utilization of ring closing metathesis in alkaloid synthesis i. synthetic studies on the...
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Utilization of Ring Closing Metathesis in Alkaloid Synthesis
I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines A-C
Suvi T. M. Simila
Martin Group, University of Texas at AustinGroup Meeting, Research
September 17, 2007
N
H2O3PO
OH
(-)-FR901483 (1)
MeHN
OMe
N
MeO
CO2Me
N
O
14
15
lundurine A = amide (2)
lundurine B = 14,15 (3)
lundurine C = amine (4)
Utilization of Ring Closing Metathesis in Alkaloid Synthesis
I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines A-C
Suvi T. M. Simila
Martin Group, University of Texas at AustinGroup Meeting, Research
September 17, 2007
N
H2O3PO
OH
(-)-FR901483 (1)
MeHN
OMe
N
MeO
CO2Me
N
O
14
15
lundurine A = amide (2)
lundurine B = 14,15 (3)
lundurine C = amine (4)
Retrosynthetic Analysis
N N
CO2R3
O
BrMg
+
3
9
7
CO2R3
N
H2O3PO
OH
MeHN
OMe
N
R1OO
R2O
R2O
MeO2CR2O
TMS CO2Me
3 3
7
3
lactone-lactamrearrangement
RCM
stereoselective
addition to an N-acyl iminium ion
9
N
R3O2C
CO2MeR2O
NO
O
R3O2C
R2O
9
7
3
lactonization
Addition of the Allylzinc to the Chiral Imine
N
TBDPSOPd(PPh3)4 benzotriazole
CH2Cl2TrocCl, THF
-78 °C - 25 °C
37% (dr = 45:55)
NHO
TBDPSO
OO
N
TBDPSO
Troc
TBSO
IZnOTBS
HON
HOO
TBDPSO3
11
N
RO
TBDPSO3
11 PhOMe
Simila, S. T. M.; Martin, S. F. J. Org. Chem. 2007, 72, 5342.
Grubbs II
CH2Cl2, 20 h
90% (dr = 45:55)
N
TBDPSO
Troc
OTBS
H N
TBDPSO
Troc
H
OTBS
+
H HnOE
nOEH H
33
1112
Model studies: Simila, S. T. M.; Reichelt, A.; Martin, S. F. Tetrahedron Lett. 2006, 47, 2933.
Weinreb’s ResultsOvershadowing Our Endgame
Weinreb. et al. J. Org. Chem. 2006, 71, 2046.
HON
TIPSOO
N
TIPSOO
Ph Ph
LDA
Davisoxaziridine
60% useless intermediate;cannot remove N-Bn efficiently
HON
Boc
O
N
Boc
ONaHMDS
Davisoxaziridine
98%
OTIPS OTIPS
BnON
Boc
OMe
OTIPS1) LAH2) Sc(OTf)3
MeOH
3) BnBr, NaH
73%
BnON
Boc
OTIPS
PhOMeArMgCl
TiCl4
87% (dr 5:4)
N
TIPSO
Boc
O
N
TIPSO
Boc
ONaHMDS
Davisoxaziridine
53%
OH
N
TIPSO
Boc
OOBn
N
TIPSO
Boc
OBn
PhOMeArMgCl
then NaCNBH3
62% (dr ~3:1)
BnBr
NaH
69%
incorrect stereoisomer
SummaryPart I
• A new route to azaspirane core structure of FR901483 was developed via a nucleophilic addition to an acyl iminium ion followed by a ring-closing metathesis
• Lactone-lactam rearrangement gave the azatricyclic core structure of FR901483 • 1-Ethylallylcarbamate protecting group and its cleavage was developed
• Allylzinc reagent was developed and it was successfully added to the chiral imine, however with lack of diastereoselectivity that persuaded us to divert our initial studies toward (-)-FR901483
N
NMeO
CO2Me
O
lundurine A
14
1516
N
NMeO
CO2Me
N
NMeO
CO2Me
lundurine B lundurine C
II. Toward the Total Synthesis of Lundurines A-CIsolation and Biological Activity
- Isolated in 1995 from the leaf extract of the Borneo species Kopsia tenuis - Biological studies were reported in 2004 - Lundurine B is cytotoxic against B16 melanoma cells (in vitro); 2.8 µg/mL
- Unique hexacyclic core containing dihydroindole-cyclopropane moiety
- No reported total syntheses to date
Kam, T. S.; Yoganathan, K.; Chuah, C. H. Tetrahedron Lett. 1995, 36, 759.Kam, T. S.; Lim, K.; Yoganathan, K.; Hayashi, M.; Komiyama, K. Tetrahedron 2004, 60, 10739.
N
NMeO
CO2MeO OtBu
O
N
NMeO
CO2MeO
O
N2N
NMeO
CO2Me
O
RCM
N
N
MeO
MeO2C
O
O
OtBu
lundurine A (1)lundurine B = 14,15 (2)
lundurine C (3)
amide reduction
olefin reduction
2
316
16
14
1516
RCM
cyclopropanation
Retrosynthetic Analysis
N
NH2MeO O
HO
O
Ugi 4CC
NC
N
N
MeO
MeO2C
O
O
OtBu
R R
R = masked divinyl moiety
16
+ +
+
CO2Me
Retrosynthetic Analysis
N
H2N
MeO
CO2MeO
OtBu
O
+
reductive amination
thenCl
O
Synthesis of the Ugi Components:2-Vinyltryptamine
N
MeO HNO
A, Pd(PPh3)4
LiCl, Na2CO3 (aq)
PhCH3/EtOH, 80 °C
87%
N
MeO HN
O
NH
MeO HNO
1) Py·HBr3, THF/CHCl32) Boc2O, DMAP
90% (2 steps)
BO
B
OB
O
NH
MeO NH2
requisite Ugi component
KOH, EtOHNa2S2O4,
A
Br
Boc
Boc
·pyr
Trivinylboroxane: O’Shea, et. al. J. Org. Chem. 2002, 67, 4968.
Synthesis of the Ugi Components:Masked Divinylketone
PhSH, PhMe70 °C, 24 h
79%
O+ HNMe2·HCl + (CH2O)n
AcOH, 90 °C
40%
O O
Me2N NMe2
NMe
OTsCl, PhCH3
100 °C
then DIPEA 100 °C
30%
NMe
O
Ts
PhSK, PhCH3
20%
O
PhS SPh
S
MeO2C CO2Me
NaOMe, Et2O
>99% S
O
CO2Me
S
O
H2SO4,
70%
TMS
i) n-BuLi, 0 °Cii) HCO2Me, THF
0 °C
87%
OH
TMSTMS
10% H2CrO4
Acetone
0 °C to 25 °C
80%
O
TMSTMS S
ONaSH·H2ONaHCO3, EtOH
25 °C
79%
MeO2C NRCOR'
R R
MeO2C NRCOR'
·2 HCl
Blicke, F.; McCarty, F. et. al. J. Org. Chem. 1959, 24, 1376.Sapi, J. et. al. Synthesis 1988, 619.Ward, D. E. et. al. J. Org. Chem. 2002, 67, 1618.Detty, M. L. et. al. Organometallics 1992, 11, 2157.Angiolini, L. et al. Polymer 1989, 30, 564.
Successful Ugi Reactions
NH
NH2+CO2H
NH
N
O
HN
ONMe
O
NMe
tBuNC, MeOH
99%
NH
NH2+CO2H
NH
N
O
NHO
MeOH
83%
NMe
O
NMe
NC
NH
N
O
OMe
O
NMe
AcCl, MeOH55 °C
50%
NC
O
a) NaCN, NH4Cl, Et2O; 61%
b) HCOOH, Ac2O; 44%
NC NHCHOc) tBuOK, THF; 60%
b) triphosgene, DABCO; 35%
Convertible isocyanide: Armstrong, R. W.; Keating, T. A. J. Am. Chem. Soc. 1999, 118, 2574.
NMe
O
Hoffmann type elimination trials of the methyl piperidine ring unsuccessful
Ugi with the Thiopyranone
NH2+
HO2CSPh
S
O
N
OPhS
HN
O
S NaIO4, MeOH
H2O
90%
N
OPhS
HN
O
S O
PhCH3
180-200 °C
(W, 300W)
65%
N
O
HN
O
S O
O
resubjected to
reaction condX
N
O
HN
O
SOH
tBuNC, MeOH
55%
S
O
Sulfoxide eliminations: Rapoport, H. et. al. J. Org. Chem. 1980, 45, 4817. Galons, H. et. al. Synth. Commun, 1991, 21, 1743.
Ugi with Bisthiophenylpentanone
N
O
NHO
MeO
SPh
SPh
NH2PhMe, Dean-Stark
120 °C
or TiCl4, Et3NCH2Cl2
MeO
N SPh
SPh
tBuNC, MeOH
5 days
30%
MeOO
SPhPhS
mCPBA, CH2Cl2-78 -(-20 °C)
96%N
O
NHO
SOPh
SOPh
MeO
N
O
NHO
MeO
CO2H
p-xylene, pyr, W140 °C, 300W
97%
O
PhS SPh
Ugi with the 5-Methoxy-2-vinyltryptamine
N
O
NHO
NH
PhS SPh
MeO
O
SPh
SPh
1) PhMe, Dean-Stark
120 °C
2)
tBuNC, MeOH 4 days
NH
NH2MeO
O
O
NHO
SPh
SPh
8%5%
+
+ 55% of A
CO2H
A
Would a protected indole be more soluble?
Protected Tryptamine Piece
NH
OHMeO TBDPS-Cl, imid., DMF
0 - 25 °C
95%NH
OTBDPSMeO NBS, CH2Cl2
71%
NH
OTBDPSMeO
Br
B OBO B O
Pd(PPh3)4, LiClNa2CO3 (aq), EtOH
PhMe, 80 °C
88%
N
OTBDPSMeO
Br
·pyrNaHMDS
MeOCOCl, THF
-78 - 25 °C
79%
N
OTBDPSMeO
CO2Me
TBAF, CH3CO2H
THF, 0 - 25 °C
99%
N
OHMeO
CO2Me
DPPA, DIAD
PPh3, THF 0 - 25 °C
99%
N
N3MeO
CO2Me
PPh3, THF/H2O
55%N
NH2MeO
CO2Me
CO2Me
Ugi with the 5-Methoxy-2-vinyltryptamine
N
O
NHO
NH
PhS SPh
MeO
O
SPh
SPh
1) PhMe, Dean-Stark
120 °C
2)
tBuNC, MeOH 4 days
NH
NH2MeO
O
O
NHO
SPh
SPh
8%5%
+
+ 55% of A
CO2H
A
N
O
NHO
N
PhS SPh
MeO
O
SPh
SPh
1) PhMe, Dean-Stark
120 °C
2)
tBuNC, MeOH 5 days
N
NH2MeO
CO2H
A
CO2Me
MeO2C
X
the intermediate imine is not soluble in MeOH, CH2Cl2
Synthesis of the RCM Precursor
N
O
NHO
NH
SPh
MeOSPh
N
O
NHO
N
SPh
MeOSPh
Boc
N
O
NHO
N
SOPh
MeOSOPh
Boc
N
O
NHO
N
MeO
Boc
Boc2O, DMAPEt3N, CH2Cl2
60%
NaIO4, MeOHH2O
0-25 °C 48%
p-xylene, pyr
W, 140 °C300 W
44%
(0.9 mg)
N
N
Boc
MeO
O
NHtBuO
Grubbs II
CH2Cl2
rsm (0.4 mg) + new product by TLC
N
NH2MeO O
HO
O
Ugi 4CC
NC
R R
R = masked divinyl functionality
+ +
+
CO2Me
Execution of the Back-up Plan
N
H2N
MeO
CO2MeO
OtBu
O
+
reductive amination
thenCl
O
N
N
MeO
MeO2C
O
O
OtBu
16
Preparation of the Divinylglycine Piece
N
Ph Ph
CO2Me
SOPh
Et3BnN+Cl-, K2CO3
60 °C, 4 h
N
Ph Ph
CO2Me
SOPh
SOPhN
Ph Ph
CO2Me
SOPh
NH
Ph Ph
H2N CO2Me
CH2Cl2, rt24 h
78%0%
82%
subjected to rxn cond
+
N
Ph Ph
CO2tBu
Br CO2tBuDIEA, MeCNreflux, 12 h
83%
2 x
X
SOPh
Et3BnN+Cl-, K2CO3
60 °C, 4 h
2 x
N
Ph Ph
CO2tBu
SOPh
SOPhN
Ph Ph
CO2tBu
SOPh
0% 30%
+
Bis-conjugate addition: Galons, H. et. al. Synth. Commun, 1991, 21, 1743.
Preparation of the Divinylglycine Piece
N
Ph Ph
CO2Me
SOPh
Et3BnN+Cl- K2CO3, 60 °C
N
Ph Ph
CO2Me
SOPh
SOPhN
Ph Ph
CO2Me
SOPh
0%0%0%
82%45%57%
+
N
Ph Ph
CO2Me
SOPh
SOPh
Conditions1) LDA, THF, -78 °C 0%2) K2CO3, Et3BnN+Cl- H2O (cat) , 60 °C 19% 3) KOtBu, Et3BnN+Cl-
H2O (1 eq), 60 °C 23%
SOPh
2 x
Conditions18 h W, 4 hW, 4 h (H2O)
Bis-conjugate addition: Galons, H. et. al. Synth. Commun, 1991, 21, 1743.
N
Ph Ph
CO2tBu
SOPh
SOPh
N
Ph Ph
CO2tBu
KOtBuEt3BnN+Cl-
60 °C, 1 h
61%
SOPh
2 x
Successful Formation of the RCM Precursors
N
OMeO
N
OHMeO
IBX, EtOAc80 °C
>99%
N
NH
MeOCO2tBu
CO2Me CO2MeCO2Me
N
Ph Ph
CO2tBu
SOPh
SOPh
N
Ph Ph
CO2tBu
KOtBuEt3BnN+Cl-
60 °C
61%
SOPh
2 x
p-xylene, pyr140 °C
66%
H2N
CO2tBuN
Ph Ph
CO2tBu
citric acid (aq)THF
71%
citric acid (aq)THF
89%
H2N
CO2tBu
SOPh
SOPh
H2N
CO2tBu
Na(OAC)3BHCH2Cl2
81%
H2N
CO2tBu
i) Na(OAC)3BHCH2Cl2, 89%
ii) p-xylene, pyr W, 140 °C
69%
SOPh
SOPh
Et3N, CH2Cl2 94%
N
NMeO
CO2Me
O
CO2tBu
COCl
N
NMeO
CO2MeCO2tBu
Br
K2CO3, TBAI, CH3CN W, 80 °C
72%
Tandem-RCM Attempts
catalyst
C6H6, N
N
MeO
MeO2C
O
CO2tBuN
N
MeO
MeO2CCO2tBu
O
A B
CatalystGrubbs II 26 % A 0% B (39% RSM)Schrock 0% A 0% B (99% RSM)Lance 0% A 0% B (99% RSM)
Grubbs II or SchrockC6H6,
N
NMeO
CO2Me
O
CO2tBu
Grubbs II
CH2Cl2, W150 W, 50 °C
orPhMe, 100 °C
N
N
MeO
MeO2CCO2tBu
40% 0%
N
NMeO
CO2MeCO2tBu
N
N
MeO
MeO2CCO2tBu
+
Grubbs IIPhMe, 100 °C
RuPh
PCy3
NMesMesN
ClCl Ru
NN
ClCl
Oi-Pr
Grubbs 2nd Generation catalyst
"Lance"
i-Pr i-Pr
N
Mo
Ph(F3C)2MeCO
(F3C)2MeCO
Schrock catalystGrubbs catalysts: Grubbs, R. H. Angew. Chem. Int. Ed, 2006, 45, 3760.Lance: Grubbs, R. H. et. al. Org. Lett. 2007, 9, 1589.Schrock catalysts: Schrock, R. R. Angew. Chem. Int. Ed. 2006, 45, 3748.
Possible Explanations for Unsuccessful RCM
N
NMeO
[Ru]N
N
MeO
MeO2COO OO
N
N
MeO
MeO2C
O
CO2tBu[Ru]
O
O
Modes of catalyst inhibition: Grubbs, R. H. Acc. Chem. Res, 1995, 28, 446.
Troubleshooting the Functional Group Problems
NH
NMeO
CO2tBu
NH
N
MeO
CO2tBu
Grubbs II
PhMe, W150W, 80 °C, 6 h
~10%
(sm consumed)
Grubbs IIPhMe, W150 W, 80 °C, 3h
N
NMeO
CO2tBuCO2Me
KOH, MeOH
reflux, 18 h
>99%
new spot, sm consumed>>not the desired pdt by MS
Troubleshooting the Functional Group Problems
N
NH
MeOCO2tBu
CO2Me
N
NMeO
CO2tBu
CO2Me
Grubbs IIPhMe
W, 80 °C, 3 hthen 70 °C, 2 d
XN
NMeO
CO2Me
CO2tBu
PhOMe
MeO
Cl
TBAI, K2CO3
CH3CN, W150 W, 80 °C, 3 h
26%
PhOMe
KOH(aq), MeOHreflux, 18 h
84%
NH
NMeO
CO2tBu
PhOMe
Grubbs IIPhMe
W, 80 °C, 3 hthen 70 °C, 24 h N
H
MeON PhOMe
CO2tBu
X
Examples of 8-membered RCM: Martin, S. F. et. al. Tetrahedron Lett. 1994, 35, 691.Lubell, W. D. et. al. J. Org. Chem. 2005, 70, 3838.Rodriguez, J. Angew. Chem. Int. Ed. 2006, 45, 5740.Bennasar, M.-L. Tetrahedron, 2007, 63, 861.
Ts-indole and Cyanide in Place of the t-Butyl Ester
N
OMeO
N
NH
MeOCN
Ts Ts
H2N
CN
Na(OAC)3BHCH2Cl2
45%
H2N
CN
i) Na(OAC)3BHCH2Cl2, 58%
ii) p-xylene, pyr, 140 °C
SOPh
SOPh
N
NMeO
TsCN
Br
K2CO3, TBAI CH3CN, 80 °C
DECOMPOSITION
N
NMeO
TsCN
Br
NaH, TBAI DMF
~50%
//
N
N
MeO
TsCN
Grubbs II2 x 25 mol%C6D6
LRMS shows correct mass;however not enough material to verify the structure by NMR
Scale-up attempts unsuccessful
Methyl Ester in Place of the t-Butyl Ester
N
OMeO
N
NH
MeOCO2Me
Ts Ts
H2N
CO2Me
i) Na(OAC)3BHCH2Cl2, 58%
ii) p-xylene, pyr W, 140 °C, 50%
SOPh
SOPh
N
NMeO
TsCO2Me
Br
K2CO3, TBAI CH3CN, W 80 °C
79%
N
NMeO
TsCO2Me
Grubbs II2 x 25 mol%
PhMe, rt, 48 h
49%
+ a product that looks like8-membered ring closure; however, mass doesn't match
NH
NMeO
CO2MeNH
NMeO
CO2Me
a) Na, naphthalene (decomp)b) K2CO3, MeOH (saponification)c) Mg, MeOH: (the amine not soluble)
Mg, MeOH
30%
NH
NMeO
CO2Me
Grubbs II
PhMeX
TLC looks terrible...
Methyl Ester in Place of the t-Butyl Ester
N
NMeO
TsCO2Me
Grubbs I2 x 25 mol%
CH2Cl2, uW150W, 50 oC
2 x 3 h
N
NMeO
CO2Me
TsLCMS matches!!!
Reduction of the Ester
N
NMeO
TsCO2tBu
LiAlH4, THF
-20 C to rt
93%
N
NMeO
TsOH
Ac2O, DMAP
Et3N, CH2Cl2
63%
N
NMeO
TsOAc
N
NMeOGrubbs II
PhMe
TsAcO
N
NMeO
TsAcO
N
NMeO
TsAcO
25 mol% cat, 7 h, rt only A50 mol% cat, 24 h, rt about 1:1 ratio of A and B
A B C
75 mol% cat, 48 h, rt only B; no A nor C
Substrate for 8-Membered Ring Closure
N
NH
MeOCO2Me
Ts
Mg, MeOH
Grubbs II
NH
NH
MeOCO2Me
MOMCl, LHMDS
THF
N
NMeO
CO2Me
MOM
MOM N
N
MeO
MOM
MOM CO2Me
End Game
NH
N
MeO
CO2Me
Pd/C, H2
MeOCOCl N
N
MeO
MeO2CCO2Me
i) H+
ii) iPrCOCl
iii) CH2N2
N
N
MeO
MeO2CO N2
i) CuOTfii) TsNHNH2
NaCNBH2N
N
MeO
MeO2Clundurine C
NH
N
MeO
CO2Me
Rh, H2
MeOCOCl N
N
MeO
MeO2CCO2Me
i) H+
ii) iPrCOCl
iii) CH2N2
N
N
MeO
MeO2CO N2
i) CuOTfii) TsNHNH2
NaCNBH2N
N
MeO
MeO2Clundurine A
O O
OO
MeOBF4
N
N
MeO
MeO2Clundurine B
SummaryPart II
• Ugi reactions with cyclic ketones appeared to give better results than acyclic
• Successful route to the RCM precursor via Ugi was developed; however, the low yielding Ugi step steered us to develop another route
• Bisalkylation of an imine, reductive amination and acylation/alkylation provided an efficient route to the RCM precursors
• Preliminary experiments to cyclize 5- and 8-membered rings have been accomplished and further studies are in progress
Acknowledgements
University of Texas at AustinProf. Stephen F. Martin
Martin GroupLab 1
$$$$$$Robert A. Welch Foundation
NIH (GM 25439)RochePfizerMerck
Materia Inc. for catalyst supportProf. Robert H. Grubbs for catalyst support
Woerpel: Inside Addition
Me
inside attack
O
Nu
Nu
O
BnO
MeO
NuMe
OBn
inside attack
Nu
O
Me
BnOOBn
OBnO
Nu
inside attack
Nu
O
OBn
BnOOBn
1,3-cis product
1,3-cis product
1,3-trans product
Woerpel K. A. et al. J. Am. Chem. Soc. 1999, 121, 12208.
Addition to the Acyl Iminium IonWoerpel’s Model
N
OR2 R3
outside attack
Nu
N
OR2 R3
NuH
H
eclipsed product
N
R3
R2ONu
Stereoselective additions to oxonium ions: Woerpel, K. A. et al. J. Am. Chem. Soc. 1999, 121, 12208.Stereoselective additions to iminium ions: Martin, S. F.; Bur, S. K. Org. Lett. 2000, 2, 3445; Tetrahedron Lett. 1997, 38, 7641.
inside attack
Nu
N
OR2
R3
Nu
H
H
staggered product
N
R3
R2ONu
Hydroboration of the Azaspirane
borane fromthe top
borane from the bottom
N
OO
MeO2C
HO N
OO
MeO2C
OH
A B
NN
MeO2C OO
O
O
CO2Me
Predicted selectivity:
N
Cbz
CO2R
OHN
Cbz
CO2R
BHR2
[O]
Development of a New Protecting GroupSubstituted Alloc
NO
HN
O
TMEDA, THF-78 °C, 1 h
MgBr
NH
O
OCOCl
R
O O
R
O
O
R
Et3N, DMAPCH3CN, 24 h
R = Me 42%R = Pr 48%R = i-Bu 41%
R = Me 73%R = Pr 87%R = i-Bu 74%
Development of the Deprotection Conditions
HN
O
O
O N
Pd(PPh3)4 (20-mol%)nucleophile (5 equiv)
solvent, [0.08 M], 25 °C
Entry Nucleophile Solvent Time (25 °C) Yield
1 Morpholine CH2Cl2/EtOAc 4 h >99%
2 Morpholine CH2Cl2 3 h >99%
3 Pyrrolidine CH2Cl2 1 h >99%
4 Phthalimide CH2Cl2 >18 h N/A
5 Phthalimide K-salt CH2Cl2 >18 h N/A
6 HoBt/DIEA CH2Cl2 >18 h N/A
7 Benzotriazole CH2Cl2 45 min >99%
8* Benzotriazole (1 equiv) CH2Cl2/[0.45 M] 45 min >99%
*) 10-mol% Pd(PPh3)4
Allylsilane Addition
Allylsilane acid synthesis: Weiler, L. Can. J. Chem. 1983, 61, 2530.
CO2MeTMS
TMS MgClO
O CO2HTMSNiCl2, THF
0 °C - 25 °C, 6 h
80%
CH3I, K2CO3, DMF
0 °C - 25 °C,1 h
85%
+
N
R
CO2MeR-Cl, AgOTfCH2Cl2
-78 °C - 25 °C, 18 h
R = Cbz 42%R = Troc 56%
N
Troc = O
O
Cl
ClCl
Staudinger/Aza-Wittig/Ugi
N
O
NHO
N
N
NH
PhS
MeO
CO2H
SPh
MeO
NC
O
SPh
SPh
MeOH
CO2Me
NN :PPh3, MeOH
N
NMeO
CO2Me
PPh3
N
NMeO
CO2Me
NN PPh3
N
NMeO
CO2Me
N
Ph3P N
Staudinger
Aza-Wittig
N
NMeO
CO2Me
SPh
SPh
Ugi
Towards the Divinyl Functionality
O
OOH
OH
OH
HO
TBS-Cl, imidazole
DMF, 0 oC, 30 min
94%
O
OTBSTBSO
NH
N
O
NHO
OH
O
mono-oxidized pdt
NH
NH2+HO
O
NH
N
O
NHO
MeOH, 25 °C, 20 h
83%
TBSO OTBS
O
OTBS
OTBS
NC
NH
N
O
NHO
OH
OH
TBAF, THF
0 °C, 30 min
94%NH
N
O
NHO
O
O[O], cond
Conditions:1) Dess-Martin, CH2Cl2, 18 h, 18% mono-ox, 40% rsm 2) Dess-Martin, 2,6-lutidine, CH2Cl2, 17% mono-ox, 45% rsm3) IBX, EtOAc, 80 C, 3 h: mono-ox only; 6 h: unidentified pdt 4) Pyr-SO3, Et3N, DMSO, 18 h, mono-ox & rsm (NMR)
R1
N
OR2
NHR3
OOR
ORO
ORRO
R1NH2 + R2CO2H+ R3NC
R1
N
OR2
NHR3
OO
O
R1
N
OR2
NHR3
O
[O] PPh3