Total Synthesis of (+)- Cortistatin A

1

TOTAL SYNTHESIS OF (+)-CORTISTATIN A

Malcolm P. HuestisSupervisor: Keith Fagnou

N

OH

Me2NO

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

Me2NO

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

NO

NH

Sorafenib (Bayer and Onyx)FDA-December 20, 2005

NH

FO

NH

O

NH

NEt2

Sutent (Pfizer)FDA-January 26, 2006

NN

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

Me2NO

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

Me2NO

H

HOMe

H

Me

OH

OOH

OMe

O

HH

Baran15 steps

1.0% overall yield

Me OTBSO

Nicolaou 25 steps 0.007% overall yield

Shair24 steps0.14% overall yield

Prednisone ($1.20/g) Hajos-Parrish

(+)-Cortistatin A

5

FOCUSING ON METHODS1) 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


OMeOH

N

O

H OO

H

H

O

O

Me

H

HOH

N

O

H OO

H

O

H

O

OMeBrH

OH

Me OTBSO

H

Me OTBSHO

O O

OTBSOAc

Me2NO

H

AcOMeOTBS

OAc

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

Me2NO

H

HOMe

(+)-Cortistatin AStille Cross-Coupling,Reduction

OH

Me2NO

H

HOMe I

Lewis-acid initiatedintramolecularnucleophilic addition/acetate elimination

H

AcO

O

OMe

OHMe2N

OAcAcOSteps

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

OOH

OMe

O

HH

Steps

7

BARAN RETROSYNTHESIS


N

OH

Me2NO

H

HOMe

(+)-Cortistatin AStille Cross-Coupling,Reduction

OH

Me2NO

H

HOMe I

Lewis-acid initiatedintramolecularnucleophilic addition/acetate elimination

H

AcO

O

OMe

OHMe2N

OAcAcOSteps

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

OOH

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


H

Me

OH

OOH

OMe

O

HH

i) BH3.THF (1 equiv.)

Prednisone ($1.20/g)

H

Me

OH

OHOH

OMe

O

HH

THF, 0 - 23°C

H

MeO

MeO

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

OMeO

THF, 23°C82%

9

i) NH4OAc (10 equiv.)Na(BH3)CN (1.5 equiv.)

H

OMe

H2N

HH

O

OMeO

H

OMe

H2N

HH

O

OMeO

H

OMe

O

HH

O

OMeO

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


ii) HCO2Et (74 equiv.)NEt3 (11 equiv.)

54°C73%

H

OMeH

N

HH

O

OMeO

O

H

10


H

OMe

H2N

HH

O

OMeO

H

OMe

H2N

HH

O

OMeO

H

OMe

O

HH

O

OMeO

reduction

1:2.4 THF/MeOH23°C



benzene, 90°C48%H

OMeH

N

HH

O

OMe

O

H

AcO OH



54°C73%

H

OMeH

N

HH

O

OMeO

O

H

AcO

« Chem3D Embed »

11


H

OMe

H2N

HH

O

OMeO

H

OMe

H2N

HH

O

OMeO

H

OMe

O

HH

O

OMeO

reduction

1:2.4 THF/MeOH23°C



benzene, 90°C48%H

OMeH

N

HH

O

OMe

O

H

AcO OH



54°C73%

H

OMeH

N

HH

O

OMeO

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


H

OMeH

N

HH

O

OMe

O

H

AcO OH i) 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

O2

H

R2

R3R1

CoIIIO

O2

R1H

R3R2

H

H

CoIIO

O2

R1H

R3O O

+R2

HR1H

R3O O CoII

O

O2

R2

H

R1H

R3O O CoIII

O

O2

R2

H

H

OMeH

N

HH

O

OMe

O

H



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


H

OMeH

N

HH

O

OMe

O

H



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

HBrBr


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

OHMe2N

OAcAcO

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

IOAc

OAcPh

Br Br

Br I OAcPh+BrOAc

Br

IPh + BrOAc

KEY STEP # 1



OMeOH

N

O

H OO

H

H

O

O

Me

H

H


CH2Cl2, 0°C57%

OOTMS

N

O

H OO

H

H

O

O

Me

H

HBrBr

or

IOAc

OAcPhBr I

OAcOAc

PhBrBr I

OAcOAc

Ph

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

BrO

OH

N

O

H OO

H

H

O

O

Me

H

HBr

Repeat

OOH

N

O

H OO

H

H

O

O

Me

H

HBrBr

OOTMS

N

O

H OO

H

H

O

O

Me

H

HBrBr

Protection

18



OMeOH

N

O

H OO

H

H

O

O

Me

H

H


CH2Cl2, 0°C57%

OOTMS

N

O

H OO

H

H

O

O

Me

H

HBrBr


OTMSO

N

O

H OO

H

O

O

Me

H


THF, 23°C85%

OTMS

N

O

H OO

H

O

H

O

OMeBrH


ii) TBCHD, -72°C



OTMS

N

O

H OO

H

O

H

O

OMe

H

AcO

O

OMe

OHMe2N

OAcAcO





89%

19

KEY STEP # 2O

TMSO

N

O

H OO

H

O

O

Me

H


THF, 23°C85%

OOTMS

N

O

H OO

H

H

O

O

Me

H

HBrBr


OTMSO

N

O

H OO

H

O

O

Me

H

HBrOTMSO

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



OMeOH

N

O

H OO

H

H

O

O

Me

H

H


CH2Cl2, 0°C57%

OOTMS

N

O

H OO

H

H

O

O

Me

H

HBrBr


OTMSO

N

O

H OO

H

O

O

Me

H


THF, 23°C85%

OTMS

N

O

H OO

H

O

H

O

OMeBrH


ii) TBCHD, -72°C



OTMS

N

O

H OO

H

O

H

O

OMe

H

AcO

O

OMe

OHMe2N

OAcAcO





89%

21

KEY STEP # 3


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

OMeH

BrBrO

BrBr

TBCHD

22



OMeOH

N

O

H OO

H

H

O

O

Me

H

H


CH2Cl2, 0°C57%

OOTMS

N

O

H OO

H

H

O

O

Me

H

HBrBr


OTMSO

N

O

H OO

H

O

O

Me

H


THF, 23°C85%

OTMS

N

O

H OO

H

O

H

O

OMeBrH


ii) TBCHD, -72°C



OTMS

N

O

H OO

H

O

H

O

OMe

H

AcO

O

OMe

OHMe2N

OAcAcO





89%

23

OTMS

N

O

H OO

H

O

H

O

OMe

H

AcO

O

OMe

OHMe2N

OAcAcO





89%

OTMS

N

O

H OO

O

H

O

OMeOTMS

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

AlH2H

OTMS

NMe2OAlH2

OAlH2

H2AlO

H

O

OMe

ii)iii)

H

AcO

O

OMe

OHMe2N

OAcAcO


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

Me2NO

H

HOMe O

"(+)-Cortistatinone"

H

AcO

O

OMe

OHMe2N

OAcAcO

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

Me2NO

H

HOMe N NH2

i) H2NNH2 (10 equiv.)NEt3 (10 equiv.)

EtOH, 50°C

OH

Me2NO

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

Me2NO

H

HOMe

N

OH

Me2NO

H

HOMe

(+)-Cortistatin A

Raney Ni (88 wt. equiv.)

1:1 iPrOH/H2O50°C~50%

25

KEY STEP #4


OH

Me2NO

H

HOMe O


H

AcO

O

OMe

OHMe2N

OAcAcO





23°C82%

H

O

O

OMe

OHMe2N

OAcAcO

OMgBr2

H

O

OMe

OMe2N

OAcAcO

H

N tButBu



H

O

OMe

OMe2N

OAcAcO

OH

Me2NO

H

HOMe O


deprotections

26

FINAL STEPS


OH

Me2NO

H

HOMe O


H

AcO

O

OMe

OHMe2N

OAcAcO





23°C82%

OH

Me2NO

H

HOMe N NH2


EtOH, 50°C

OH

Me2NO

H

HOMe I


THF, 23°C


53%

NMe3Sn

(4 equiv.)

N

OH

Me2NO

H

HOMe

N

OH

Me2NO

H

HOMe

(+)-Cortistatin A


1:1 iPrOH/H2O50°C~50%

27Barton, D. H. R.; O’Brian, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470-476.

OH

Me2NO

H

HOMe O


OH

Me2NO

H

HOMe N NH2


EtOH, 50°C

OH

Me2NO

H

HOMe I


THF, 23°C

OH

Me2NO

H

HOMe N NH2

I IOH

Me2NO

H

HOMe N N

HI

H

NEt3

OH

Me2NO

H

HOMe N N

I

H

OH

Me2NO

H

HOMe N

N H

NEt3

OH

Me2NO

H

HOMe N

NOH

Me2NO

H

HOMe N

N

I

H H

NEt3

OH

Me2NO

H

HOMe I

2) I2 (2 equiv.)NEt3 (3 equiv.)

THF, 23°C

I I

28

FINAL STEPS


OH

Me2NO

H

HOMe O


H

AcO

O

OMe

OHMe2N

OAcAcO





23°C82%

OH

Me2NO

H

HOMe N NH2


EtOH, 50°C

OH

Me2NO

H

HOMe I


THF, 23°C


53%

NMe3Sn

(4 equiv.)

N

OH

Me2NO

H

HOMe

N

OH

Me2NO

H

HOMe

(+)-Cortistatin A


1:1 iPrOH/H2O50°C~50%

29

NICOLAOU/CHEN RETROSYNTHESISN

OH

Me2NO

H

HOMe

(+)-Cortistatin ASuzuki-Miyaura Cross-Coupling,Reduction

OH

Me OTfOO

Steps

OH

Me OTBSO

1,4-addition/aldol/dehydrationcascade

H

Me OTBSHO

O O

Sonogashira Cross-Coupling,Reduction

H

Me OTBSHO

H

S

SSteps

H

Me OTBSO

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

HOMe OTBSO

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 REACTIONO

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

HOO

O

O

O

O

NO

O

H

H2O

O

O

NO

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

Me OTBSO

H

Me OTBSOHO

OH

OsO4 (0.02 equiv.)NMO (2.5 equiv.)

8:1 acetone/H2O23°C73%

H

Me OTBSOO

OOs

O

Ohydrolysis

Me2C(OMe)2 (5 equiv.)p-TsOH (0.04 equiv.)

acetone, 23°C87%

H

Me OTBSO

O

O

NaHMDS (1.2 equiv.)PhNTf2 (1.1 equiv.)

H

Me OTBS

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

Me OTBS

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

Me OTBS

O

OMeO2C

DIBAL-H (3 equiv.)

toluene, -78°C79% H

Me OTBS

O

O

HO DMP (1.5 equiv.)NaHCO3 (4.6 equiv.)

CH2Cl2, 23°C86%

IO

O

OAcOAc

AcO

DMP =

H

Me OTBS

O

OOHC

HS(CH2)3SH (3 equiv.)BF3

.OEt2 (3.5 equiv.)CH2Cl2, -78°C

70%

H

Me OTBSHO

S

SHO

SO3.py (3 equiv.)

NEt3 (5 equiv.)

4:1 CH2Cl2/DMSO23°C72%

H

Me OTBSHO

S

SH

Op-TsN3 (1.5 equiv.)K2CO3 (3.5 equiv.)

1:1:3 MeCN/THF/MeOH23°C31%

OPO

OMeOMe

(1.5 equiv.)

H

Me OTBSHO

H

S

S

34

PARIKH-DOERING OXIDATIONSO3

.py (3 equiv.)NEt3 (5 equiv.)


H

Me OTBSHO

S

SH

OH

Me OTBSHO

S

SHO

Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-5507.

SO

OO

H

Me OTBSHO

S

SHO

SO

SO

OON

SO

OOO

S H

Me OTBSHO

S

SO

S HHH

H H

Et3N

H

Me OTBSHO

S

SO

S HHH

Me OTBSHO

S

SH

O

- 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

Me OTBS

O

OMeO2C

DIBAL-H (3 equiv.)

toluene, -78°C79% H

Me OTBS

O

O

HO DMP (1.5 equiv.)NaHCO3 (4.6 equiv.)

CH2Cl2, 23°C86%

IO

O

OAcOAc

AcO

DMP =

H

Me OTBS

O

OOHC

HS(CH2)3SH (3 equiv.)BF3

.OEt2 (3.5 equiv.)CH2Cl2, -78°C

70%

H

Me OTBSHO

S

SHO

SO3.py (3 equiv.)

NEt3 (5 equiv.)


H

Me OTBSHO

S

SH

Op-TsN3 (1.5 equiv.)K2CO3 (3.5 equiv.)


OPO

OMeOMe

(1.5 equiv.)

H

Me OTBSHO

H

S

S

36Roth, G. J.; Liepold, B.; Müller, S. G.; Bestmann, H. J. Synlett 2004, 59-62.

H

Me OTBSHO

S

SH

O

p-TsN3 (1.5 equiv.)K2CO3 (3.5 equiv.)


OPO

OMeOMe

(1.5 equiv.)

H

Me OTBSHO

H

S

S

Me

S OON

NN

OPO

OMeOMe

H H

OPO

OMeOMe

H

Me

S OON

NN

O3CK

OPO

OMeOMe

H

Me

SO ON

NN

H-O3CK

OPO

OMeOMe

H

Me

SO OHN

NNO

PO

OMeOMe

HNN

O3CK

OPO

OMeOMe

NN

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.

OPO

OMeOMe

NNOMe

PO

MeOMeO

NN H

Me OTBSHO

S

S

HO H

MeOTBS

HO

S

SO

PO

MeOMeO

NN

H

MeOTBS

HO

S

S

OP

O

MeOMeO

NN

H

Me OTBSHO

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

Me OTBSHO

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

Me OTBSHO

S

S

O

H

Me OTBSHO

OHC

O

IBX (4 equiv.)

DMSO0 - 23°C

81%

IO

O

OOH

IBX =

H

Me OTBSHO

OOHC

Pd/BaSO4 (5% wt/wt, 0.24 equiv.)H2 atm, 1:1 MeOH/THF, 23°C

64%

39

H

Me OTBSHO

S

S

O

H

Me OTBSHO

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

Me OTBSOH

S

S

O

IO

O

OOH

H

Me OTBSOHS

O

IO

O

OOH

S

H

Me OTBSOH

O

IO

O

OOH

SSH

Me OTBSOH

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

Me OTBSHO

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

Me OTBSHO

S

S

O

H

Me OTBSHO

OHC

O

IBX (4 equiv.)

DMSO0 - 23°C

81%

IO

O

OOH

IBX =

H

Me OTBSHO

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

Me OTBSHO

O OK2CO3 (1.2 equiv.)

dioxane, 125°C52% H

Me OTBSO

O O

OH

Me OTBSO

OH

Me OTBSO OH

H

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.

OH

Me OTBSO

OH

Me OTBSOO

TMSO(CH2)2OTMS (5 equiv.)TMSOTf (1.5 equiv.)

CH2Cl2-60 to -10°C

OH

Me OHOOTBAF (7 equiv.)

THF, 23°C56% over 2 steps

OH

MeOO

SO3.py (6 equiv.)

NEt3 (10 equiv.)3:1 CH2Cl2/DMSO

23°C80%

OKHMDS (3 equiv.)PhNTf2 (5 equiv.)

THF, -78°CO

H

MeOOOTf


Pd(PPh3)4 (0.3 equiv.)K2CO3 (3 equiv.)

NB

(3.3 equiv.)

O

O

OH

MeOO

N

p-TsOH (1.5 equiv.)10:1 acetone/H2O

23°C88%

OH

Me

N

O

43

OH

Me OTBSO

OH

Me OTBSOO

TMSOOTMS

TMS OTf

OH

Me OTBSO

TMS

OH

Me OTBSOTMSOTMSO

TMSOTf

OH

Me OTBSOTMSOTMSO

TMS OTf

OH

Me OTBSOTMSOTMSO

TMS

OH

Me OTBS

- (TMS)2O

O

TMSO

OH

Me OTBSOO

TMS

OTf

TMSOTf

Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357-1358.

OH

Me OTBSO

OH

Me OTBSOO


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.

OH

Me OTBSO

OH

Me OTBSOO


CH2Cl2-60 to -10°C

OH

Me OHOOTBAF (7 equiv.)


OH

MeOO

SO3.py (6 equiv.)

NEt3 (10 equiv.)3:1 CH2Cl2/DMSO

23°C80%

OKHMDS (3 equiv.)PhNTf2 (5 equiv.)

THF, -78°CO

H

MeOOOTf


Pd(PPh3)4 (0.3 equiv.)K2CO3 (3 equiv.)

NB

(3.3 equiv.)

O

O

OH

MeOO

N

p-TsOH (1.5 equiv.)10:1 acetone/H2O

23°C88%

OH

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.

OH

Me

N

OPd/C (0.3 equiv.)

H2 atm

MeOH23°C50%

OH

Me

N

O

1) TMSOTf (14 equiv.)NEt3 (30 equiv.)THF, -78 - 0°C

2) IBX.MPO (6 equiv.)DMSO, 23°C

46%

OH

Me

N

O


CH2Cl2, 0 - 23°C70%

OH

Me

N

O

O

NaBH4 (1 equiv.)CeCl3 (4 equiv.)

MeOH, 0°C40% of desired

OH

Me

N

OH

OMe2NH (2.0 M in THF)

80°C45% of desired

Ti(OiPr)4 (5 equiv.)

N

OH

Me2NO

H

HOMe

(+)-Cortistatin A

46

IBX AS AN ALTERNATIVE TO THE SAEGUSA OXIDATION

OH

Me

N

O



46%

OH

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

OH

Me

N

OSiMe3

IO

O

ON

O

MeO OH

Me

N

O

-HOSiMe3

IO

O

NO

MeO OH

Me

N

OO

H

IO

O

OH

Me

N

O

OHNO

OMe

47

FINAL STEPS


OH

Me

N

OPd/C (0.3 equiv.)

H2 atm

MeOH23°C50%

OH

Me

N

O



46%

OH

Me

N

O


CH2Cl2, 0 - 23°C70%

OH

Me

N

O

O



OH

Me

N

OH

OMe2NH (2.0 M in THF)80°C

45% of desired


N

OH

Me2NO

H

HOMe

(+)-Cortistatin A

48

FINAL STEPS


OH

Me

N

OPd/C (0.3 equiv.)

H2 atm

MeOH23°C50%

OH

Me

N

O



46%

OH

Me

N

O


CH2Cl2, 0 - 23°C70%

OH

Me

N

O

O



OH

Me

N

OH


45% of desired


N

OH

Me2NO

H

HOMe

(+)-Cortistatin A

« Chem3D Embed »

49

FINAL STEPS


OH

Me

N

OPd/C (0.3 equiv.)

H2 atm

MeOH23°C50%

OH

Me

N

O



46%

OH

Me

N

O


CH2Cl2, 0 - 23°C70%

OH

Me

N

O

O



OH

Me

N

OH


45% of desired


N

OH

Me2NO

H

HOMe

(+)-Cortistatin A

50

SHAIR RETROSYNTHESISOTBS

OAc

Me2NO

H

AcOMe

N

OH

Me2NO

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

Me OTBSO

Steps


51

THE AZA-PRINS REACTION


N N N Nu NNu

OAc

H

Me OTBS

ORN

Me

Me

OAc

OTBSOAc

Me2NO

H

AcOMe

lewis acid

52

POTENTIAL PITFALLS OF THE REACTION


OTBSOAc

NRO

H

AcO Me

Me

MeH

OTBSOAc

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


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

Me2NO

H

AcOMe

54

CONCLUSION1) May 14th, 2008 - Phil Baran

2) August 14th, 2008 - K.C. Nicolaou and David Chen

3) November 19th, 2008 - Matthew Shair


N

OH

Me2NO

H

HOMe

H

Me

OH

OOH

OMe

O

HH

Baran15 steps

1.0% overall yield

Me OTBSO

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-SABEHProf. Keith FagnouNot shown:Michelle KUHNKevin BURGESS

ACKNOWLEDGMENTS

Total Synthesis of (+)- Cortistatin A

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