natural products with halogen-bearing stereogenic centers...
TRANSCRIPT
Natural Products with Halogen-Bearing Stereogenic Centers:Natural Origin and Synthesis
Dr. Jared T. Shaw
Evans Group SeminarFebruary 1, 2002
Occurrence of Halogenated Natural Products:Gribble, G. W., Progress in the Chemistry of Organic Natural Products, 1996, 68, 1-498. 2288 references!Gribble, G. W., Acc. Chem. Res., 1998, 31, 141-152.Constituents of Laurencia:Erickson, K. L., Marine Natural Products, 1983, 31-256.Fluorinated Natural Products:Harper, D. B., O'Hagan, D. O., Natural Product Reports, 1994, 11, 123-133.Haloperoxidases:Butler, A., Walker, J. V., Chem. Rev., 1993, 93, 1937-1944.Butler, A., Coord. Chem. Rev., 1999, 187, 17-35.Franssen, M. C. R., Catalysis Today, 1995, 22, 441-457.Synthesis of Halogenated Natural Products:Murai, A., Studies in Natural Products Chemistry, 1997, 19, 411-461.
Halogenated Natural Products Synthesized in the Evans Group
HN
N
Completed:
In Progress:
Me
Br
MeO
O
HHO
ON
OMe
HHH
HO
H
MeO
MeO
OHH
N
O
H
H
O
O
H
H
Me
HO
Cl
Cl
HO
HO
OHOH
H
NH
HO
O
NH
O
O
HO
HO
OHN
O
HN
O
HN
O
NH
OH
O ONH2
HO
Phorboxazole B
O
OH
O O
NH
HN
O
HN
HN
O
HO
HO
O
O
NH
OH
NHMeO
Me
MeH2N
O
NH
H
OHOH
O H
HO
Cl
Cl
Epibatidine
Teicoplanin
O
OMe
MeO
Me
O
ClH
Me
OH
O O Me
MeO NHOMe
O
H
H
Callipeltoside A
Vancomycin
Cl
shaw 01/02 2/4/02 1:54 PM
FCl
BrI
"Chiral"
Total0
500
1000
1500
2000
2500
Distribution of Halogenated Natural Products
"Chiral" = Contains A Halogen-Bearing Stereocenter
16/103812/2051
630/17828/70
Outline
I. Fluorinated natural productsII. Chlorinated/brominated natural products A. biogenesis B. Methods of stereoselective chlorination and bromination 1. SN2 Displacement: "X-" 2. Electrophilic halogenation: "X+" 3. Polycyclization 4. Acyclic stereocontrol employing haloalkenes 5. The Kharasch reaction C. Syntheses 1. Oppositiol, prepinnaterpene, laurencial, dactylyne 2. Comparative syntheses of laurencin and related structures 3. Comparative syntheses of kumausyne and kumausallene 4. Syntheses aplysiapyranoids and thyrsiferol/venusatriol by electrophilic monocyclization 5. Selected polycyclzations leading to natural products 6. Diels-Alder spproaches to plocamium natural products and virantmycin 7. Callipeltoside sidechain 8. Halomon 9. Outlyers: Hapalindole G & Axinellamines
shaw 03/04 2/4/02 1:56 PM
The Fluorinated Natural Products
Gribble, 1996
•Most fluorinated natural products are derived from fluoroacetyl Co-A
FSCoA
O
SCoA
O
Fn
n=4, 6, 7, 8
FOH
O
FMe
O
F
O
FOH
O
H
HO2C CO2HOHHO2C
F
OH
OH
OH
O
F
OH
NH2
O
HO OH
H2NSO2
F
N
N
N
N
NH2
Nucleocidin
4-fluorothreonine(2R, 3R)-2-fluorocitric acid
The Fluorinated Natural Products:Moffatt's Synthesis of Nucleocidin
O
HO OH
H2NSO2
F
N
N
N
N
NH2
Nucleocidin
OHON
N
N
N
NHBz
O O
MeMe
MsCl;KOt-Bu
58%
ON
N
N
N
NHBz
O O
MeMe
ON
N
N
N
NBz2
O O
MeMe
ON
N
N
N
NBz2
O O
MeMe
F
I
ON
N
N
N
NH2
O O
MeMe
F
HO
BzCl/Pyr
97%
AgF/I277%
1) LiN3/DMF; 93%2) hv; H+/H2O; NaBH4; 26%
(Bu3Sn)2O;H2NSO2Cl
87%
ON
N
N
N
NH2
O O
MeMe
F
H2NSO2
TFA/H2O
77%
Moffatt, J. G., et al, J. Am. Chem.Soc., 1976, 98, 3346-3357.
diastereoselection 65:35
shaw 05/06 2/4/02 1:57 PM
The Biogenic Origin of Halogenated Natural Products
• Chlorine is incorporated by nucleophilic displacement as Cl- or through the reactions of alkenes with
chloroperoxidases (CPO's), ie as "Cl+"
• Bromine is almost exlusively incorproated as "Br+" by bromoperoxidases (BrPO's)
• Iodoperoxidases have been identified, but not studied in as much detail as CPO and BrPO
As a result, most halogen-bearing stereogenic centers occur as halohydrins or polycyclics!
RR'
RR'
+X
Nu
RR'
X
Nu"X+"
Nu = H2O, X-, ROH, C=C
Examples of Halogen Biosynthesis
MeMeMe
Me
Me
OH
Geranyllinalool"Br+"
MeMeMe
Me
Me
O
Br
3-Bromobarekoxideisolated from Laurencia luzonensis
Me Me
ClHO
Br+
O
BrH H
Cl
O
BrH H
Cl
O
BrH H
Cl
O HHHO Cl
Laurencenyne Prerogioloxepane
Rogioloxepane ARogioloxepane BRogioloxepane C
epoxidationCl- attack
Isolated from Laurencia microcladia
Pietra, F., et al, Helv. Chim. Acta, 1992, 75, 310-322Jefford, C. W. Chem. Commun., 2000, 1155-1156shaw 07/08 2/4/02 1:58 PM
Examples of Halogen Biosynthesis
• The vast majority of the natural products herein discussed are isolated from the seaweeds (algae) of the genus Laurencia and Plocamium. • Sea hares of the species Aplysia that feed on the seaweed are also sources of the natural products and can modify them
Laurencia seaweedAplysia sea hare
Me
MeOHMe
Br
Me
Br
O Me
Me
Me
O
Me Me
Br
Cl
MeBr
O
Me Me
Br
Cl
MeBr
O
Me Me
Br
Me
Cl
MeBr
MeHO
Cl+
Faulkner, D. J., et al, Comp. Biochem. Physiol., 1974, 49B, 37-41
Haloperoxidases Catalyze Selective Oxidations
S S+
O-
SMe
S+
Me
O-
pH 6.525 °C
V-BrPO/H2O2
Yield (%) ee (%)
6 0
99 89
PhMe
pH 5.525 °C
H-CPO/H2O2 Ph
Me
O
67 96
Me Me
O
78 96n-Bu n-Bu
MeAcO
MeAcO
OH
52 95
Ph MepH 5.525 °C
H-CPO/H2O2
Ph Me 20 90
Sulfoxidation: Allenmark, A., et al, J. Org. Chem., 1997, 62, 8455-8458Epoxidation: Hager, L. P. & Jacobsen, E. N., et al, J. Am Chem. Soc., 1993, 115, 4415-4416Propargylic Oxidation: Hager, L. P. & Hu, S., J. Am. Chem. Soc., 1999, 121, 872-873Benzylic Oxidation: Zaks, A., et al, J. Am. Chem. Soc., 1995, 117, 10419-10424
OH
V-BrPO=VanadiumBromoperoxidase
H-CPO=Heme-Chloroperoxidase
shaw 09/10 2/4/02 2:00 PM
Haloperoxidases Catalyze Unselective Bromohydrin Formation
Me
OH
Me
OH
Me
OHOH
Br
OH
Br
H-CPO, Br-, H2O2 61% 39%H-LPO, Br-, H2O2 - -V-BrPO, Br-, H2O2 66% 34%
N-Bromoacetamide 75% 25%
H-CPO=Heme-dependent chloroperoxidase from Caldariomyces Fumago (fungus)H-LPO=Heme-dependent lactoperoxidase (haloperoxidase) from bovine milkV-BrPO=Vanadium-dependent bromoperoxidase from Corallina Officinalis (marine algae)
"One of the most interesting, yet unsolved problems in the area of marine biohalogenation, is the biogenesis of the chiral halogenated marine natural products." Butler, A. Chem. Rev., 1993, 93, 1937–1944.
"All haloperoxidases catalyze smooth, yet unselective chlorination, bromination or iodination of relatively electron-rich groups in organic compounds...However, there must be more stereo- and/or regioselective halogenating enzymes in nature, regarding the presence of halometabolites like 44 and 45."Franssen, M. C. R., Catalysis Today, 1994, 22, 441-457
(+/-) (+/-)
O
O
Cl
Br
Me
HBr
H
H
C
Br
Cl
Me Me
Cl
Cl Cl
44 45
Coughlin, P., et al, Biotechnology Letters, 1993, 15, 907-912
Enzyme-Catalyzed Bromohydrin Formation
Me
HO
OH
Lactoperoxidase;NaBr, H2O2, pH 5.5
O
OH
H
Me Br
0.05% Yield(0.41% BORSM)
OH
Me Br
O
Laurediol
E-Prelauretin
O
OH
H
Me Br
E-Prelauretin
Lactoperoxidase;NaBr, H2O2, pH 5.5
0.03% Yield(0.19% BORSM)
Laurallene
Murai, A., et al:Tetrahedron Lett., 1995, 36, 737-740Tetrahedron, 1997, 53, 8371
H
Br
shaw 11/12 2/4/02 2:01 PM
Methods of Halogenation
Nucleophilic Displacement:
R R'
OR
Br-
-or-CBr4/PR3
R R'
Br
RR'
O
LA/Br-
RR'
OH
Br
Cycloaddition/Sigmatropic Rearrangement:
R
R' Br
R
R'Br
R Cl
OH
RCl
O
OMe
Bromoetherification/ Oxymercuration-BrominationPolyene Cyclization
Me
Me
OH
"Br+"O
Me MeBr
Me
Me
OH
O
Me MeTfHg
Hg(OTF)2 LiBr; Br2O
Me MeBr
Me
Me
Me MeBr
Hg(OTFA)2, etcor Br+
R
R
Methods of HalogenationThe Kharasch Reaction:
R1 CCl3
O
R1
O
Cl
Cl
R2
R3
R1
O
Cl Cl
R2
R2
R1
O
Cl Cl
R2
R2
Cl
Mn Mn+1ClM = Cu, Fe, Ru, Mo
HN
HN
CCl3
CCl3
O
O
HN
HN
Cl
Cl
Cl
Cl
Cl
Cl
O
O
CuCl/BiPy
CuCl/BiPy
61%
98%
OO
O
O
MeMe
Me
Me
O
CCl3OO
O
Me
Me
CuCl/BiPy
74%
O
O
O
OCl
Cl
ClMe
Me
Weinreb, S. M., et al, Tetrahedron, 1988, 44, 4671-4678Itoh, K., et al, J. Org. Chem, 1993, 58, 464-470Speckamp, W. N., et al, Synlett, 1993, 739
shaw 13/14 2/4/02 2:02 PM
Me
Synthesis of Laurencia Natural Products:T. Masamune's Prepinnaterpene & Oppositol
O
OH
HMsO
BnOH
Me
OBn
MeMsO
OBn
MeBr
OBn
Bu4NBr100 °C
Br
O
OBn
Bu4NBr, 100 °C55% (35% alkene)
MeOH
Me
OBnBr
Br
H
Me
MeHO
Me
Me
Br
H
Me
MeHO Me
Me
Me
BnO BnOMe
OBn
BnO
Br10%
(+ 20% alkene)
Oppositol
Prepinnaterpene
Masamune, T., et al, Tetrahedron Lett, 1987, 28, 4303-4306
MeBr
OBnO
H
H
PPTs
96%
MeLi
100%
MeOH
Me
OBn
Br
Br
H
Me
CHOMeHO
Br-
63%
3 steps95%
2 steps
92%
Synthesis of Prepinnaterpene & Oppositol:Improved Core Syntheses
Shibasaki, M., et al, Tetrahedron Asymm, 1995, 28, 757-766Kim, D., et al, Tetrahedron Lett, 1997, 38, 415-416
X
OTBS
PdCl2(BINAP)H
TBSO
86%eeX=I, OTf Me
HO
Br
OBn
MasamuneIntermediate
PMBO
O O
CO2EtEtO2C
PMBO
O O
MeEtO2C
PMBO
O O
MeEtO2C
Br
Br
OO OPMB
Me
EtO
KO
Br
BrPMBO
O O
EtO2C
Me
KHMDS
ds = "excellent"
O O
MeO
Me
Me
Oppositol
5 steps
KOt-Bu
shaw 15/16 2/4/02 2:03 PM
Synthesis of Laurencia Natural Products:Iwata's Laurencial
MeMe
Me
O
MeMe
OsO4
83%O
OH
Me
OH
MeMe
O
Me Me
MeO OMe
O
OMe
Me
Me MeMe
O
O
OMe
Me
Me
Br
O O
MeMe
O OBrBr
PPTs
89%
MeMe
O
OH
MeO
H
O
Me
MeMe O
MeMe
O
MeO
1) MsCl2) DBN
73%
MeMgI
81%
O
Me
MeMeOH
Me
diastereoselection 95:5
O
Me
MeMeCl
Me
O
Me
Cl
MeMeMe
OHC
O3, MeOHpTSA
46%
(+/-)-LaurencialA: diastereoselection >95:5B: diastereoselection 70:30
Iwata, C, et al, Tetrahedron, 1998, 54, 1396-1406
SOCl2,ZnCl2
O
Me
MeMeMe
OH
A
B
87%
81%
Synthesis of Dactylyne
Murai, A, et al, Tetrahedron Lett, 1992, 33, 4349-4352
Murai's regioselective epoxy alcohol opening:
R OH
O
R
OOH
Ti(Oi-Pr)4/Et2NH-HX
Et2AlCl/Et2NH-HX
R OH
ROH
HO
HO
X
X
OR
HOOMPM
OBzOTi(Oi-Pr)4/Et2NH-HBr
78%OMPM
OBzBr
OH
HO
OH
OMsBr
OTBS
PivOO
OH
OMsBr
OTBS
PivO
90-100%
Et2AlCl
HO
Cl
O
ClBr
Me
Br
8 steps
E = DactylyneZ = Isodactylyne
see also Sharpless, K. B., et al, J. Org. Chem., 1985, 50, 15571560
shaw 17/18 2/4/02 2:05 PM
Synthesis of Laurencia Natural Products
O
Cl
Laurenyne
O
Br
Laurencin
Me
OAc
H
• Before the 1988 synthesis of Laurenyne by Overman, there was only one synthesisof an oxocane-containing natural product known, ie T. Masumune's synthesis of Laurencin in0.003% yield.
• In the last decade, however, many syntheses of medium-ring ether natural products from theLaurencia series have appeared.
Principle Synthetic Challenges:1) medium ring formation2) diastereoselectivity across ring3) regiochemical control of unsaturation
Overman's Synthesis of Laurencia Natural Products:Laurenyne
O
Cl
MeLaurenyne
TMS Cl
OHHO
TMS
OH
TMS
OH
O
TMS OH
Cl
OH
+SAD
Et3NHCl/Ti(Oi-Pr)4
regioselectivity 25:75
68%
TMS Cl
OTsHO
TsCl/Pyr86%
O
Cl
OTsTBDPSO
OEt
TMS
O
Cl
OTs
TMS
TBDPSO
SnCl437%
single diastereomer
10 steps
20 Steps, 0.6% yield Absolute Configuration
Reassigned
EtO
OTBDPS
PPTs
98%
Overman, L. E., et al, J. Am. Chem. Soc., 1988, 110, 2248-2256shaw 19/20 2/4/02 2:07 PM
Overman's Synthesis of Laurencia Natural Products:Laurencin
O
OAc
Me
H
OSEM
n-BuLi; (-)-Ipc2BOMe;EtCHO
70% yield92% ee OSEM
Me
OH
1) TBSOTf2) 9-BBN3) Pd(PPh3)4
Br
SPhOSEM
Me
OTBSSPh
OSEM
Me
OSPh
87% for3 steps
Br
OMe
OPiv
OPiv
MeO
1) TBAF 2) /DIPEA
O
OAc
Me
PhS
PivOOMe
OSEMOAc
80%
SnCl4
57%5g scale
PivO
O
Br
Laurencin
Me
OAc
H
PhS
13 Steps
O
OH
Me
OAc
H
i-Pr3Si
1) Br2/DPPE2) TBAF
40%
24 steps/2% yield
Overman, L. E., et al, J. Am. Chem. Soc., 1995, 117, 5958-5966
Overman's Synthesis of Laurencia Natural Products:Isolaurepinnacin
Overman, L. E., et al, J. Am. Chem. Soc., 1993, 115, 9305-9306
OH
O
OSO2Ph
OH
Br
1) PhSO2Cl2) Et2AlCl/ Et2NH2Br
94%Br
O
MeLi
91%
Me Me Me
SnBu3
SiMe3 Et2AlCl
88% Me
Br
OH
SiMe3
MeO
Br
Cl
OTIPSMeO
OMe
O
OTIPSMeO
OMe
OH
OTIPS
(R)-BINAl-HAgOTf/DIPEA95%
Me O
Br
OMe
Cl
SiMe3
OTIPSO
OHMe
H HBr Cl
1) BCl32) TBAF
90%!OMe
H HBr Cl
5 steps/49%
(+)-Isolaurepinnacin
12 steps/15% Yield
diastereoselection >95:5
5 stepstotal
shaw 21/22 2/4/02 2:08 PM
Murai's Synthesis of Laurencia Natural Products:Laurencin
Murai, A., et al, Tetrahedron Lett, 1992, 4345-4348
OTBS
O Br
O
O
Me
Me+Li°77%
OTBS
OO
MeMe
OH
O
OO
MeMe
OH
1) TBAF/95%2) SO3-Pyr/86%
1) pTSA2) PivCl85%
OOH
OH
PivO
O92%
O
O
PivO
O
Br
Laurencin
Me
OAc
H
O
OH
Me
OAc
H
TMS
1) CBr4/Oct3P; 87% 2) TBAF-HF/97%
regioselection7:1
thermodynamiccontrol, 12:1
A B
27 steps from A & B2.5% yield
Pb(OAc)4
O
Synthesis of Laurencia Natural Products:Holmes & Clark's Laurencin
MeO
OHO
OH
OO
OTBDPS
O
O
OTBDPS
O
OTBDPS
O
O
O
OTBDPS
O
O
OTBDPSHO
O
OTBDPSO
Si
H
Me
Me
O
OTBDPSO
Si
KOH/H2O2
65% O
OTBDPSHO
HO
diastereoselection3.5:1
OBr
LaurencinMe
OACH
26 steps0.4% yield
Holmes, A. B., et al, J. Am. Chem. Soc., 1993, 115, 10400-10401.
KHMDS(2R,8αS)-CSO
74%
diastereoselection >95:5Me
Me
SN
OO
PtSi
SiO
Me Me
Me Me
= "Pt(DVS)2
shaw 23/24 2/4/02 2:12 PM
Synthesis of Laurencia Natural Products:Holmes & Clark's Laurencin - Retraction!
OBr
LaurencinMe
OACH
O
O
OTBDPS
O
O
OTBDPSHO
O
O
OTBDPSHO
KHMDS(2R,8αS)-CSO
1
"The synthesis of lactone 1 as reported by J. S. Clark, Ph. D. Thesis, Cambridge University,1988, is correct. The synthesis of (+)-laurencin in ref 1 is difficult to account for and must probably be charged to the fallibility of the other junior author and the gullibility of the senior author."
Holmes, A. B., et al, J. Am. Chem. Soc., 1996, 118, 6806.
Synthesis of Laurencia Natural Products:Holmes & Clark's Laurencin - Retooled
OBr
LaurencinMe
OACH
O
O
OTBDPS
O
O
OTBDPSHOBad
Reaction!
Various [O]
HOOH
O
O
OH
(R)-Malic Acid
HHO
O
O
OH
Br-PPh3+
OO Me
MeHO
O
OH
OO Me
Me
• Use of various oxidants in the enolate oxidations failed to provide acceptable yields or selectivities
• Route was abandoned and the correct diastereomer of hydroxy-lactone was prepared from malic acid
• Stereochemical assignments were carefully monitoreden route to laurencin
Holmes, A. B., et al, J. Am. Chem. Soc., 1997, 119, 7483-7498shaw 25/26 2/4/02 2:13 PM
Synthesis of Laurencia Natural Products:Murai's Obtusenyne
O
O
OTBS
Cl
O+
1) n-BuLi2) Lindlar's Cat.
89%O O
OTBS
OH
Cl
OO OTBS
Cl
O OOTBS
Cl
OH
KHMDS/PhNTf2
OTfO OTBS
ClO OTBS
Cl
Me
O OTBS
Cl
MeO OTBS
Cl
Me
HOHO
diastereoselection2:1
O
Cl
Me
Br
(+)-Obtusenyne
Murai, A., et al, J. Org. Chem., 1999, 64, 2616-2617
EtMgBrCuI
DMDO; DIBALH
71%
Synthesis of Laurencia Natural Products:Suzuki's Rogioloxepane A
OMPM
OTBS
O
OTBS
Me
OBn
(+)-DET12
steps
+n-BuLi/BF3•OEt2
78% OTBS
Me
OBn
OMPM
OTBS
OH
OH
Me
OBn
OMPM
O
(Bu3Sn)2O;Zn(OTf)2
75%
OHH
Me OMPM
BnO OH
27 steps/5% yieldAbsolute ConfigurationConfirmed
11steps
OHH
Me
Br Cl
(+)-Rogioloxepane
Suzuki, T., et al, Tetrahedron Lett., 2001, 42, 1543-1546shaw 27/28 2/4/02 2:15 PM
Synthesis of Laurencia Natural Products:Crimmins' Laurencin
ON
Bn
O
BnO
O
ON
Bn
O
BnO
ONaHMDS/Allyl-I
75%Me
OBn
OH
Me
OBn
O
BrCH2CO2HNaH; 88%
HO2CPivCl/Et3NLiXp
76%O
BnO
Me O
N
HH
O
O
Bn
OBnO
Me O
N
H
O
O
BnNaHMDS/Allyl-I
71%
OBnO
Me O
N
HH
O
O
Bn
(Cy3P)2RuCl2CHPh94%
OBr
Laurencin
MeH
OAc
18 Steps/6% yield
Crimmins, M. T., et al, Org. Lett., 1999, 1, 2029-2032
diastereoselection >95:5
diastereoselection >95:5
Synthesis of Laurencia Natural Products:Crimmins' Isolaurallene
OBnO
Me O
N
H
O
O
Bn
BnOI
+NaHMDS
75%
OBnO
Me O
N
H
O
O
Bn
BnO
OBnO
Me H
OBn
CHONaBH4;Swern
83%
OBnO
Me H
OBn
OAc
OTESO
Me H
OH
OAc
O OOHMe
TESO OAc
O
(Cy3P)2RuCl2CHPh
94%
OMe
TESO O
OSO2Ar
HO
Me
TESO OH
CBr
H
LiCuBr2
67%O
Me
Br OH
CBr
H
PPTs/MeOHCBr4/Oct3P
58%
(-)-Isolaurallene
1) (4-dIcr)2BCH2CHCH22) Ac2O; 93%
4 steps
65%
7 steps49%
Crimmins, M. T., et al, J. Am. Chem. Soc., 2001, 123, 1533-1534shaw 29/30 2/4/02 2:23 PM
Boeckman's Laurencin
OBr
LaurencinMe
OACH
Boeckman, R. K. Jr., et al, Unpublished Results
PMBO CO2Et
O
CO2Et
1) CBSReduction
2) PhCOClPMBO CO2Et
O
CO2Et82%
98% ee
KHMDS
O
O
PMBO
MeO2C
MeO2C
PMBO
76%
1) LiAlH42) Dess- Martin
HH
O
OPMB
O
H
O
OPMB
8 steps
9 steps
O
MuraiIntermediate
Me
78%
Synthesis of Laurencia Natural Products:Summary
OBr
Laurencin
MeH
OAc
Principle Synthetic Challenges:
1) Medium Ring Ether Formation2) Alkene Regiochemistry3) Diastereoselectivity
OvermanMuraiHolmesBoeckmanCrimmins
dsacross ring
rsof alkene #steps %yield
>95:592:858:42
->99:1
>95:588:12>95:5
->95:5
24>27 (30)
>282218
22.51.246
commentsgood ds, general route*first, but not bestgood if claisen route panned out...Good 8-membered ring synthesishigh yielding, general, but uses oxazolidinone auxiliary at 3 stages of the synthesis
*"first" post-masamune
year
19951992199720011999
shaw 31/32 2/4/02 2:23 PM
Synthesis of Laurencia Natural Products:Kumausyne & Kumausallene
O
AcO
Me
H HBr
- HOAc
"Br+"
Kumausyne Kumausallene
OMe
H HBr
OCH
Br
H
O
O
MeBr
Cl
(+/-)-trans-maneonene-B
Holmes, A. B., et al, Chem Comm, 1984, 1594-1595.
Synthesis of Laurencia Natural Products: Overman's Kumausyne
O
AcO
Me
H HBr
OH
OH
BnOCH2CHORSO3H
69% O
H
H
OBn
O
mCPBA
72% O
H
H
OBnOO
58%
O
H
H
OBnO
14%
O
O
H
H
CHO
OO
58%
Me
SiMe3
BF3•OEt2
O
H
H
OO
Me
OH
H
73%diastereoselection >95:5
O
TMSO
Me
H HOTBS
O
O
TMSO
Me
H HOTBS
O
TMSO
Me
H HOTBS
Cl
Cl
(EtO)2P(O)CLiCl288%
n-BuLi88%
(+/-)-Kumausyne
Overman, L. E., et al, J. Am. Chem. Soc., 1991, 113, 5378-5384
4 steps
+
shaw 33/34 2/4/02 2:24 PM
Synthesis of Laurencia Natural Products: Boukouvalas Kumausyne
MeOOMe
O
O
OH
OTBDPS
HO OH
O
OO
OTBDPS
PdCl2(0.1 equiv)CuCl2(3 equiv)CO, NaOAc, HOAc
93%
O
OHO
OTBDPS
DIBAL-H100%
OOTBDPS
TMS
P+Ph3Br-
93%91:9 E:Z
HOTMS
O
AcO
Me
H HBr
(+/-)-Kumausyne
5 steps
5 steps
SugimuraIntermediate
Boukouvalas, J., et al, J. Org. Chem., 1998, 63, 916-917
Synthesis of Laurencia Natural Products: Martín's Biomimetic synthesis of Kumausyne
O
HO
Me
H HBr
(+)-Deacetylkumausyne
O
TBDPSO
Me
H HBr
O
TBDPSO
Me
H HBr
OH
TBDPSO
Me
H
R
OTHP
O
TBDPSO
Me
H HBr
OTHP +
diastereoselection 50:50
1) TBCD2) HCl/MeOH 92%
diastereoselection 83:17
OH
TBDPSO
Me
H
OTHP
OTHP
1) TBCD2) HCl/MeOH 79%
7 steps
OH11 steps12 steps
Martín, V. S., et al, J. Org. Chem., 1997, 62, 1570-1571
Br Br
BrBr
O
TBCD
shaw 35/36 2/4/02 2:25 PM
Synthesis of Laurencia Natural Products: Overman's Kumausallene
O
H
H
OBnOO
kumausyneintermediate
1) LHMDS/PhSeCl2) O3, Pyridine
70% O
H
H
OBnOO
NaOMe/MeOH
83%O
O
H
HMeO2C
OH
diastereoselection>90:10
O
O
H
HHO2C
Me
OTBSH
1) DCC/DMAP2) Sb(SPh)3 SHON
Me
S
78%+
O
O
H
H
Me
OTBSH
HO
O
O
H
H
Me
OTBSH
OH
TMS
OMe
HBr
OCH
Br
H
(+/-)-Kumausallene
H
H
Overman, L. E., et al, J. Org. Chem., 1993, 58, 2468-2477
TMS Ti(Oi-Pr)4
1) Swern2) TiCl4; 78%;
O
O
H
H
Me
OTBSH
OSO2Ar
OMe
H
OCH
Br
H
H
HOTBS
LiBr2Cu;73%
ds=84:16
OH H
OCH
Br
H (-)-Kumausallene
Synthesis of Laurencia Natural Products:Evans' Kumausallene
BnOOH
OH
1) TBS-Cl/Im.2) PBu3,
CO2Me
97%BnO
OTBS
OCO2Me
1) Jones [O]2) Et3N, Bu3P, PhSeBr
57-74%BnO COSePh
OCO2Me
Et3B, O2,(TMS)3SiH92%
OCO2MeBnO
O
OBnO
O
H
HO 1) K-Selectride
2) PPTs
84%O
1) DIBAL-H2)3)TBAF
TMS
-BrPh3+P
HO
OBn
O
BrBr
BrBr
(TBCD)86%
OMe
H HBr
OCH
Br
H
OBn
Evans, P. A., et al, Angew. Chem. Int. Ed., 1999, 38, 3175-3177
diastereoselection 29:71
diastereoselection 94:6
shaw 37/38 2/4/02 2:30 PM
Synthesis of Laurencia Natural Products:Lee's Kumausyne & Kumausallene
O
AcO
Me
H HBr
Kumausyne
Kumausallene
OMe
H HBr
OCH
Br
H
O
OHHO
OHHO
8 steps OMeO
OCO2Et
I
H
HOMeO
H
H
OCO2Et
Bu3SnH, AIBN
13 steps
HO CO2Et
EtO2C OH
H
H
6 stepsO
H
H
OCO2Et
EtO2CSePh
PhSe
86%
O
HO
CO2Et
Bu3SnH, AIBN
86%EtO2C
H
diastereoselection >95:5
O
HO
OH
EtO2C
H
9 Steps
Overman Intermediate
13 steps
Lee, E, et al, Tetrahedron Lett, 1997, 38, 7757-7758Lee, E, et al, Tetrahedron Lett, 1998, 39, 317-318
Synthesis of Aplysia Natural Products:Successful Application of Lee's Radical Methodology
Lee, E, et al, J. Am. Chem. Soc. , 1995, 117, 8017-8017
CCl3
O
O
OMeO2C
H
H
Ph
O
O
O
H
H
Ph
MeO2C
Cl
ClAIBNCy3SnH
67% O
O
O
H
H
Ph
MeO2C
Et3BTMS3SiH
98%
Cl
O
O
H
H
Cl
Br
BrCO2Me
AIBNCy3SnH
67%O
OH
H
Cl
TBDPSOBrTBDPSO
CO2Me
diastereoselection >95:5
diastereoselction 93:7
O
OH
Cl
Br
Et
(3Z)-Dactomelyne
Diethyl Tartrate
7 steps;45%
9 steps40%
O
O
OPh
HSiR3
7 steps55%
Cl
MeO2C
shaw 39/40 2/4/02 2:31 PM
Synthesis of Laurencia Natural Products:Sugimura's Kumausyne
O
AcO
Me
H HBr
Kumausyne
Sugimura, H., et al, Tetrahedron Lett, 1995, 38, 5789-5792
CHO
OO
OO
MeMe
MeMe
L-arabinose
3steps
+ SiMe2Ph BF3•OEt2O
O
OO
MeMe
MeMe
HO
O O
OO
OMe
Me
MeMe
SiMe2Ph
12%
73%
+
diastereoselection >95:5
7 steps
30%O
OO
OTBDPS
O
OHO
OTBDPSDIBAL-H
100%
O
OTBDPSTMS
HO
TMSPPh3
+Br-81%
5 steps11%
Synthesis of Laurencia Natural Products:Summary of Kumausyne and Kumausallene
O
AcO
Me
H HBr
Kumausyne Kumausallene
OMe
H HBr
OCH
Br
H
OvermanSugimuraLeeMartínBoukoulavas
19911995199719971998
13/5.416/1.317/2.521/1313/6.2
OvermanLeeEvans
199319981998
17/229/0.414/6
year #steps/%yield year #steps/%yield
shaw 41/42 2/4/02 2:33 PM
Synthesis of Aplysia Natural Products:Jung's Aplysiapyranoid D
MeOH
Me Me
4 stepsN SH
Cl
Me +Me
OH
Me Me
SAE
90%>95%ee
O
NH4Cl/DMSOTi(OiPr)484%
Me
Me
Cl
OH
Me
OHMe
Me
Cl
OH
Me
OTBS
TBSCl
83%
O
Me
OTBS
MeBr
ClMe
O
Me
OTBSCl
Me
MeBr
+
regioselection 33:66 TBAF43% (two steps)
TBCD
O
Me
OH
MeBr
ClMe
1) Swern2) Cr2Cl2/CHCl3
77%
O
Me
MeBr
ClMe
Cl
Aplysiapyranoid D
Jung, M. E., et al, J. Org. Chem., 1992, 56, 1347-1348
Synthesis of Aplysia Natural Products:Jung's Aplysiapyranoids A & C
MeOH
Me Me
O
Me
Me
Me
OH1) Swern2) CrCl2/CHCl3
22%
O
Me
MeBr
Me
Aplysiapyranoid A
Jung, M. E., et al, Tetrahedron Lett., 1993, 34, 923-926Jung, M. E., et al, J. Org. Chem., 1998, 63, 2982-2987
Br
OH
NH4Br/DMSOTi(OiPr)4
94%Me
Me
Me
OH
Br
ClTBCD40%
Cl
Me Me
MeOH
OHCl
Me
Me
Me
OH
Cl
Cl
O
Me
MeBr
ClMe
Aplysiapyranoid CCl
4 steps
MeBr
Me
5 steps
TBCD
41%
Br
shaw 43/44 2/4/02 2:34 PM
Synthesis of Laurencia Natural Products:Thyrsiferol & Venusatriol
O
O
OMe
Me
Br
Me
MeMe OH
OH
O
Me
MeOH
Me H
O
O
OMe
Me
Br
Me
MeMe OH
OH
O
Me
MeOH
Me H
(+)-Thysiferol (+)-Venusatriol
MeMe
MeMe
Me
O
O
O Me
Me Me
O
MeO
H+
H2O
"Br+"
H H
Synthesis of Laurencia Natural Products:Corey's Venusatriol
O
O
OMe
Me
Br
Me
MeMe OH
OH
O
Me
OH
Me H
(+)-Venusatriol
O
O
HO
MeCN
Me
Me
E,E-Farnesol
O
O
OMe
Me
Br
Me
MeCN
H
H
TBCDOBr
R+
Zn°/HOAc +epimer 5%
61% 26%
Geraniol
Me
Me
Me
BnOH
OH
OH
PCCO
Me
OH
Me H
OH
BnO43%Me
O
O
OMe
Me
Br
Me
MeCHO
H
DIBAL-H54%
O
Me H
O
O
OMe
Me
Br
Me
MeHO H
H
A
t-BuLi; CeCl3; A85%
Me
MeO O
H
Br
HH
1) Swern2) MeMgBr3) TsOH/H2O
84%Me
O
Me HMe
MeO O
H
diastereoselection >95:5 diastereoselection >95:5
Corey, E. J., et al, Tetrahedron Lett., 1988, 26, 3171-3174
7 steps22%
shaw 45/46 2/4/02 2:36 PM
+Br
Me
Synthesis of Laurencia Natural Products:Shirahama and Forsyth Improve the Bromocyclization
OMe
R
Me
Me
R
Me
O
+Br
H
HMe Me
Me R OH "Br+"
OR+Br
Me
R
Me
O H
O OO
MeMe
Me Me RRMe Me
Br Br
Me MeMe
RMe
MeBr
Shirahama
R = H 80% 0% 20%
R = 0% 10% 90%
Forsyth
R =
R =OBz
OBz
47% 32% 21%
12% 36% 52%
Shirahama, H., et al, J. Org. Chem., 1990, 55, 5088-5107Forsyth, C. J., et al, J. Am. Chem. Soc, 2000, 122, 9099-9108
• Bulky R favors correct diastereomer, but also favors THF formation
Hg
Me
Synthesis of Laurencia Natural Products:Forsyth's Oxymercuration as an alternative
OMe
CN
Me
Me
CN
Me
O
Hg
H
HMe Me
Me NC OHOR
HgMe
CN
Me
O H
O OO
MeMe
Me Me CNCNMe Me
BrHg BrHg
Me MeMe
CNMe
MeBrHg
100%(79% isolated)
0% 0%
X
X XX
XX
Hg(TFA)2KBr
OMe RMe Me
Br
Br2, Pyridine300 nm79%
Me Me
Me NC OH
Cannot Be PreparedEnantioselectively orResolved!
shaw 47/48 2/4/02 2:37 PM
Synthesis of Aplysia Natural Products:Hoye's Polycyclization
OH
MeMe
Me
O
O
MeMeBr
O
Me
H
O
MeMeBr
O
Me
H
AgBF4/Br2
+
<15% yield (often 0-5%)
MeMe
MeHO
Me
CO2Et
1) Hg(TFA)22) KBr3) Br2, LiBr, pyr, O2
44%
OMe
MeMeBr
Me CO2EtO
Me
MeMeBr
Me CO2Et
diastereoselection 50:50
OMe
MeMeBr
Me
dl-3ββββ-Bromo-8-epicaparappi Oxide
4 steps
Hoye, T. R., et al, J. Org. Chem., 1978, 48, 3693-3697Hoye, T. R., et al, J. Org. Chem., 1979, 49, 3461-3467
Hg(TFA)2;Br2 30-40% yield
+
Synthesis of Aplysia Natural Products:Hoye's Aplysistatin
MeMe
MeMe
MeHO
H
CO2Me
SPhO Ph
Homogeraniol
LDABnOCH2CHO
75%
Me SPhCO2Me
MeMe
MeHO
H
CO2Me
SPhO Ph
OMe
HMe Me
Br CO2Me
H
SPh
OBn
OMe
HMe Me
Br SPh
H
CO2Me
OBn
OMe
HMe Me
Br CO2Me
H
SPh
OBn
OMe
HMe Me
Br CO2Me
H
SPh
OBn
OMe
HMe Me
Br
CO2Me
OBnH
OMe
HMe Me
Br
CO2Me
OBnH
OMe
HMe Me
Br
HO
O
Ph3C+
BF4-
52%
Ph3C+
BF4-
75%
Hg(TFA)2; KBr; Br2, LiBr, O2
15% 15% 14% 11%
mCPBA/∆
65% 68%(+/-)-Aplysistatin
12-epi-(+/-)-Aplysistatin
Hoye, T. R., et al, J. Am. Chem. Soc., 1979, 101, 5065-5067
2 steps
+
+ + +
+
shaw 49/50 2/4/02 2:39 PM
Synthesis of Aplysia Natural Products:White's Aplysistatin
MeMe
MeO
Me
HMe Me
Br
O
O
O
O
HO
OMe
HMe Me
Br
HO
O
(+/-)-Aplysistatin
Me
HMe Me
Br
O
O
O
13% 28%
MeMe
Me
O
O
HO
SPh
OMe
HMe Me
Br
O
O
26%
OMe
HMe Me
Br
O
O
7%
H
SPh
H
SPh
+
+
1) NPS*/Et3N2) NaBH479%
Hg(TFA)2KBrBr2, LIBr, O2, pyr
mCPBA/∆68%
White, J. D., J. Am. Chem. Soc., 1982, 104, 3923-3928
NPS =N
O
O
SPh
Corey's Use of Mercuriocyclization:Aphidicolin & Stemodinone
CO2Me
Me
R
OPO(OEt)2
Me
ClHg
Hg(OTFA)2;NaCl
R
O
CO2Me
60%R=H or R=OTBS
MeMe
O
CO2Me
Me
O
CO2Me
O
Ot-Bu
Me Me
H
H
Me Me
H
H
MeH
HO
HO
O
H
MeH
Me
HO Me
(+/-)-Aphidicolin (+/-)-Stemodinone
O
Corey, E. J. et al, J. Am. Chem. Soc., 1980, 102, 1742-1744Corey, E. J. et al, J. Am. Chem. Soc., 1980, 102, 7612-7613
shaw 51/52 2/4/02 2:41 PM
Me
Me
Synthesis of Laurencia Natural Products:Nishizawa's Isoaplysin-20
Me
MeMe
Me
Me
OAc OAc
OHMe
MeMe
Me Me
H H
BrOAc
Me
MeMe
Me Me
H H
Br
16%
17%
+
Hg(TFA)2/PhNMe2KBr; LiBr, Br2, O2
H
H
OAc
OHMe
MeMe
Me Me
H H
Br
1.8%H
NaOH/H2OOH
OHMe
MeMe
Me Me
H H
Br
1.8%
H
chair/chair/chair
chair/boat/chair
(+/-)-Isoaplysin-20
Me
Me
H
Me
H
OO
Me
Me
Me
Me
H H
Me
Nishizawa, M., et al, J. Am. Chem. Soc., 1984, 106, 4290-4291
Me
O
O
Me
H
(E, E)-Farnesyl Acetate
Synthesis of Plocamium Natural Products:The Diels-Alder approach
Me CHO
Cl Cl
CHO
MeTol/170 °C
diastereoselection 77:23
53%Li+CHClBr-
30%Cl
Me
+ BrOH
Cl
O
Me
ClPhSe
Cl
Br
PhSeCl68%
Me
ClPhSe
Cl
Zn/HOAc"100%"
HOMe
ClPhSe
Cl
O
+ Z isomer
Cl
O
Zn/HOAc89%
64%
CH2Br2Zn°/TiCl4
"10%"
NaOCl75%
ClMe
Cl
ClMe
Cl
ClMe
Cl
Cl
ClMe
Cl
ClMe
BrBr+
NBS
19% 33% Cl
ClMe
PHICl223%
Cl
Williard, P. G., et al, J. Org. Chem., 1985, 50, 3738-3749.shaw 53/54 2/4/02 2:43 PM
Synthesis of Plocamium Natural Products:Shea's T2IM Diels-Alder Approach
Si
Cl
ClMe
Me
Si
Cl
OHMe
Me96%
MeMgBr/Mg°Si
Me
Me Mg
OMgBr
NiCl2(dppp)/ Cl
SiMe
Me
OMgBrCl Br
O
MeSiMe
Me
O Br
O
Me
Si O
Me
Br
Me
Me
Cl
ClDIBAL-H
85%BrCl
Me
OH
Si O
Me
Br
Me
Me
PhICl261%
onepot!
BrCl
MeCl
1) TPAP/NMO2) CrCl2/CHCl3 E/Z=94:6
89%; 58%
Tol/∆
74%O
O
Shea, K. J., et al, J. Org. Chem., 1997, 62, 8962-8963
Synthesis of Callipeltoside Sidechain:Chloroalkene Cyclopropanation
Olivo, H., et al, Org. Lett., 2001, 2, 4055-4058Evans, D. A., et al, Org. Lett., 2001, 3, 503-505Patterson, I., et al, Angew. Chem. Int. Ed., 2001, 603-607
O
O
O
O
OH
OH
O
OCl
Et2Zn, TFA,CH2I2
82%
O
OCl3 steps
66%
61%R=CH2OH
Cl
Cl
CO2t-BuCO2t-Bu
57% Cl
ClOH
DIBAL-H
90%
NOVOZYM-435vinylpropionate
Cl
ClOR
LAH84%
ClOH
<40%
R
Cl64%
R=CHCHCO2Et
diastereoselection >98:2
HO Cl
O
BBuOMe2NOC
Me2NOC
Et2Zn; CH2I2
shaw 55/56 2/4/02 2:45 PM
Synthesis of Virantmycin:Corey's Ortho-Azaxylylene Intramolecular Diels-Alder
Corey, E. J., et al, Org. Lett., 1999, 1, 824-825
Me
O LiClPd(OAc)2 (2 mol%)HOAc Me
O
CO2Et
Cl
CO2Et
+ 85%
5 steps
48%Me
Cl
OHMe Me
NCO
IOTBS
84%
NH
IOTBS
OO
Cl
Me
Me Me
1) TBAF2) SOCl23) Cs2CO3
N
OO
Cl
Me
Me
MeI
N
Cl
OO
I
Me
Me Me
4 steps<45%
NH
Cl
OMe
HO2C
Me
Me Me
(+/-)-Virantmycin
Synthesis of Virantmycin:Previous Syntheses by Raphael and Shirahama
(+/-)-Virantmycin
N
OH
Me
Me
Me
OR
SOCl2
OH
N
OSOCl
Me
Me
Me
OROH
MeO2C
MeO2C
MeO2C
N
H
H
OR
Me
Me
Me
Cl-
HN
Cl
Me
Me
Me
OMe
MeO2C
45%
HN
Cl
Me
Me
Me
OMe
HO2C
N3
CO2Et
MeMe
Me
EtO2CR = Me
hυ; 93%LiAlH(Ot-Bu)3; 93%
R = H
3 steps60%
Shirahama, H., et al, Synlett, 1991, 202-204Raphael, R. A. , et al, Tetrahedron, 1990, 46, 4587-4594
73%
LiOH,H2O
shaw 57/58 2/4/02 2:48 PM
Halomon: The Final Frontier• The biggest challenge in HNP synthesis is the preparation of acyclic halogenated terpenes• Only two syntheses of Halomon have been reported, and there is still much room for improvement
OH
HO TBSO
OH
Cl
Cl MeC(OMe)3pTsOH/ 170 °C
55%TBSO
Cl
ClOMe
O
1) TBSCl2) Et4N+Cl2
-
59%
Br
Cl
ClCHO
Me
MgBr
Cl
Me
OHBr
Cl
Et4N+Br3-
97%Cl Me
Me
OHBr
Cl
Br
Cl Me
Me
BrBr
Cl
Cl
N+Me Me
Cl Cl
Cl-
Viehe's Salt
75%
Halomon
Me
Me
Bu4NBrCl2HPLC
Myrcene
Me
Me
Br
Cl
Me
Me
Br
Cl DBU
86%
Bu4NBrCl2HPLC
27%
25%
Neither SynthesisGives ANY
DIastereoselectivity
Mioskowski, C., et al, Angew. Chem. Int. Ed., 1998, 37, 2085-2086Hirama, M., et al, Angew. Chem. Int. Ed., 2000, 39, 3430-3431
87%
6 steps73%
Cl Cl
Br
Outlyers• Several recent diastereoselective syntheses of halogenated natural products
employ selective, but not terribly general, halogenation reactions.
Me
O
HMe
O
O
Me
O
Me
Me Me O
Me
H
Cl
O
(-)-Carvone
LiCl/CSA
75%
NH
Me
Me H
H
ClMe
NC
(-)-Hapalindole G
HO
HO2C
NHCBz
OO
OTBS
PhtN NPht
N+HS
O-
EDC
CO2
NH
S
+
NHCBz
OO
OTBS
PhtN NPht
CCl4
NHCBz
OO
OTBS
PhtN NPht
Cl
N
NH
HN
HN
NH
HHO
NH
RO
Cl
NHRNHR
diastereoselection >91:9
Fukuyama, T., et al, J. Am. Chem. Soc., 1994, 116, 3125-3126Carreira, E. M., et al, J. Am. Chem. Soc., 2000, 122, 8793-8794
Axinellaminesshaw 59/60 2/4/02 2:49 PM
Outlyers II
NNH
HN
HN
NH
H
OH
HN
RO
Axinellamines
HN
NN
X
Cl
NH2
O
Y
R1 R2
N
HN
H2N
H
HH2N
HO
Palauamines/Styloguanidines
N
HN
NH2
H2N
N
N
O
R1 R2
N
HNH2N
N
HN
NH2
H2N
N
N
O
R1 R2
N
HN
H2N
H
H
Cl+
N
N
OH
O
NTs
O
OTIPSBn
Bn
N
N
OH
O
NTs
HBn
OTIPSBn
O
N
N
OTBS
O
NTs
HBn
OTIPSBn
O
H HOH
NTsN
N
O
Cl OTBS
O
O
Bn
Bn
OTIPS
H
H
Cl
NHR
NHR
diastereoselection 81:19
∆; 79%
mCPBA
NCS; 79%
Kinnel, R. G., et al, J. Am. Chem. Soc., 1993, 115, 3376-3377Romo, D., et al, Org. Lett., 2001, 3, 1535-1538Poitier, P., et al, Eur. J. Org. Chem., 2001, 237-243
Summary
• Many selective approaches to the construction of halogen-bearing stereocenters have been developed
• Nucleophilic displacement of alcohols is an important and selective method for the construction of a bromine-bearing center
• Mono- and polycyclizations provide the opportunity to use the introduction of bromine to control the stereo- and regiochemistry of other stereogenic centers
• Few methods are truly general and most are developed in the context of one particular natural product class
shaw 61/62 2/4/02 2:51 PM