling MeOH was removed in vacuo, then
the mixture was diluted with water (30 mL) and extracted with DCM (4 x 30 mL). The
combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an
oil (472 mg, 1.237 mmol, 92.9 %) which was not purified any further.
[α]D25: -16 (c 0.71, CHCl3).
MS (CI+) m/z 382 (36 %) (M+1), HRMS (CI+) found 382.2581, calc for C21H36NO5
382.2593 (M+1).
NH
PMBO
OHOHOH
H H1
2
34
5 4'3'
2'1'
1''2''
3''4''
5''
208
δH (300 MHz, CDCl3): 1.26-1.90 (14H, m, H3, H4, H2', H3', H2'', H3'' and H4''), 2.90-3.40
(2H, m, H2 and H5), 3.14-3.32 (2H, m, H4' and H1''), 3.43 (2H, t, J=6.0 Hz, H5''), 3.50-
3.68 (2H, m, H1'), 3.77 (3H, s, OCH3), 3.86 (4H, br. s, NH and 3 x OH), 4.40 (2H, s,
OCH2Ar), 6.85 (2H, dt, J=8.7, 2.7 Hz, 2 x ArCH), 7.23 (2H, dt, J=8.7, 2.7 Hz, 2 x ArCH).
δC (75 MHz, CDCl3): 22.4 (t, C3''), 29.1, 29.1, 29.3, 29.6, 31.9, 34.4 (C3, C4, C2', C3', C2''
and C4''), 55.2 (q, OCH3), 62.5 (t, C1'), 62.7, 62.9 (d, C2 and C5), 70.0 (t, C5''), 72.5 (t,
OCH2Ar), 73.9, 74.0 (d, C4' and C1''), 113.7 (d, 2 x ArCH), 129.2 (d, 2 x ArCH), 130.6 (s,
ArC), 159.1 (s, ArC).
(2S,5S)-2-[(1S )-1-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-
[(methoxyphenyl)methoxy]pentyl]-5-[(1S)-1,4-bis[[(1,1-
dimethylethyl)dimethylsilyl]oxy]butyl]-pyrrolidine (328).
The oxazolidinone 326 (51 mg, 0.0804 mmol)
was dissolved in MeOH (4.5 mL) then NaOH
(116 mg, 2.90 mmol) in water (1.5 mL) was
added. The mixture was heated at reflux under N2 for 2 d, then diluted with water (20 mL)
and extracted with DCM (3 x 20 mL). The combined organic extracts were dried (MgSO4),
filtered and evaporated in vacuo to give crude 327. This was dissolved in CH3CN (3 mL),
then TBSCl (93 mg, 0.63 mmol) and imidazole (53 mg, 0.756 mmol) were added. The
mixture was heated in a sealed tube at 80 oC for 1 d, then poured into sat. NaHCO3 solution
(30 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were dried
(MgSO4), filtered and in vacuo to give an oil. The pure product was obtained by column
chromatography (increasing polarity from 2.5 % to 7.5 % MeOH in DCM as eluant), which
gave the title compound (40 mg, 0.0552 mmol, 68.6 %, 2 steps) as a clear oil.
[α]D29: 0 (c 0.39, CHCl3).
MS (ES+) m/z 724.5 (100 %) (M+1), HRMS (CI+), found 724.5179, calc for C39H78NO5Si3
724.5188 (M+1).
δH (300 MHz, CDCl3): 0.03 (6H, s, (CH3)2Si), 0.06 (3H, s, CH3Si), 0.07 (3H, s, CH3Si),
0.08 (3H, s, CH3Si), 0.09 (3H, s, CH3Si), 0.88 (27H, s, 3 x (CH3)3CSi), 1.30-1.86 (14H, m,
H3, H4, H2', H3', H4', H2'' and H3''), 2.04 (1H, br. s, NH), 3.16-3.26 (2H, m, H2 and H5),
3.42 (2H, t, J=6.6 Hz, H5'), 3.50-3.65 (4H, m, H1', H1'' and H4''), 3.80 (3H, s, OCH3), 4.42
NH
PMBO
OTBSOTBS
TBSO HH1
2
34
5 1''2''
3''4''
1'2'
3'4'
5'
209
(2H, s, OCH2Ar), 6.86 (2H, dt, J=8.7, 2.1 Hz, 2 x ArCH), 7.25 (2H, dt, J=8.7, 2.1 Hz, 2 x
ArCH).
δC (75 MHz, CDCl3): -5.3 (q, (CH3)2Si), -4.3 (q, (CH3)2Si), -4.2 (q, (CH3)2Si), 18.1 (s, 2 x
(CH3)3CSi), 18.3 (s, (CH3)3CSi), 21.3 (t, C3'), 25.9 (q, 3 x (CH3)3CSi), 25.9, 28.0, 28.0,
30.1, 30.9, 34.5 (t, C3, C4, C2', C4', C2'' and C3''), 55.2 (q, OCH3), 61.5, 61.5 (br. d, C2
and C5), 63.4 (t, C4''), 70.0 (t, C5'), 72.5 (t, OCH2Ar), 75.1, 75.1 (br. d, C1' and C1''), 113.7
(d, 2 x ArCH), 129.2 (d, 2 x ArCH), 130.7 (s, ArC), 169.1 (s, ArC).
(2S,5S)-2-[(1S )-1-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-5-
[(methoxyphenyl)methoxy]pentyl]-5-[(1S)-1,4-bis[[(1,1-
dimethylethyl)diphenylsilyl]oxy]butyl]-pyrrolidine (329).
The triol 327 (454 mg, 1.190 mmol) was
dissolved in CH3CN (10 mL), then
imidazole (836 mg, 12.00 mmol) and
TBDPSCl (2.20 g, 8.00 mmol) were added. The mixture was heated in a sealed tube at 75 oC for 2 d, then poured into sat. NaHCO3 solution (50 mL) and extracted with DCM (3 x 35
mL). The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo
to give an oil. The pure product was obtained by column chromatography (increasing
polarity from 5 % to 20 % EtOAc in pet. sp. as eluant), which gave the title compound
(1.057 g, 0.964 mmol, 81.0 %) as a clear oil.
[α]D25: -3 (c 1.48, CHCl3).
MS (ES+) m/z 1096.6 (60 %) (M+1), HRMS (ES+) found 1096.6118, calc for
C69H90NO5Si3 1096.6127 (M+1).
δH (300 MHz, CDCl3): 1.03 (9H, s, (CH3)3CSi), 1.08 (18 H, s, 2 x (CH3)3CSi), 1.10-1.70
(14H, m, H3, H4, H2', H3', H4', H2'' and H3''), 1.87 (1H, br. s, NH), 3.14-3.30 (4H, m, H2,
H5 and H5'), 3.34-3.52 (2H, m, H4''), 3.58 (2H, q, J=5.1 Hz, H1' and H1''), 3.82 (3H, s,
OCH3), 4.37 (2H, s, OCH2Ar), 6.90 (2H, dt, J=8.4, 1.8 Hz, 2 x ArCH), 7.25 (2H, dt, J=8.4,
1.8 Hz, 2 x ArCH), 7.28-7.48 (18H, m, SiPh), 7.60-7.76 (12H, m, SiPh).
δC (75 MHz, CDCl3): 19.1 (s, (CH3)3CSi), 19.6 (s, 2 x (CH3)3CSi), 21.8 (t, C3'), 26.8 (q,
(CH3)3CSi), 27.1 (q, (CH3)3CSi), 28.2, 28.5, 28.6, 29.7, 30.5, 34.1 (t, C3, C4, C2', C4', C2''
and C3''), 55.2 (q, OCH3), 61.6, 61.8 (d, C2 and C5), 64.0 (t, C4''), 70.0 (t, C5'), 72.4 (t,
NH
PMBO
OTBDPSOTBDPS
TBDPSO H H1
2
34
5 1''2''
3''4''
1'2'
3'4'
5'
210
OCH2Ar), 76.5, 76.7 (d, C1' and C1''), 113.7 (d, 2 x ArCH), 127.3, 127.4, 127.4, 127.5,
129.1, 129.3, 129.3, 129.4 (d, 2 x ArCH and 6 x SiPh), 130.8 (s, ArC), 134.1, 134.5, 134.6,
134.6, 134.7 (s, 6 x SiPh), 135.5, 135.8, 135.9, 136.0 (d, 6 x SiPh), 159.0 (s, ArC).
(2S,5S,δS)-δ-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-5-[(1S)-1,4-bis[[(1,1-
dimethylethyl)diphenylsilyl]oxy]butyl]-pyrrolidinepentanol (330).
The PMB ether 329 (61 mg, 0.0556 mmol)
was dissolved in CH3CN (2 mL), then water
(0.3 mL), DCM (0.5 mL) and CAN (55 mg,
0.100 mmol) were added. The mixture was stirred at RT for 40 min, then poured into sat.
NaHCO3 solution (30 mL) and extracted with DCM (3 x 25 mL). The combined organic
protions were dried (MgSO4), filtered and evaporated in vacuo to give an oil. The pure
product was obtained by column crhromatography (increasing polarity from 5 % to 10 %
MeOH in DCM as eluant), which gave the title compound (48 mg, 0.0517 mmol, 93.0 %)
as a clear oil.
[α]D26: -6 (c 2.0, CHCl3).
MS (ES+) m/z 976.4 (100 %) (M+1), HRMS (ES+) found 976.5560, calc for C61H82NO4Si3
976.5552 (M+1).
δH (300 MHz, CDCl3): 1.04 (9H, s, (CH3)3CSi), 1.10 (9H, s, (CH3)3CSi), 1.11 (9H, s,
(CH3)3CSi), 1.10-1.80 (14H, m, H3, H4, H2', H3', H4', H2'', and H3''), 2.08 (2H, br. s, NH
and OH), 3.18-3.32 (2H, m, H2 and H5), 3.36-3.53 (4H, m, H4'' and H1'), 3.56-3.70 (2H,
m, H5' and H1''), 7.30-7.48 (18H, m, 6 x SiPh), 7.62-7.78 (12H, m, 6 x SiPh).
δC (75 MHz, CDCl3): 19.1 (s, (CH3)3CSi), 19.5 (s, 2 x (CH3)3CSi), 21.3 (t, C3'), 26.8 (q,
(CH3)3CSi), 27.2 (q, (CH3)3CSi), 28.1, 28.4, 28.4, 30.6, 32.5, 33.8 (t, C3, C4, C2', C4', C2''
and C3''), 61.5, 61.8 (d, C2 and C5), 62.3, 63.9 (t, C1' and C4''), 76.2, 76.5 (d, C5' and C1''),
127.3, 127.4, 127.4, 127.5, 129.3, 129.4 (d, 6 x SiPh), 133.9, 133.9, 134.2, 134.4, 134.5,
134.6 (s, 6 x SiPh), 135.5, 135.8, 135.8, 135.9 (d, 6 x SiPh).
NH
OH
OTBDPSOTBDPS
TBDPSO HH1
2
34
5 1''2''
3''4''
5'4'
3'2'
1'
211
(3S,9S,9aS)-9-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3-[(1S)-1,4-bis[[(1,1-
dimethylethyl)diphenylsilyl]oxy]-butyl]-1H-pyrrolo[1,2-a]azepine (331).
The amino alcohol 330 (727 mg, 0.744 mmol) was
dissolved in DCM (60 mL), then the solution was
cooled to 0 oC. Carbon tetrabromide (604 mg,
1.828 mmol) and triphenylphosphine (475 mg,
1.828 mmol) were added, then the mixture was stirred at 0 oC for 10 min, before
triethylamine (3.70 g, 36.56 mmol) was added. The mixture was stirred at 0 oC for 5 h,
then left to stand at 4 oC for 20 h, then stirred at RT for 24 h. The mixture was poured into
water (50 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were
dried (MgSO4), filtered and evaporated to give a black semi-solid. The pure products were
obtained by column chromatography (increasing polarity from 5 % to 25 % EtOAc in pet.
sp. as eluant), which gave the title compound (451 mg, 0.470 mmol, 63.2 %) and the
partially stable bromide intermediate 333 (mass not taken). The bromide intermediate was
dissolved in DCM (10 mL) and triethylamine (5 mL), then heated at reflux for 3 h. Work
up and column chromatography as described above gave further title compound (128 mg,
0.134 mmol, 17.9 %, total yield 81.1 %) as a colourless oil.
[α]D24: -35 (c 1.28, CHCl3).
MS (ES+) m/z 958.6 (100 %) (M+1), HRMS (ES+) found 958.5452, calc for C61H80NO3Si
958.5446 (M+1).
δH (300 MHz, CDCl3): 1.07 (9H, s, (CH3)3CSi), 1.11 (18 H, s, (CH3)3Si), 0.80-1.80 (13H,
m, H1, H2, H6, H7, H8a, H2' and H3'), 1.84-2.00 (1H, m, H8b), 2.34 (1H, dd, J=13.2, 9.0
Hz, H7a), 2.55 (1H, dd, J=13.5, 6.6 Hz, H7b), 3.10-3.20 (1H, m, H9a), 3.28-3.36 (1H, m,
H5), 3.50 (2H, t, J=6.0 Hz, H4'), 3.76-3.84 (1H, m, H9), 3.84-3.92 (1H, dd, J=7.2, 3.0 Hz,
H1'), 7.28-7.44 (18H, m, SiPh), 7.58-7.73 (12H, m, SiPh).
δC (75 MHz, CDCl3): 19.2 (s, (CH3)3CSi), 19.3 (s, (CH3)3CSi), 19.5 (s, (CH3)3CSi), 26.8
(q, (CH3)3CSi), 27.1 (q, (CH3)3CSi), 27.2 (q, (CH3)3CSi), 25.0, 25.1, 26.2, 27.1, 28.1, 30.0,
34.1 (t, C1, C2, C6, C7, C8, C2' and C3'), 48.3 (t, C7), 64.2 (t, C4'), 66.2 (d, C3), 66.7 (d,
C9a), 74.0 (d, C9), 76.5 (d, C1'), 127.4, 127.5, 129.4, 129.5 (d, SiPh), 134.2, 134.2, 134.2,
134.5, 134.6, 134.7 (s, SiPh), 136.0, 136.0, 136.0 (d, SiPh).
NOTBDPS
OTBDPSTBDPSO
HH
1 2
34
5
67
8
99a 3'1'
4'2'
212
(3S,9S,9aS)-3-[(1S)-1,4-Dihydroxybutyl]-9-hydroxy-1H-pyrrolo[1,2-a]azepine (334).
The tri-O-silyl ether 331 (61 mg, 0.0636 mmol) was dissolved
in CHCl3 (0.5 mL), then MeOH (4.0 mL) and conc HCl (1.0
mL, 38 % w/w) were added. The mixture was heated in a
sealed tube at 90 oC for 3d then cooled. The mixture was
poured into ether (40 mL) and extracted with 1M HCl (3 x 15 mL). The combined aqueous
extracts were evaporated to dryness in vacuo to give a gum. This was dissolved in water (2
mL) and applied to basic ion exchange resin (OH- form). Elution with water (50 mL) and
evaporation of the eluant gave the title compound (13 mg, 0.0534 mmol, 83.9 %) as a pale
brown gum.
[α]D22: -34 (c 1.3, MeOH).
MS (CI+) m/z 244 (100 %) (M+1), HRMS (CI+) found 244.1916, calc for C13H26NO3
244.1913 (M+1).
δH (300 MHz, CDCl3): 1.30-2.10 (17H, m, H1, H2, H6, H7, H8, H2', H3' and 2 x OH),
2.85 (1H, ddd, J=12.3, 6.3, 2.4 Hz, H5a), 2.94-3.08 (2H, m, H3 and H5b), 3.29 (1H, td,
J=6.9, 2.4 Hz, H9a), 3.38 (1H, ddd, J=9.0, 6.3, 2.4 Hz, H1'), 3.60-3.76 (2H, m, H4'), 3.94
(1H, br. d, J=6.9 Hz, H9).
δC (75 MHz, CDCl3): 22.9 (t, C7), 27.9, 28.9, 29.4, 30.1, 32.1, 34.8 (t, C1, C2, C6, C8,
C2' and C3'), 52.5 (t, C5), 62.9 (t, C4'), 65.3 (d, C9a), 71.0 (d, C3), 72.6 (d, C9), 72.8 (d,
C1').
(3S,5S,9S,9aS)-3-[(5S)-tetrahydro-5-oxo-2-furanyl]-5,9-epoxy-1H-pyrrolo[1,2-
a]azepine (338).
The triol 334 (25 mg, 0.103 mmol) was dissolved in AcOH (2 mL),
then TEMPO (5 mg, 0.032 mmol) and BAIB (113 mg, 0.35 mmol)
were added. The mixture was stirred at RT for 24 h, then
Na2S2O3.5H2O (125 mg, 0.504 mmol) was added. After 20 min the
mixture was poured into 5 % NH4OH solution (40 mL) and extracted with DCM (3 x 20
mL). The combined organic extracts were dried (MgSO4) filtered and evaporated in vacuo
to give an oil. The pure product was obtained by column chromatography (2 % MeOH in
NOH
OHOH
H HH
4'3'
2'1'3
21
9a9
8
7 6
5
4
ON
OO
H
H1 2
34
5
67
8
9 9a
1'2'
3'4'
5'
213
DCM as eluant) which gave the title compound (7 mg, 0.029 mmol, 28.6 %) as a pale
yellow semi solid.
MS (CI+) m/z 238 (100 %) (M+1).
δH (300 MHz, CDCl3): 0.80-2.00 (10H, m, H1a, H2, H6, H7, H8 and H4'a), 2.00-2.14 (1H,
m, H1b), 2.25 (1H, dddd, J=12.6, 8.1, 6.9, 5.7 Hz, H4'b), 2.53 (1H, dd, J=9.6, 3.3 Hz,
H3'a), 2.55 (1H, dd, J=9.6, 0.9 Hz, H3'b), 3.02 1H, ddd, J=10.2, 7.5, 5.4 Hz, H3), 3.46-3.80
(1H, m, H9a), 4.02 (1H, d, J=1.5 Hz, H9), 4.37 (1H, dt, J=7.8, 7.2 Hz, H5'), 4.82 (1H, s,
H5).
δC (75 MHz, CDCl3): 16.8 (t, C7), 25.4 (t, C4'), 28.8 (t, C3'), 28.9, 29.2 (t, C6 and C8),
31.5 (t, C2), 31.6 (t, C1), 68.7 (d, C9a), 70.9 (d, C3), 78.9 (d, C9), 85.3 (d, C5'), 96.0 (d,
C5), 177.0 (s, C2).
214
Chapter 8: References (1) Sakata, K.; Aoki, K.; Chang, C. F.; Sakurai, A.; Tamura, S.; Murakoshi, S. Agric.
Biol. Chem. 1978, 42, 457.
(2) Pilli, R. A.; Ferreira de Oliveira, M. d. C. Nat. Prod. Rep. 2000, 17, 117-127.
(3) Shinozaki, H.; Ishida, M. Brain Res. 1985, 33, 334.
(4) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989, 111, 1923-
5.
(5) Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106-12.
(6) Morimoto, Y.; Iwahashi, M.; Nishida, K.; Hayashi, Y.; Shirahama, H. Angew.
Chem., Int. Ed. Engl. 1996, 35, 904-906.
(7) Morimoto, Y.; Iwahashi, M.; Kinoshita, T.; Nishida, K. Chem. Eur. J. 2001, 7,
4107-4116.
(8) Chen, C. Y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840-9.
(9) Williams, D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35, 6417-20.
(10) Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356-8357.
(11) Kinoshita, A.; Mori, M. Heterocycles 1997, 46, 287-299.
(12) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119, 3409.
(13) Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69, 2063.
(14) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299.
(15) Martin, S. F.; Barr, K. J.; Smith, D. W.; Bur, S. K. J. Am. Chem. Soc. 1999, 121,
6990-6997.
(16) Morimoto, Y.; Nishida, K.; Hayashi, Y.; Shirahama, H. Tetrahedron Lett. 1993, 34,
5773-6.
(17) Goldstein, D. M.; Wipf, P. Tetrahedron Lett. 1996, 37, 739-42.
(18) Rigby, J. H.; Laurent, S.; Cavezza, A.; Heeg, M. J. J. Org. Chem. 1998, 63, 5587-
5591.
(19) Kende, A. S.; Smalley, T. L.; Huang, H. J. Am. Chem. Soc. 1999, 121, 7431-7432.
(20) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295-4303.
(21) Jung, S. H.; Lee, J. E.; Joo, H. J.; Kim, S. H.; Koh, H. Y. Bull. Korean Chem. Soc.
2000, 21, 159-160.
215
(22) Golden, J. E.; Aube, J. Angew. Chem., Int. Ed. Engl.2002, 41, 4316-4318.
(23) Hinman, M. M.; Heathcock, C. H. J. Org. Chem. 2001, 66, 7751-7756.
(24) Kende, A. S.; Hernando, J. I. M.; Milbank, J. B. J. Org. Lett. 2001, 3, 2505-2508.
(25) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J. Tetrahedron 2002, 58, 61-74.
(26) Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721-2724.
(27) Gurjar, M. K.; Reddy, D. S. Tetrahedron Lett. 2002, 43, 295-298.
(28) Rosenthal, A.; Sprinzl, M. Can. J. Chem. 1969, 47, 4477.
(29) Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc. 2002, 124, 14848-14849.
(30) Booker-Milburn, K. I.; Hirst, P.; Charmant, J. P. H.; Taylor, L. H. J. Angew. Chem.,
Int. Ed. Engl.2003, 42, 1642-1644.
(31) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645-1680.
(32) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem. 1979, 32, 2257-64.
(33) Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.; Pryce, R. J.; Arnold,
E.; Clardy, J. Phytochem. 1981, 20, 811.
(34) Molyneux, R. J.; James, L. F. Science 1982, 216, 190.
(35) Chandra, K. L.; Chandrasekhar, M.; Singh, V. K. J. Org. Chem. 2002, 67, 4630-
4633.
(36) Kim, Y. G.; Cha, J. K. Tetrahedron Lett. 1989, 30, 5721-4.
(37) Diaz-Perez, P.; Garcia-Moreno, M. I.; Mellet, C. O.; Garcia Fernandez, J. M. Synlett
2003, 341-344.
(38) El Nemr, A. Tetrahedron 2000, 56, 8579-8629.
(39) Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693-5706.
(40) Zhao, H.; Hans, S.; Cheng, X.; Mootoo, D. R. J. Org. Chem. 2001, 66, 1761-1767.
(41) Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1994, 59, 1358-64.
(42) Hashimoto, H.; Asano, K.; Fuji, F.; Yoshimura, J. 1982, 102, 87-100.
(43) Mukai, C.; Moharram, S. M.; Kataoka, O.; Hanaoka, M. J. Chem. Soc., Perkin
Trans. I 1995, 2849.
(44) Carmona, A. T.; Fuentes, J.; Robina, I.; Rodriguez Garcia, E.; Demange, R.; Vogel,
P.; Winters, A. L. J. Org. Chem. 2003, 68, 3874-3883.
(45) Pearson, W. H.; Guo, L. Tetrahedron Lett. 2001, 42, 8267-8271.
216
(46) Pearson, W. H.; Hembre, E. J. Tetrahedron Lett. 2001, 42, 8273-8276.
(47) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 7217-7221.
(48) Hembre, E. J.; Pearson, W. H. Tetrahedron 1997, 11021-11032.
(49) Pearson, W. H.; Ren, Y.; Powers, J. D. Heterocycles 2002, 58, 421-430.
(50) Klitzke, C. F.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 5605-5608.
(51) Paolucci, C.; Mattioli, L. J. Org. Chem. 2001, 66, 4787-4794.
(52) Paolucci, C.; Musiani, L.; Venturelli, F.; Fava, A. Synthesis 1997, 1415.
(53) Buschmann, N.; Rueckert, A.; Blechert, S. J. Org. Chem. 2002, 67, 4325-4329.
(54) Punniyamurthy, T.; Irie, R.; Katsuki, T. Chirality 2000, 12, 464-468.
(55) De Vicente, J.; Arrayas, R. G.; Canada, J.; Carretero, J. C. Synlett 2000, 53-56.
(56) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774-7780.
(57) Ayad, T.; Genisson, Y.; Baltas, M.; Gorrichon, L. Chem. Commun. 2003, 582-583.
(58) Ayad, T.; Genisson, Y.; Baltas, M.; Gorrichon, L. Synlett 2001, 866.
(59) Somfai, P.; Marchand, P.; Torsell, S.; Lindstrom, U. M. Tetrahedron 2003, 59,
1293-1299.
(60) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett. 2001, 42, 4633-4635.
(61) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett. 2000, 41, 4113-4116.
(62) Davies, S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla, H.
Synlett 2002, 1146-1148.
(63) Wright, D. L.; Schulte, J. P., II; Page, M. A. Org. Lett. 2000, 2, 1847-1850.
(64) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org. Chem. 2002, 67, 1982-
1992.
(65) Ginesta, X.; Pericas, M. A.; Riera, A. Tetrahedron Lett. 2002, 43, 779-782.
(66) Subramanian, T.; Lin, C. C. Tetrahedron Lett. 2001, 42, 4079-4082.
(67) Martin, R.; Moyano, A.; Pericas, M. A.; Riera, A. Org. Lett. 2000, 2, 93-95.
(68) Baker, S. R.; Cases, M.; Keenan, M.; Lewis, R. A.; Tan, P. Tetrahedron Lett. 2003,
44, 2995-2999.
(69) Felpin, F.-X.; Lebreton, J. Tetrahedron Lett. 2002, 44, 527-530.
(70) Wallace, D. J.; Cowden, C. J.; Kennedy, D. J.; Ashwood, M. S.; Cottrell, I. F.;
Dolling, U.-H. Tetrahedron Lett. 2000, 41, 2027-2029.
(71) Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett 1996, 67-8.
217
(72) Phillips, A. J.; Abell, A.D. Aldrichim. Acta 1999, 32, 75-89.
(73) Furstner, A. Chem. Commun. 1998, 1315-1316.
(74) Furstner, A.; Liebl, M.; Lehmann, C. W.; Picquet, M.; Kunz, R.; Bruneau, C.;
Touchard, D.; Dixneuf, P. H. Chem. Eur. J. 2000, 6, 1847-1857.
(75) Furstner, A.; Liebl, M.; Hill, A. F.; Wilton-Ely, J. D. E. T. Chem. Commun. 1999,
601-602.
(76) Ahmed, M.; Barrett, A. G. M.; Braddock, D. C.; Cramp, S. M.; Procopiou, P. A.
Tetrahedron Lett. 1999, 40, 8657-8662.
(77) Ahmed, M.; Arnauld, T.; Barrett, A. G. M.; Braddock, D. C.; Procopiou, P. A.
Synlett 2000, 1007-1009.
(78) Ackermann, L.; Furstner, A.; Weskamp, T.; Kohl, F. J.; Herrmann, W. A.
Tetrahedron Lett. 1999, 40, 4787-4790.
(79) Furstner, A.; Ackermann, L. Chem. Commun. 1999, 95-96.
(80) Cho, J. H.; Kim, B. M. Org. Lett. 2003, 5, 531-533.
(81) Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 9904-9909.
(82) Martin, R.; Alcon, M.; Pericas, M. A.; Riera, A. J. Org. Chem. 2002, 67, 6896-
6901.
(83) Evans, P. A.; Robinson, J. E. Org. Lett. 1999, 1, 1929-1931.
(84) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621-4.
(85) Hunt, J. C. A.; Laurent, P.; Moody, C. J. Chem. Commun. 2000, 1771-1772.
(86) Ostergaard, N.; Pedersen, B. T.; Skjaerbaek, N.; Vedso, P.; Begtrup, M. Synlett
2002, 1889-1891.
(87) Yang, C.; Murray, W. V.; Wilson, L. J. Tetrahedron Lett. 2003, 44, 1783-1786.
(88) Huwe, C. M.; Velder, J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 2376-
2378.
(89) Bujard, M.; Briot, A.; Gouverneur, V.; Mioskowski, C. Tetrahedron Lett. 1999, 40,
8785-8788.
(90) Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney,
A. K.; Martin, S. F. J. Am. Chem. Soc. 2002, 124, 8584-8592.
(91) Martin, S. F.; Liao, Y.; Chen, H.-J.; Paetzel, M.; Ramser, M. N. Tetrahedron Lett.
1994, 35, 6005-8.
218
(92) Lim, S. H.; Ma, S.; Beak, P. J. Org. Chem. 2001, 66, 9056-9062.
(93) Donohoe, T. J.; Headley, C. E.; Cousins, R. P. C.; Cowley, A. Org. Lett. 2003, 5,
999-1002.
(94) Falb, E.; Bechor, Y.; Nudelman, A.; Hassner, A.; Albeck, A.; Gottlieb, H. E. J. Org.
Chem. 1999, 64, 498-506.
(95) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418-5424.
(96) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994, 116, 3231-9.
(97) Wiberg, K. B.; Bailey, W. F. J. Am. Chem. Soc. 2001, 123, 8231-8238.
(98) Wiberg, K. B.; Bailey, W. F. Tetrahedron Lett. 2000, 41, 9365-9368.
(99) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O'Brien, P. J. Am. Chem. Soc. 2002,
124, 11870-11871.
(100) Dieter, R. K.; Topping, C. M.; Nice, L. E. J. Org. Chem. 2001, 66, 2302-2311.
(101) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. J. Am. Chem. Soc.
1989, 111, 5335-40.
(102) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. J. Am. Chem. Soc.
1989, 111, 5330-4.
(103) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C. K.; Duggan, M. E.; Veale, C. A. J.
Am. Chem. Soc. 1989, 111, 5321-30.
(104) Jayaraman, S.; Hu, S.; Oehlschlager, A. C. Tetrahedron Lett. 1995, 36, 4765-8.
(105) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org. Chem. 1996, 61, 7513-7520.
(106) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org. Chem. 1999, 64, 3719-3721.
(107) Hertweck, C.; Boland, W.; Goerls, H. Chem. Commun. 1998, 1955-1956.
(108) Chini, M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990, 31, 4661.
(109) Cossy, J.; Bellosta, V.; Hamoir, C.; Desmurs, J.-R. Tetrahedron Lett. 2002, 43,
7083-7086.
(110) Kotsuki, H.; Teraguchi, M.; Shimomoto, N.; Ochi, M. Tetrahedron Lett. 1996, 37,
3727-3730.
(111) Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 287-289.
(112) Beaton, M.; Gani, D. Tetrahedron Lett. 1998, 39, 8549-8552.
(113) Chini, M.; Crotti, P.; Favero, L.; Macchia, F.; Pineschi, M. Tetrahedron Lett. 1994,
35, 433-6.
219
(114) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi, M. Tetrahedron Lett.
1996, 37, 1675-8.
(115) Meguro, M.; Asao, N.; Yamamoto, Y. J. Chem. Soc., Perkin Trans. 1 1994, 2597-
601.
(116) Hou, X.-L.; Wu, J.; Dai, L.-X.; Xia, L.-J.; Tang, M.-H. Tetrahedron: Asymmetry
1998, 9, 1747-1752.
(117) Sagawa, S.; Abe, H.; Hase, Y.; Inaba, T. J. Org. Chem. 1999, 64, 4962-4965.
(118) Canas, M.; Poch, M.; Verdaguer, X.; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron Lett. 1991, 32, 6931-4.
(119) Smith, J. G. Synthesis 1984, 629-56.
(120) Posner, G. H.; Rogers, D. Z. J. Am. Chem. Soc. 1977, 99, 8214-18.
(121) Posner, G. H.; Rogers, D. Z. J. Am. Chem. Soc. 1977, 99, 8208-14.
(122) Das, U.; Crousse, B.; Kesavan, V.; Bonnet-Delpon, D.; Begue, J.-P. J. Org. Chem.
2000, 65, 6749-6751.
(123) Rampalli, S.; Chaudhari, S. S.; Akamanchi, K. G. Synthesis 2000, 78-80.
(124) Fagnou, K.; Lautens, M. Org. Lett. 2000, 2, 2319-2321.
(125) Mojtahedi, M. M.; Saidi, M. R.; Bolourtchian, M. J. Chem. Res. 1999, 128-129.
(126) Huemmer, W.; Gracza, T.; Jaeger, V. Tetrahedron Lett. 1989, 30, 1517-20.
(127) Lindstroem, U. M.; Franckowiak, R.; Pinault, N.; Somfai, P. Tetrahedron Lett.
1997, 38, 2027-2030.
(128) Lindstroem, U. M.; Somfai, P. Synthesis 1998, 109-117.
(129) Lindstrom, U. M.; Somfai, P. Tetrahedron Lett. 1998, 39, 7173-7176.
(130) Lindstrom, U. M.; Olofsson, B.; Somfai, P. Tetrahedron Lett. 1999, 40, 9273-9276.
(131) Olofsson, B.; Khamrai, U.; Somfai, P. Org. Lett. 2000, 2, 4087-4089.
(132) Olofsson, B.; Somfai, P. J. Org. Chem. 2002, 67, 8574-8583.
(133) Olofsson, B.; Somfai, P. J. Org. Chem. 2003, 68, 2514-2517.
(134) Zhou, Z.; Shi, L.; Huang, Y. Tetrahedron Lett. 1990, 31, 7657-60.
(135) Hertweck, C.; Boland, W. J. Org. Chem. 2000, 65, 2458-2463.
(136) Brown, H. C.; Racherla, U. S.; Liao, Y.; Khanna, V. V. J. Org. Chem. 1992, 57,
6608-14.
220
(137) Diez-Martin, D.; Kotecha, N. R.; Ley, S. V.; Mantegani, S.; Menendez, J. C.;
Organ, H. M.; White, A. D.; Banks, B. J. Tetrahedron 1992, 48, 7899-938.
(138) Garbaccio, R. M.; Danishefsky, S. J. Org. Lett. 2000, 2, 3127-3129.
(139) Antonioletti, R.; Bovicelli, P.; Fazzolari, E.; Righi, G. Tetrahedron Lett. 2000, 41,
9315-9318.
(140) Nystroem, J. E.; McCanna, T. D.; Helquist, P.; Amouroux, R. Synthesis 1988, 56-8.
(141) Millar, J. G.; Oehlschlager, A. C. J. Org. Chem. 1984, 49, 2332-8.
(142) Haddad, M.; Imogaie, H.; Larcheveque, M. J. Org. Chem. 1998,63, 5680-5683.
(143) Wang, Z.; Zhou, W. Tetrahedron 1987, 43, 2935-44.
(144) Rossiter, B. E.; Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 464-5.
(145) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B.
J. Am. Chem. Soc. 1987, 109, 5765-80.
(146) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647-50.
(147) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13-19.
(148) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480-2.
(149) Olofsson, B.; Somfai, P. Tetrahedron Lett. 2003, 44, 1279-1281.
(150) Paquette, L. A.; Hormuth, S.; Lovely, C. J. J. Org. Chem. 1995, 60, 4813-21.
(151) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 1999, 121, 11680-11683.
(152) Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58, 6109-13.
(153) Davies, S. G.; Fenwick, D. R. Chem. Commun. 1997, 565-566.
(154) Mukai, C.; Hanaoka, M. J. Org. Chem. 1998, 63, 6281.
(155) De Vicente, J.; Arrayas, R. G.; Canada, J.; Carretero, J. C. Synlett 2000, 53-56.
(156) Bose, D. S.; Thurston, D. E. Tetrahedron Lett. 1990, 31, 6903-6.
(157) Keck, G. E.; Romer, D. R. J. Org. Chem. 1993, 58, 6083-9.
(158) Erdik, E.; Kahya, D. J. Phys. Org. Chem. 2002, 15, 229-232.
(159) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung, J.; Kawanami, Y.;
Lubben, D.; Manoury, E.; Ogino, Y.; et al. J. Org. Chem. 1991, 56, 4585-8.
(160) Cha, J. K.; Bennett, R. B., III In PCT Int. Appl.; (Vanderbilt University, USA). Wo,
1990, p 31 pp.
(161) Macdonald, T. L. J. Org. Chem. 1980, 45, 193-4.
(162) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem. 1984, 37, 1503-9.
221
(163) Yadav, J. S.; Mishra, R. K. Tetrahedron Lett. 2002, 43, 5419-5422.
(164) St-Denis, Y.; Chan, T. H. J. Org. Chem. 1992, 57, 3078-85.
(165) Berry, M. B.; Blagg, J.; Craig, D.; Willis, M. C. Synlett 1992, 659-60.
(166) Katz, S. J.; Bergmeier, S. C. Tetrahedron Lett. 2002, 43, 557-559.
(167) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis. 2nd Ed,
John Miller and Sons Inc., New York, 1991.
(168) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974-6977.
(169) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. Engl.2003, 42, 343-347.
(170) Swaminathan, K.; Venkatasubramanian, J. J. Chem. Soc., Perkin Trans. II 1975,
1161.
(171) Mikami, K.; Yamaoka, M. Tetrahedron Lett. 1998, 39, 4501-4504.
(172) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem. Soc., Perkin Trans. 1
1988, 1669-75.
(173) Tang, M.; Pyne, S. G. J. Org. Chem. 2003, 68, 7818-24.
(174) Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539-542.
(175) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals, Fourth
Edition, Pergamon Press Ltd., Oxford England, 1997.
(176) Furniss, B. S.; Hannaford, A. J.; Rogers, V.; Smith, P. W. G.; Tatchell, A. R.
Vogel's Textbook of Practical Organic Chemistry, Including Qualitative Organic
Analysis. 4th Ed, Longmann Scientific and Technical, London, 1978.
(177) Danishefsky, S. J.; Pearson, W. H. J. Org. Chem. 1983, 48, 3865-6.
(178) Bundy, G. L.; Lin, C. H.; Sih, J. C. Tetrahedron 1981, 37, 4419-29.
(179) Schwartz, J.; Loots, M. J.; Kosugi, H. J. Am. Chem. Soc. 1980, 102, 1333-40.
(180) Lipshutz, B. H.; Ellsworth, E. L. J. Am. Chem. Soc. 1990, 112, 7440-1.
(181) Hayashi, N.; Fujiwara, K.; Murai, A. Tetrahedron 1997, 53, 12425-12468.
(182) Marshall, J. A.; DeHoff, B. S. J. Org. Chem. 1986, 51, 863-72.
(183) Coe, J. W.; Roush, W. R. J. Org. Chem. 1989, 54, 915-30.
(184) Mhaskar, S. Y.; Lakshminarayana, G. Synth. Commun. 1990, 20, 2001-9.
(185) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856-7.
222
(186) Hasegawa, H.; Suzuki, M.; Arai, N.; Fujita, M.; Watanabe, K. Kenkyu Hokoku -
Asahi Garasu Kogyo Gijutsu Shoreikai 1980, 37, 295-303.
(187) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45, 2139-45.
(188) Schneider, M. J.; Ungemach, F. S.; Broquist, H. P.; Harris, T. M. Tetrahedron 1983,
39, 29-32.
(189) Stephenson, G. R.; Bunce, N. J.; Makowski, R. I.; Curry, J. C. J. Ag. Food Chem.
1978, 26, 137-40.
(190) Trost, B. M.; Patterson, D. E. Chem. Eur. J. 1999, 5, 3279-84.