malcolm p. huestis supervisor: keith fagnou 1. isolation and structure elucidation: aoki, s.;...
TRANSCRIPT
1
TOTAL SYNTHESIS OF (+)-CORTISTATIN A
Malcolm P. HuestisSupervisor: Keith Fagnou
N
OH
Me2N
O
H
HOMe
2Isolation and structure elucidation:Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.; Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148-3149.
N
OH
Me2N
O
H
HOMe
Marine Sponge Corticium simplex(22 mg from 1.5 kg organism)
-Selectively inhibits angiogenesis.
-IC50 = 1.8 nM
Cl
F3C NH
NH
OO
N
O
NH
Sorafenib (Bayer and Onyx)FDA-December 20, 2005
NH
F
O
NH
O
NH
NEt2
Sutent (Pfizer)FDA-January 26, 2006
N
N
HN
N
Cl
Vatalanib (Novartis and Schering AG)Finished Phase III
-Anti-angiogenetic substances inhibit the formation of new capillary blood vessels.
-Cancer, diabetic eye disease, rheumatoid arthritis
3
Total Synthesis:
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313.
Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864-16866.
Partial Syntheses (all from 2008):
Danishefsky – Sloan-Kettering Institute and Columbia UniversityCorey – Harvard University
Yamashita and Hirama – Tohoku UniversitySarpong – University of California (Berkeley)
Gung – Miami UniversityKobayashi – Osaka University
Highlight:
Nising, C. F.; Bräse, S. Angew. Chem. Int. Ed. 2008, 47, 9389-9391.
ONGOING SYNTHETIC EFFORTSN
OH
Me2N
O
H
HOMe
4
THIS SEMINAR – COMPLETED SYNTHESES
1) May 14th, 2008 - Phil Baran – Highly chemoselective semi-synthetic strategy
2) August 14th, 2008 - K.C. Nicolaou and David Chen – From the Hajos-Parrish bicyclic ketone
3) November 19th, 2008 - Matthew Shair’s key step - An efficient aza-prins cyclization
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313.Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864-16866.
N
OH
Me2N
O
H
HOMe
H
Me
OH
O
OH
OMe
O
HH
Baran15 steps
1.0% overall yield
MeOTBSO
Nicolaou 25 steps 0.007% overall yield
Shair24 steps0.14% overall yield
Prednisone ($1.20/g) Hajos-Parrish
(+)-Cortistatin A
5
FOCUSING ON METHODS
1) Phil Baran – -Radical ring expansion reaction
-Co(III)-catalyzed alkene hydration-Alcohol-directed dibromination reaction-Chemo- and stereoselective double bond reduction
2) K.C. Nicolaou and David Chen –-A single cascade reaction to fuse the entire oxabicycle
-Mild aldehyde alkynylation-IBX deprotects dithiane-protected carbonyl-IBX-mediated enone synthesis
3) Matthew Shair’s key step – -Late-stage aza-prins cyclization
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313.Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864-16866.
OMeOH
N
O
H OO
H
H
O
O
Me
H
HOH
N
O
H OO
H
O
H
O
OMeBrH
O
H
MeOTBS
O
H
MeOTBS
HO
O O
OTBSOAc
Me2N
O
H
AcOMe
OTBSOAc
ORO
H
AcOMe
6
BARAN RETROSYNTHESIS
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
N
OH
Me2N
O
H
HOMe
(+)-Cortistatin AStille Cross-Coupling,Reduction
OH
Me2N
O
H
HOMe
I
Lewis-acid initiatedintramolecularnucleophilic addition/acetate elimination
H
AcO
O
OMe
OH
Me2N
OAc
AcOSteps
OMeOH
N
O
H OO
H
H
O
O
Me
H
H
OH
N
O
H OO
H
O
H
O
OMeBrH
Bromination/cyclopropanation/radicalRing Expanion Sequence
H
Me
OH
O
OH
OMe
O
HH
Steps
7
BARAN RETROSYNTHESIS
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
N
OH
Me2N
O
H
HOMe
(+)-Cortistatin AStille Cross-Coupling,Reduction
OH
Me2N
O
H
HOMe
I
Lewis-acid initiatedintramolecularnucleophilic addition/acetate elimination
H
AcO
O
OMe
OH
Me2N
OAc
AcOSteps
OMeOH
N
O
H OO
H
H
O
O
Me
H
H
OH
N
O
H OO
H
O
H
O
OMeBrH
Bromination/cyclopropanation/radicalRing Expanion Sequence
H
Me
OH
O
OH
OMe
O
HH
Steps
Prednisone ($1.20/g)
Same price as:
9-BBNKOtBuHg(OAc)2TBDPS-ClClCH2ITri-O-acetyl-D-glucal
8
ELABORATION OF THE STEROID CORE
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
H
Me
OH
O
OH
OMe
O
HH
i) BH3.THF (1 equiv.)
Prednisone ($1.20/g)
H
Me
OH
OH
OH
OMe
O
HH
THF, 0 - 23°C
H
Me
OMe
O
HH O
ii) NaIO4 (5 equiv.)
H
Me
OO
OMe
O
HH
OH
IO
OHO
OH1:1 acetone/H2O0 - 23°C
H
OMe
O
HH
O
OMeethylene glycol (25 equiv.)p-TsOH.H2O (0.07 equiv.)
toluene, reflux92% over 2 steps
tBuOOH (2 equiv.)DBU (2 equiv.)
H
OMe
O
HH
O
OMe
O
THF, 23°C82%
9
i) NH4OAc (10 equiv.)Na(BH3)CN (1.5 equiv.)
H
OMe
H2N
HH
O
OMe
O
H
OMe
H2N
HH
O
OMe
O
H
OMe
O
HH
O
OMe
O
reduction
1:2.4 THF/MeOH23°C
ELABORATION OF THE STEROID CORE II
Bu4NOAc (5 equiv.)Co(acac)2 (0.2 equiv.)
benzene, 90°C48%H
OMeH
N
HH
O
OMe
O
H
AcO OH
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
ii) HCO2Et (74 equiv.)NEt3 (11 equiv.)
54°C73%
H
OMeH
N
HH
O
OMe
O
O
H
10
i) NH4OAc (10 equiv.)Na(BH3)CN (1.5 equiv.)
H
OMe
H2N
HH
O
OMe
O
H
OMe
H2N
HH
O
OMe
O
H
OMe
O
HH
O
OMe
O
reduction
1:2.4 THF/MeOH23°C
ELABORATION OF THE STEROID CORE II
Bu4NOAc (5 equiv.)Co(acac)2 (0.2 equiv.)
benzene, 90°C48%H
OMeH
N
HH
O
OMe
O
H
AcO OH
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
ii) HCO2Et (74 equiv.)NEt3 (11 equiv.)
54°C73%
H
OMeH
N
HH
O
OMe
O
O
H
AcO
« Chem3D Embed »
11
i) NH4OAc (10 equiv.)Na(BH3)CN (1.5 equiv.)
H
OMe
H2N
HH
O
OMe
O
H
OMe
H2N
HH
O
OMe
O
H
OMe
O
HH
O
OMe
O
reduction
1:2.4 THF/MeOH23°C
ELABORATION OF THE STEROID CORE II
Bu4NOAc (5 equiv.)Co(acac)2 (0.2 equiv.)
benzene, 90°C48%H
OMeH
N
HH
O
OMe
O
H
AcO OH
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
ii) HCO2Et (74 equiv.)NEt3 (11 equiv.)
54°C73%
H
OMeH
N
HH
O
OMe
O
O
H
AcO
12
ELABORATION OF THE STEROID CORE III
OMeOH
N
O
H OO
H
H
O
O
Me
H
H
iii) K2CO3 (5 equiv.)MeOH, 23°C
63%
ii) p-TsOH.H2O (3 equiv.)23°C
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
H
OMeH
N
HH
O
OMe
O
H
AcO OHi) Co(acac)2 (0.2 equiv.)
PhSiH3 (2.2 equiv.)
3.2:1 THF/HC(OMe)3O2 atm23°C
OMeOAc
NH
O
H OHHO H
O
O
Me
H
H
H
OMeH
N
HH
O
OMe
O
H
AcO OH
HO
13Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 1071-1074. Takahiro, T.; Kunikawa, S.; Masuyama, A.; Nojima, M. Org. Lett. 2002, 4, 3595-3598.
CoIIIO
O
2
H
R2
R3R1
CoIIIO
O
2
R1H
R3R2
H
H
CoIIO
O
2
R1H
R3O O
+R2
HR1H
R3O O CoII
O
O
2
R2
H
R1H
R3
O O CoIIIO
O
2
R2
H
H
OMeH
N
HH
O
OMe
O
H
AcO OHi) Co(acac)2 (0.2 equiv.)
PhSiH3 (2.2 equiv.)
3.2:1 THF/HC(OMe)3O2 atm23°C
H
OMeH
N
HH
O
OMe
O
H
AcO OH
HO
R1H
R3O O
H2Si Ph
H3SiPh
R2
HR1
H
R3R2
H
OH
14
ELABORATION OF THE STEROID CORE III
OMeOH
N
O
H OO
H
H
O
O
Me
H
H
iii) K2CO3 (5 equiv.)MeOH, 23°C
63%
ii) p-TsOH.H2O (3 equiv.)23°C
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
H
OMeH
N
HH
O
OMe
O
H
AcO OHi) Co(acac)2 (0.2 equiv.)
PhSiH3 (2.2 equiv.)
3.2:1 THF/HC(OMe)3O2 atm23°C
OMeOAc
NH
O
H OHHO H
O
O
Me
H
H
H
OMeH
N
HH
O
OMe
O
H
AcO OH
HO
15
CONSTRUCTION OF THE OXABICYCLIC RING
i) PhI(OAc)2 (5 equiv.)Br2 (8 equiv.)75W sunlampCH2Cl2, -30°C
OMeOH
N
O
H OO
H
H
O
O
Me
H
H
ii) TMSCl (5 equiv.)imidazole (5 equiv.)
CH2Cl2, 0°C57%
OOTMS
N
O
H OO
H
H
O
O
Me
H
H
BrBr
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
OTMSO
N
O
H OO
H
O
O
Me
H
HBrDBU (2 equiv.)
LiCl (5 equiv.)
THF, 23°C85%
OTMS
N
O
H OO
H
O
H
O
OMeBrH
i) SmI2 (2.2 equiv.)9:1 THF/DMPU, 23°C
ii) TBCHD, -72°C
Li2CO3 (20 equiv.)LiBr (20 equiv.)
DMF, 60°C63% over 2 steps
OTMS
N
O
H OO
H
O
H
O
OMe
H
AcO
O
OMe
OH
Me2N
OAc
AcO
i) AlH3 (5 equiv.)THF, 23°C
ii) K2CO3 (2 equiv.)MeOH, 23°C
iii) Ac2O (20 equiv.)NEt3 (40 equiv.)
DMAP (0.1 equiv.)CH2Cl2, 23°C
89%
16
I
OAc
OAcPh
Br Br
Br I OAcPh+BrOAc
Br
IPh + BrOAc
KEY STEP # 1
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
i) PhI(OAc)2 (5 equiv.)Br2 (8 equiv.)75W sunlampCH2Cl2, -30°C
OMeOH
N
O
H OO
H
H
O
O
Me
H
H
ii) TMSCl (5 equiv.)imidazole (5 equiv.)
CH2Cl2, 0°C57%
OOTMS
N
O
H OO
H
H
O
O
Me
H
H
BrBr
or
I
OAc
OAcPhBr I
OAc
OAc
Ph
BrBr I
OAc
OAcPh
Br
Br
Reductive Elimination x 2
2 BrOAc + IPh
h
17
KEY STEP # 1
Čeković, Ž. Tetrahedron 2003, 59, 8073-8090
OMeOH
N
O
H OO
H
H
O
O
Me
H
H
Br OAc
OMeO
N
O
H OO
H
H
O
O
Me
H
HBr H
OAc
-AcOH
OMeO
N
O
H OO
H
H
O
O
Me
H
HBr
OCH2O
N
O
H OO
H
H
O
O
Me
H
HH
OCH2OH
N
O
H OO
H
H
O
O
Me
H
H
Br
OOH
N
O
H OO
H
H
O
O
Me
H
HBr
Repeat
OOH
N
O
H OO
H
H
O
O
Me
H
H
BrBrO
OTMS
N
O
H OO
H
H
O
O
Me
H
H
BrBr
Protection
18
CONSTRUCTION OF THE OXABICYCLIC RING
i) PhI(OAc)2 (5 equiv.)Br2 (8 equiv.)75W sunlampCH2Cl2, -30°C
OMeOH
N
O
H OO
H
H
O
O
Me
H
H
ii) TMSCl (5 equiv.)imidazole (5 equiv.)
CH2Cl2, 0°C57%
OOTMS
N
O
H OO
H
H
O
O
Me
H
H
BrBr
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
OTMSO
N
O
H OO
H
O
O
Me
H
HBrDBU (2 equiv.)
LiCl (5 equiv.)
THF, 23°C85%
OTMS
N
O
H OO
H
O
H
O
OMeBrH
i) SmI2 (2.2 equiv.)9:1 THF/DMPU, 23°C
ii) TBCHD, -72°C
Li2CO3 (20 equiv.)LiBr (20 equiv.)
DMF, 60°C63% over 2 steps
OTMS
N
O
H OO
H
O
H
O
OMe
H
AcO
O
OMe
OH
Me2N
OAc
AcO
i) AlH3 (5 equiv.)THF, 23°C
ii) K2CO3 (2 equiv.)MeOH, 23°C
iii) Ac2O (20 equiv.)NEt3 (40 equiv.)
DMAP (0.1 equiv.)CH2Cl2, 23°C
89%
19
KEY STEP # 2
OTMSO
N
O
H OO
H
O
O
Me
H
HBrDBU (2 equiv.)
LiCl (5 equiv.)
THF, 23°C85%
OOTMS
N
O
H OO
H
H
O
O
Me
H
H
BrBr
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
OTMSO
N
O
H OO
H
O
O
Me
H
HBrO
TMSO
N
O
H OO
H
O
O
Me
H
BrBr
N
N
OOTMS
N
O
H OO
H
H
O
O
MeBrBrDBU (2 equiv.)LiCl (5 equiv.)
THF, 23°C85%
H
H
20
CONSTRUCTION OF THE OXABICYCLIC RING
i) PhI(OAc)2 (5 equiv.)Br2 (8 equiv.)75W sunlampCH2Cl2, -30°C
OMeOH
N
O
H OO
H
H
O
O
Me
H
H
ii) TMSCl (5 equiv.)imidazole (5 equiv.)
CH2Cl2, 0°C57%
OOTMS
N
O
H OO
H
H
O
O
Me
H
H
BrBr
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
OTMSO
N
O
H OO
H
O
O
Me
H
HBrDBU (2 equiv.)
LiCl (5 equiv.)
THF, 23°C85%
OTMS
N
O
H OO
H
O
H
O
OMeBrH
i) SmI2 (2.2 equiv.)9:1 THF/DMPU, 23°C
ii) TBCHD, -72°C
Li2CO3 (20 equiv.)LiBr (20 equiv.)
DMF, 60°C63% over 2 steps
OTMS
N
O
H OO
H
O
H
O
OMe
H
AcO
O
OMe
OH
Me2N
OAc
AcO
i) AlH3 (5 equiv.)THF, 23°C
ii) K2CO3 (2 equiv.)MeOH, 23°C
iii) Ac2O (20 equiv.)NEt3 (40 equiv.)
DMAP (0.1 equiv.)CH2Cl2, 23°C
89%
21
KEY STEP # 3
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
OTMSO
N
O
H OO
H
O
O
Me
H
HOH
N
O
H OO
H
O
H
O
OMeBrH
Br i) SmI2 (2.2 equiv.)9:1 THF/DMPU, 23°C
ii) TBCHD (2 equiv.)-72°C
OTMSO
N
O
H OO
H
O
O
Me
H
Br 1) SmI2 (2.2 equiv.)9:1 THF/DMPU, 23°C
SmI2
OSmI2TMSO
N
O
H OO
H
O
O
Me
H
Br OSmI2TMSO
N
O
H OO
H
O
O
Me
H
HBr
OH
N
O
H OO
H
O
H
O
OMeBrH
OH
N
O
H OO
H
I2SmO
H
O
OMe
H
BrBr
O
BrBr
TBCHD
22
CONSTRUCTION OF THE OXABICYCLIC RING
i) PhI(OAc)2 (5 equiv.)Br2 (8 equiv.)75W sunlampCH2Cl2, -30°C
OMeOH
N
O
H OO
H
H
O
O
Me
H
H
ii) TMSCl (5 equiv.)imidazole (5 equiv.)
CH2Cl2, 0°C57%
OOTMS
N
O
H OO
H
H
O
O
Me
H
H
BrBr
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
OTMSO
N
O
H OO
H
O
O
Me
H
HBrDBU (2 equiv.)
LiCl (5 equiv.)
THF, 23°C85%
OTMS
N
O
H OO
H
O
H
O
OMeBrH
i) SmI2 (2.2 equiv.)9:1 THF/DMPU, 23°C
ii) TBCHD, -72°C
Li2CO3 (20 equiv.)LiBr (20 equiv.)
DMF, 60°C63% over 2 steps
OTMS
N
O
H OO
H
O
H
O
OMe
H
AcO
O
OMe
OH
Me2N
OAc
AcO
i) AlH3 (5 equiv.)THF, 23°C
ii) K2CO3 (2 equiv.)MeOH, 23°C
iii) Ac2O (20 equiv.)NEt3 (40 equiv.)
DMAP (0.1 equiv.)CH2Cl2, 23°C
89%
23
OTMS
N
O
H OO
H
O
H
O
OMe
H
AcO
O
OMe
OH
Me2N
OAc
AcO
i) AlH3 (5 equiv.)THF, 23°C
ii) K2CO3 (2 equiv.)MeOH, 23°C
iii) Ac2O (20 equiv.)NEt3 (40 equiv.)
DMAP (0.1 equiv.)CH2Cl2, 23°C
89%
OTMS
N
O
H OO
O
H
O
OMe
OTMS
NMe
OO
H2AlO
H
O
OMe
2 reductions
AlH3
HH
OTMS
NMe
OO
H2AlO
H
O
OMe
AlH2
H
OTMS
NMeOAlH2
O
H2AlO
H
O
OMe
AlH3
OTMS
NMe OAlH2O
H2AlO
H
O
OMe
AlH2
H
OTMS
NMe2
OAlH2
OAlH2
H2AlO
H
O
OMe
ii)
iii)
H
AcO
O
OMe
OH
Me2N
OAc
AcO
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
24
FINAL STEPS
Barton, D. H. R.; O’Brian, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470-476.Han, X. J.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605.
OH
Me2N
O
H
HOMe
O
"(+)-Cortistatinone"
H
AcO
O
OMe
OH
Me2N
OAc
AcO
i) MgBr2.Et2O (1.1 equiv.)
2,6-DTBP (2.1 equiv.)benzene, 78°C
ii) PPTS (5 equiv.)1:1 butanone/H2O
90°Ciii) K2CO3 (10 equiv.)
23°C82%
OH
Me2N
O
H
HOMe
NNH2
i) H2NNH2 (10 equiv.)NEt3 (10 equiv.)
EtOH, 50°C
OH
Me2N
O
H
HOMe
I
ii) I2 (2 equiv.)NEt3 (3 equiv.)
THF, 23°C
iii) Pd(PPh3)4 (0.5 equiv.)CuCl (10 equiv.)LiCl (10 equiv.)DMSO, 23°C
53%
NMe3Sn
(4 equiv.)
N
OH
Me2N
O
H
HOMe
N
OH
Me2N
O
H
HOMe
(+)-Cortistatin A
Raney Ni (88 wt. equiv.)
1:1 iPrOH/H2O50°C~50%
25
KEY STEP #4
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.
OH
Me2N
O
H
HOMe
O
"(+)-Cortistatinone"
H
AcO
O
OMe
OH
Me2N
OAc
AcO
i) MgBr2.Et2O (1.1 equiv.)
2,6-DTBP (2.1 equiv.)benzene, 78°C
ii) PPTS (5 equiv.)1:1 butanone/H2O
90°Ciii) K2CO3 (10 equiv.)
23°C82%
H
O
O
OMe
OHMe2N
OAc
AcO
OMgBr2
H
O
OMe
OMe2N
OAc
AcO
H
N tButBu
i) MgBr2.Et2O (1.1 equiv.)
2,6-DTBP (2.1 equiv.)benzene, 78°C
H
O
OMe
O
Me2N
OAc
AcO
OH
Me2N
O
H
HOMe
O
"(+)-Cortistatinone"
deprotections
26
FINAL STEPS
Barton, D. H. R.; O’Brian, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470-476.Han, X. J.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605.
OH
Me2N
O
H
HOMe
O
"(+)-Cortistatinone"
H
AcO
O
OMe
OH
Me2N
OAc
AcO
i) MgBr2.Et2O (1.1 equiv.)
2,6-DTBP (2.1 equiv.)benzene, 78°C
ii) PPTS (5 equiv.)1:1 butanone/H2O
90°Ciii) K2CO3 (10 equiv.)
23°C82%
OH
Me2N
O
H
HOMe
NNH2
i) H2NNH2 (10 equiv.)NEt3 (10 equiv.)
EtOH, 50°C
OH
Me2N
O
H
HOMe
I
ii) I2 (2 equiv.)NEt3 (3 equiv.)
THF, 23°C
iii) Pd(PPh3)4 (0.5 equiv.)CuCl (10 equiv.)LiCl (10 equiv.)DMSO, 23°C
53%
NMe3Sn
(4 equiv.)
N
OH
Me2N
O
H
HOMe
N
OH
Me2N
O
H
HOMe
(+)-Cortistatin A
Raney Ni (88 wt. equiv.)
1:1 iPrOH/H2O50°C~50%
27Barton, D. H. R.; O’Brian, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470-476.
OH
Me2N
O
H
HOMe
O
"(+)-Cortistatinone"
OH
Me2N
O
H
HOMe
NNH2
i) H2NNH2 (10 equiv.)NEt3 (10 equiv.)
EtOH, 50°C
OH
Me2N
O
H
HOMe
Iii) I2 (2 equiv.)NEt3 (3 equiv.)
THF, 23°C
OH
Me2N
O
H
HOMe
NNH2
I IOH
Me2N
O
H
HOMe
NN
H
I
H
NEt3
OH
Me2N
O
H
HOMe
N NI
H
OH
Me2N
O
H
HOMe
NN H
NEt3
OH
Me2N
O
H
HOMe
NNOH
Me2N
O
H
HOMe N
N
I
H H
NEt3
OH
Me2N
O
H
HOMe
I
2) I2 (2 equiv.)NEt3 (3 equiv.)
THF, 23°C
I I
28
FINAL STEPS
Barton, D. H. R.; O’Brian, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470-476.Han, X. J.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605.
OH
Me2N
O
H
HOMe
O
"(+)-Cortistatinone"
H
AcO
O
OMe
OH
Me2N
OAc
AcO
i) MgBr2.Et2O (1.1 equiv.)
2,6-DTBP (2.1 equiv.)benzene, 78°C
ii) PPTS (5 equiv.)1:1 butanone/H2O
90°Ciii) K2CO3 (10 equiv.)
23°C82%
OH
Me2N
O
H
HOMe
NNH2
i) H2NNH2 (10 equiv.)NEt3 (10 equiv.)
EtOH, 50°C
OH
Me2N
O
H
HOMe
I
ii) I2 (2 equiv.)NEt3 (3 equiv.)
THF, 23°C
iii) Pd(PPh3)4 (0.5 equiv.)CuCl (10 equiv.)LiCl (10 equiv.)DMSO, 23°C
53%
NMe3Sn
(4 equiv.)
N
OH
Me2N
O
H
HOMe
N
OH
Me2N
O
H
HOMe
(+)-Cortistatin A
Raney Ni (88 wt. equiv.)
1:1 iPrOH/H2O50°C~50%
29
NICOLAOU/CHEN RETROSYNTHESISN
OH
Me2N
O
H
HOMe
(+)-Cortistatin ASuzuki-Miyaura Cross-Coupling,Reduction
O
H
MeOTf
OO
Steps
O
H
MeOTBS
O
1,4-addition/aldol/dehydrationcascade
H
MeOTBS
HO
O O
Sonogashira Cross-Coupling,Reduction
H
MeOTBS
HO
H
S
S
Steps
H
MeOTBSO
Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313.
30
STARTING MATERIAL WAS NOT COMMERCIALLY AVAILABLE
Isaacs, R. C. A.; Di Grandi, M. J.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 3938-3941.Hajos, Z. G.; Parrish, D. R. Org. Synth. 1990, Coll. Vol. 7, 363-368; 1985, 63, 26-36.Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 496-497.
5 steps, 23% overall yieldMe
O O3 steps, 76% overall yieldO
HO
MeOTBSO
O
O
O
O
MeO O
HO
AcOH70°C
3 mol % S-(-)-proline
DMF, 16°C
H2SO4DMF95°C
Hajos-Parrish Reaction
31
THE HAJOS-PARRISH REACTION
O
O
O
MeO O
HO
3 mol % S-(-)-proline
DMF, 16°C
Clemente, F. R.; Houk, K. N. Angew. Chem. Int. Ed. 2004, 43, 5766-5768.Zhu, H.; Clemente, F. R.; Houk, K. N.; Meyer, M. P. J. Am. Chem. Soc. 2009, 131, 1632-1633.Hajos, Z. G.; Parrish, D. R. Org. Synth. 1990, Coll. Vol. 7, 363-368; 1985, 63, 26-36.Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.
HN
HO
HO
O
O
O
O
O
N
O
O
H
H2O
O
O
N
O
HO
O
ON
O
O
HMe
O
OHN
O
O
Me
MeO O
HOH2O
32
SYNTHESIS OF THE KEY SONOGASHIRA FRAGMENT I
VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973-1976.McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318-3326.
H
MeOTBSO
H
MeOTBSO
HO
OH
OsO4 (0.02 equiv.)NMO (2.5 equiv.)
8:1 acetone/H2O23°C73%
H
MeOTBSO
O
OOs
O
Ohydrolysis
Me2C(OMe)2 (5 equiv.)p-TsOH (0.04 equiv.)
acetone, 23°C87%
H
MeOTBSO
O
O
NaHMDS (1.2 equiv.)PhNTf2 (1.1 equiv.)
H
MeOTBS
O
OTfO
THF, 0°CCO atm, 5:2 DMF/MeOH70°C
72% over 2 steps
Pd(PPh3)4 (0.05 equiv.)NEt3 (3 equiv.)
H
MeOTBS
O
OMeO2C
33
SYNTHESIS OF THE KEY SONOGASHIRA FRAGMENT II
Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507.Ohira, S. Synth. Commun. 1989, 19, 561-564.Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.
H
MeOTBS
O
OMeO2C
DIBAL-H (3 equiv.)
toluene, -78°C79% H
MeOTBS
O
O
HODMP (1.5 equiv.)
NaHCO3 (4.6 equiv.)
CH2Cl2, 23°C86%
IO
O
OAcOAc
AcO
DMP =
H
MeOTBS
O
OOHC
HS(CH2)3SH (3 equiv.)BF3
.OEt2 (3.5 equiv.)CH2Cl2, -78°C
70%
H
MeOTBS
HO
S
S
HO
SO3.py (3 equiv.)
NEt3 (5 equiv.)
4:1 CH2Cl2/DMSO23°C72%
H
MeOTBS
HO
S
S
HO
p-TsN3 (1.5 equiv.)K2CO3 (3.5 equiv.)
1:1:3 MeCN/THF/MeOH23°C31%
O
P
O
OMeOMe
(1.5 equiv.)
H
MeOTBS
HO
H
S
S
34
PARIKH-DOERING OXIDATIONSO3
.py (3 equiv.)NEt3 (5 equiv.)
4:1 CH2Cl2/DMSO23°C72%
H
MeOTBS
HO
S
S
HO
H
MeOTBS
HO
S
S
HO
Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507.
S
O
OO
H
MeOTBS
HO
S
S
HO
S
O
S
O
OO
NS
O
OO
OS H
MeOTBS
HO
S
S
OS HH
H
H H
Et3N
H
MeOTBS
HO
S
S
OS HHH
MeOTBS
HO
S
S
HO
- DMS
- HSO4-
35
SYNTHESIS OF THE KEY SONOGASHIRA FRAGMENT II
Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507.Ohira, S. Synth. Commun. 1989, 19, 561-564.Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.
H
MeOTBS
O
OMeO2C
DIBAL-H (3 equiv.)
toluene, -78°C79% H
MeOTBS
O
O
HODMP (1.5 equiv.)
NaHCO3 (4.6 equiv.)
CH2Cl2, 23°C86%
IO
O
OAcOAc
AcO
DMP =
H
MeOTBS
O
OOHC
HS(CH2)3SH (3 equiv.)BF3
.OEt2 (3.5 equiv.)CH2Cl2, -78°C
70%
H
MeOTBS
HO
S
S
HO
SO3.py (3 equiv.)
NEt3 (5 equiv.)
4:1 CH2Cl2/DMSO23°C72%
H
MeOTBS
HO
S
S
HO
p-TsN3 (1.5 equiv.)K2CO3 (3.5 equiv.)
1:1:3 MeCN/THF/MeOH23°C31%
O
P
O
OMeOMe
(1.5 equiv.)
H
MeOTBS
HO
H
S
S
36Roth, G. J.; Liepold, B.; Müller, S. G.; Bestmann, H. J. Synlett 2004, 59-62.
H
MeOTBS
HO
S
S
HO
p-TsN3 (1.5 equiv.)K2CO3 (3.5 equiv.)
1:1:3 MeCN/THF/MeOH23°C31%
O
P
O
OMeOMe
(1.5 equiv.)
H
MeOTBS
HO
H
S
S
Me
S OO
NN
N
O
P
O
OMeOMe
H H
O
P
O
OMeOMe
H
Me
S OO
NN
N
O3CK
O
P
O
OMeOMe
H
Me
SO O
NN
NH-O3CK
O
P
O
OMeOMe
H
Me
SO O
HNN
NO
P
O
OMeOMe
HN
N
O3CK
O
P
O
OMeOMe
N
N
Ohira-Bestmann Reagent
i) p-TsN3K2CO3 (3.5 equiv.)
MeCN
37
OHIRA-BESTMANN HOMOLOGATION
Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313.
O
P
O
OMeOMe
N
NOMe
P
O
MeOMeO
N
N H
MeOTBS
HO
S
S
HO H
MeOTBS
HO
S
SO
P
O
MeOMeO
N
N
H
MeOTBS
HO
S
S
OP
O
MeOMeO
N
N
H
MeOTBS
HO
H
S
S
PO
MeOMeO O
H
MeOTBS
HO
S
S
NN
-
H
MeOTBS
HO
S
S
H
ii) aldehydeTHF/MeOH
38
INSTALLATION OF THE A RING
Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467-4470.Nicolaou; K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192-5201.
H
MeOTBS
HO
H
S
S
O
OTf
(1.4 equiv.)
Pd(PPh3)4 (0.1 equiv.)CuI (0.1 equiv.)NEt3 (3 equiv.)
DMF, 23°C85%
H
MeOTBS
HO
S
S
O
H
MeOTBS
HO
OHC
O
IBX (4 equiv.)
DMSO0 - 23°C
81%
IO
O
OOH
IBX =
H
MeOTBS
HO
OOHC
Pd/BaSO4 (5% wt/wt, 0.24 equiv.)H2 atm, 1:1 MeOH/THF, 23°C
64%
39
H
MeOTBS
HO
S
S
O
H
MeOTBS
HO
OHC
O
IBX (4 equiv.)
DMSO0 - 23°C
81%
Nicolaou; K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192-5201.
H
MeOTBSOH
S
S
O
IO
O
OOH
H
MeOTBSOH
S
O
IO
O
OOH
S
H
MeOTBSOH
O
IO
O
OOH
SSH
MeOTBSOH
O
O
HI
O
O
OH
SS
40
INSTALLATION OF THE A RING
Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467-4470.Nicolaou; K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192-5201.
H
MeOTBS
HO
H
S
S
O
OTf
(1.4 equiv.)
Pd(PPh3)4 (0.1 equiv.)CuI (0.1 equiv.)NEt3 (3 equiv.)
DMF, 23°C85%
H
MeOTBS
HO
S
S
O
H
MeOTBS
HO
OHC
O
IBX (4 equiv.)
DMSO0 - 23°C
81%
IO
O
OOH
IBX =
H
MeOTBS
HO
OOHC
Pd/BaSO4 (5% wt/wt, 0.24 equiv.)H2 atm, 1:1 MeOH/THF, 23°C
64%
41
KEY STEP – 1,4 ADDITION, ALDOL, DEHYDRATION CASCADE
H
MeOTBS
HO
O O
K2CO3 (1.2 equiv.)
dioxane, 125°C52%
H
MeOTBS
O
O O
O
H
MeOTBS
O
O
H
MeOTBS
O OHH
Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313.Same product was independently isolated:Yamashita, S.; Iso, K.; Hirama, M. Org. Lett. 2008, 10, 3413-3415.
42
Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357-1358.Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507.McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.
O
H
MeOTBS
O
O
H
MeOTBS
OOTMSO(CH2)2OTMS (5 equiv.)
TMSOTf (1.5 equiv.)
CH2Cl2-60 to -10°C
O
H
MeOH
OOTBAF (7 equiv.)
THF, 23°C56% over 2 steps
O
H
MeOO
SO3.py (6 equiv.)
NEt3 (10 equiv.)3:1 CH2Cl2/DMSO
23°C80%
O
KHMDS (3 equiv.)PhNTf2 (5 equiv.)
THF, -78°CO
H
MeOOOTf
THF, 80°C50% over 2 steps
Pd(PPh3)4 (0.3 equiv.)K2CO3 (3 equiv.)
NB
(3.3 equiv.)
O
O
O
H
MeOO
N
p-TsOH (1.5 equiv.)
10:1 acetone/H2O23°C88%
O
H
Me
N
O
43
O
H
MeOTBS
O
O
H
MeOTBS
OO
TMSOOTMS
TMS OTf
O
H
MeOTBS
OTMS
O
H
MeOTBS
OTMSOTMSOTMS
OTf
O
H
MeOTBS
OTMSOTMSO
TMS OTf
O
H
MeOTBS
OTMSOTMSOTMS
O
H
MeOTBS
- (TMS)2O
O
TMSO
O
H
MeOTBS
OOTMS
OTf
TMSOTf
Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357-1358.
O
H
MeOTBS
O
O
H
MeOTBS
OOTMSO(CH2)2OTMS (5 equiv.)
TMSOTf (1.5 equiv.)
CH2Cl2-60 to -10°C
44
Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357-1358.Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507.McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.
O
H
MeOTBS
O
O
H
MeOTBS
OOTMSO(CH2)2OTMS (5 equiv.)
TMSOTf (1.5 equiv.)
CH2Cl2-60 to -10°C
O
H
MeOH
OOTBAF (7 equiv.)
THF, 23°C56% over 2 steps
O
H
MeOO
SO3.py (6 equiv.)
NEt3 (10 equiv.)3:1 CH2Cl2/DMSO
23°C80%
O
KHMDS (3 equiv.)PhNTf2 (5 equiv.)
THF, -78°CO
H
MeOOOTf
THF, 80°C50% over 2 steps
Pd(PPh3)4 (0.3 equiv.)K2CO3 (3 equiv.)
NB
(3.3 equiv.)
O
O
O
H
MeOO
N
p-TsOH (1.5 equiv.)
10:1 acetone/H2O23°C88%
O
H
Me
N
O
45
FINAL STEPS
Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000.Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
O
H
Me
N
OPd/C (0.3 equiv.)
H2 atm
MeOH23°C50%
O
H
Me
N
O
1) TMSOTf (14 equiv.)NEt3 (30 equiv.)THF, -78 - 0°C
2) IBX.MPO (6 equiv.)DMSO, 23°C
46%
O
H
Me
N
O
tBuOOH (6 equiv.)DBU (3 equiv.)
CH2Cl2, 0 - 23°C70%
O
H
Me
N
O
O
NaBH4 (1 equiv.)CeCl3 (4 equiv.)
MeOH, 0°C40% of desired
O
H
Me
N
OH
OMe2NH (2.0 M in THF)
80°C45% of desired
Ti(OiPr)4 (5 equiv.)
N
OH
Me2N
O
H
HOMe
(+)-Cortistatin A
46
IBX AS AN ALTERNATIVE TO THE SAEGUSA OXIDATION
O
H
Me
N
O
1) TMSOTf (14 equiv.)NEt3 (30 equiv.)THF, -78 - 0°C
2) IBX.MPO (6 equiv.)DMSO, 23°C
46%
O
H
Me
N
O
Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596-7597.Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245-2258. Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem. Int. Ed. 2002, 41, 993-996.Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000.
IO
O
OOHN
O
OMe
IO
O
OOH
NO
MeO
IBX .MPO
DMSO
O
H
Me
N
OSiMe3
IO
O
O
NO
MeO O
H
Me
N
O
-HOSiMe3
IO
O
NO
MeO O
H
Me
N
OO
H
IO
O
O
H
Me
N
O
OH
N
O
OMe
47
FINAL STEPS
Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000.Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
O
H
Me
N
OPd/C (0.3 equiv.)
H2 atm
MeOH23°C50%
O
H
Me
N
O
1) TMSOTf (14 equiv.)NEt3 (30 equiv.)THF, -78 - 0°C
2) IBX.MPO (6 equiv.)DMSO, 23°C
46%
O
H
Me
N
O
tBuOOH (6 equiv.)DBU (3 equiv.)
CH2Cl2, 0 - 23°C70%
O
H
Me
N
O
O
NaBH4 (1 equiv.)CeCl3 (4 equiv.)
MeOH, 0°C40% of desired
O
H
Me
N
OH
OMe2NH (2.0 M in THF)80°C
45% of desired
Ti(OiPr)4 (5 equiv.)
N
OH
Me2N
O
H
HOMe
(+)-Cortistatin A
48
FINAL STEPS
Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000.Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
O
H
Me
N
OPd/C (0.3 equiv.)
H2 atm
MeOH23°C50%
O
H
Me
N
O
1) TMSOTf (14 equiv.)NEt3 (30 equiv.)THF, -78 - 0°C
2) IBX.MPO (6 equiv.)DMSO, 23°C
46%
O
H
Me
N
O
tBuOOH (6 equiv.)DBU (3 equiv.)
CH2Cl2, 0 - 23°C70%
O
H
Me
N
O
O
NaBH4 (1 equiv.)CeCl3 (4 equiv.)
MeOH, 0°C40% of desired
O
H
Me
N
OH
OMe2NH (2.0 M in THF)80°C
45% of desired
Ti(OiPr)4 (5 equiv.)
N
OH
Me2N
O
H
HOMe
(+)-Cortistatin A
« Chem3D Embed »
49
FINAL STEPS
Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996-1000.Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
O
H
Me
N
OPd/C (0.3 equiv.)
H2 atm
MeOH23°C50%
O
H
Me
N
O
1) TMSOTf (14 equiv.)NEt3 (30 equiv.)THF, -78 - 0°C
2) IBX.MPO (6 equiv.)DMSO, 23°C
46%
O
H
Me
N
O
tBuOOH (6 equiv.)DBU (3 equiv.)
CH2Cl2, 0 - 23°C70%
O
H
Me
N
O
O
NaBH4 (1 equiv.)CeCl3 (4 equiv.)
MeOH, 0°C40% of desired
O
H
Me
N
OH
OMe2NH (2.0 M in THF)80°C
45% of desired
Ti(OiPr)4 (5 equiv.)
N
OH
Me2N
O
H
HOMe
(+)-Cortistatin A
50
SHAIR RETROSYNTHESIS
OTBSOAc
Me2N
O
H
AcOMe
N
OH
Me2N
O
H
HOMe
(+)-Cortistatin A
Aza-Prins Cyclization
Steps
OTBSOAc
ORO
H
AcOMe
R = MEM
Suzuki-Miyaura Cross-Coupling
Bromocarbene Ring Expansion
OTBS
H
Me
ROBr
Br
SiiPrOOiPr
Me
MeOTBSO
Steps
Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864-16866.
51
THE AZA-PRINS REACTION
Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864-16866.
N N N Nu NNu
OAc
H
Me OTBS
ORN
Me
Me
OAc
OTBSOAc
Me2N
O
H
AcOMe
lewis acid
52
POTENTIAL PITFALLS OF THE REACTION
Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864-16866.
OTBSOAc
NRO
H
AcO Me
Me
Me
HOTBS
OAc
NRO
H
AcOMe
Me
Me
taut.
R = MEMEpimerization/Acetate elimination
OTBS
NRO
H
AcOMe
Me
Me
OTBSOAc
NOMEM
AcOMe
Me
Me
Br2Zn
OTBSOAc
N
AcOMe
Me
Me
tertiary allylic cation formation
53
SHAIR’S AZA-PRINS CYCLIZATION
Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864-16866.
OAc
H
Me OTBS
OMEMN
Me
Me
OAc
OAc
H
Me OTBS
OMEMO
OAc
Me2NH (3 equiv.)ZnBr2 (1.5 equiv.)
MeCN, 50°C65% (with the 2 previous steps)
OAc
Me2N OOAcH
Me OTBS
O
OMe
OTBSOAc
Me2N
O
H
AcOMe
54
CONCLUSION
1) May 14th, 2008 - Phil Baran
2) August 14th, 2008 - K.C. Nicolaou and David Chen
3) November 19th, 2008 - Matthew Shair
Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7241-7243.Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 7310-7313.Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864-16866.
N
OH
Me2N
O
H
HOMe
H
Me
OH
O
OH
OMe
O
HH
Baran15 steps
1.0% overall yield
MeOTBSO
Nicolaou 25 steps 0.007% overall yield
Shair24 steps0.14% overall yield
Prednisone ($1.20/g) Hajos-Parrish
(+)-Cortistatin A
Front: Ho-Yan SUNDave STUARTMalcolm HUESTISMégan BERTRAND-LAPERLE (gone)David LAPOINTESophie ROUSSEAUXOlivier RENÉChris WHIPPBack:Ivan PETROVBenoît LIÉGAULTElisia VILLEMURE (gone)Daniel SHOREDerek SCHIPPERNicolas GUIMONDPamela AL-SABEH
Prof. Keith Fagnou
Not shown:Michelle KUHNKevin BURGESS
ACKNOWLEDGMENTS