EpothilonesEpothilones

Th K i kiThomasKaminskiNovember 3,2008

1CopyrightUMR6510 ThomasKaminski2008

EpothilonesEpothilones

Epoxide functionThiazole groupKetone function

Epothilone

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EpothilonesEpothilonesR

OH

S

N

X

O

OO OH

Various Epothilones:

Epothilone A, R = H, X = H

Epothilone B, R = Me, X = H

Epothilone C, R = H, X = H

Epothilone D, R = Me, X = Hp

Epothilone E, R = H, X = OH

Epothilone F, R = Me, X = OH

p

Desoxyepothilone E, R = H, X = OH

Desoxyepothilone F, R = Me, X = OH

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EpothilonesEpothilones1987: First isolation at GBF (Gesellschaft fr Biologisch-chemischeForschung at Braunschweig, Germany) from the soil bacteriumSorangium cellulosum So ce90

OS

O

OH

S

N

OO OHEpothilone AEpothilone B

1996: The structure of epothilone A was determined using x-ray

Antifugal activity

crystallography

Hfle, G.; Bedorf, N.; Steinmertz, H.; Schomburg, D.; Gerth, K.; Reichenach, H. Angew. Chem. 1996, 35, 1567.Hfle, G. Bedorf, N.; Gerth, K.; Reichenbach, H. (GBF), DE-B 4138042, 1993.

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EpothilonesEpothilones1993: Epo A & Epo B are more active than Taxol (MSD chemists)1993: Epo A & Epo B are more active than Taxol (MSD chemists)

OS

O

OO

OHN

OH

Epothilone A Epothilone B10 times more active than taxol Taxol

Epothilones are active against Taxol resistant cancer cell lines

Structure simple / Taxol structure

Bollag, D.M.; McQuenay, P.A.; Zhu, J.; Lazarides, E.; Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Woods, C. Cancer Res. 1995, 55, 2325.

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EpothilonesEpothilones

1996-1997: Publications of the first total synthesis by the groups of Danishefsky, Nicolaou and Schinzer

16 approaches have been reported for Epo A & C 20 for Epo B & D16 approaches have been reported for Epo A & C, 20 for Epo B & D

Fl ibilit f th i thFlexibility of the various syntheses

Designed firstforEpoA&C

AccesstoEpoC&Dwithout majortransformations

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SynthesesSynthesesRing Closure MetathesisRing Closure Metathesis

Danishefsky,Nicolaou,SchinzerMacrolactonizationInanaga, J; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn., 1979, 52, 1989.

y, ,

Danishefsky,Nicolaou

Macroaldolization

Danishefsky 7CopyrightUMR6510 ThomasKaminski2008

DanishefskyDanishefsky

BuildingBlocC12C21Keyintermediates

Building Bloc C3C11BuildingBlocC3 C11

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DanishefskyDanishefskyMacroaldolization

1) 9-BBN TBSO N

S1) KHMDS2) HF-py3) TBSOTf

TBSO

11

N

S

OAc

H

I2)

PdCl (dppf) CsCO Ph As (75%)

TPSO O

O

O

3) TBSOTf

47%TPSO OMe

OMe3

PdCl2(dppf), CsCO3, Ph3As (75%)

3) p-TsOH (85%)

SSS

OTBSO

OTBS

O

N

OO

: = 6:1

HO

OH

O

N

S

OO

84%DMDO

49%

HO

OH

O

N

S

OO : 6:1Epo CEpo A

Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su, D.-S., Sorensen, E.J.; Danishefsky, S.J. Angew. Chem. Int. Ed. 1996, 35, 2801.Stachel, S.J.; Danishefsky, S.J. Tetrahedron Lett. 2001, 42, 6785.

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DanishefskyDanishefskyMacrolactonization:Yamaguchilactonization

TBSOTBSO

OTBS

1) 9-BBN2)

N

S

OAc

H

I6 steps

TPSO OMe

OMeOTBSO

OTBS

O

3) p-TsOH4) K2CO3, MeOH, H2O

PdCl2(dppf), CsCO3,Ph3As

OAc

56%

47%

S S

CO2HOH

NTBSO

O OTBS

1) Yamaguchi-lact.2) HF-py

86%O

NHO

O OH O

E CEpo C

Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, E.J.; Sorensen, E.J.; Danishefsky, S.J. J. Am. Chem. Soc. 1997, 119, 10073.

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DanishefskyDanishefskyRCM

R=H Epothilone C Epothilone A

R=CH3 Epothilone D Epothilone B

Bertinato, P.; Sorensen, E.J.; Meng, D.; Danishefsky, S.J. J. Org. Chem. 1996, 61, 8000.Meng, D.; Su, D.-S.; Balog, A.; Bertinato, P; Sorensen, S.J.; Danishefsky, S.J.; Zheng, H.; Chou, T.C.; He, L.; Horwitz, S.B. J. Am. Chem. Soc. 1997, 119, 2733.

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DanishefskyDanishefskyRCM

O

TBSO N

S

Grubbs IO

TBSO N

S

HF-pyO

HO N

S

O

OTBSOO OTBS

OO

86%

OHOO

90%

E / Z 1 1 7 E thil CE/Z =1:1.7 Epothilone C

epoxidationepoxidation

Epothilone Ap

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DanishefskyDanishefskyRCM

E / Z 1 1 E thil DE/Z =1:1 Epothilone D

epoxidationepoxidation

Epothilone Bp

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DanishefskyDanishefskyRCM Epothilone D

Chappell, M.D.; Stachel, S.J.; Lee, C.B.; Danishefsky, S.J. Org. Lett. 2000, 2, 1633.Rivkin, A.; Njardarson, J.T.; Biswas, K.; Chou, T.-C.; Danishefsky, S.J. J. Org. Chem. 2002, 67, 7737.Rivkin, A.; Cho, Y.S.; Gabarda, A.E.; Yoshimura, F.; Danishefsky, S.J. J. Nat. Prod. 2004, 67, 139.

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Nicolaou SynthesesNicolaou Syntheses

RCM

Macrolactonization

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NicolaouNicolaouRCM

Nicolaou, K.C.; He, Y.; Vourloumis, D.; Vallberg, H.; Yang, Z. Angew. Chem., Int. Ed. 1996, 35, 2399.16

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NicolaouNicolaouRCM:Epothilone A&C

SS12

8

S

HF-pyO

HO

OHO

N

O

N

O

HO

OOTBS

O

158

63

N

O

HO

OOTBS

O85%

DMDO

65%

HO N

SO

O

HO

OHO

N

O

( : = 3 : 1)( )

17CopyrightUMR6510 ThomasKaminski2008

NicolaouNicolaouSolid phasesynthesis Epothilone C

1) NaHMDS,

Cl 1,4-butanediolNaH, Bu4NI

OOH

1) I2, PPh3,imidazole

2) PPh3O

PPh3I 2) HF-py

OTBSO

H7

12

O

123) Swern

(67%)H

O

7

1

LDA, ZnCl2(90%)

O OTBSCO2H6

O

HO 712

N

SO

HO

N

S

OHO

HO N

S

1) Grubbs I2) TFA

O OTBSCO2H61DCC, DMAP

(80 %)OOTBS

O

O

OH OO 14 %

EpoC

Nicolaou, K.C.; Sarabia, F.; Ninkovic, S.; Yang, Z. Angew. Chem., Int. Ed. 1997, 36, 525.18

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NicolaouNicolaouMacrolactonization :Epothilone C&D

N

SPh3P

I

13 21

NaHMDS,OTBS

O

H

127

N

S

TBSO

1)

OHO3SN

S

O

OTBS

I77% OTBS

Z / E = 9 : 12) SO3-py, DMSO

(81%)OTBS

H

CO2H6 1

9 steps

S

O OTBSCO2H

3 steps

SSNEtO2C N

S

OTBSTBSO

O OTBSCO2H6

71) TBAF

2) COClClCl

N

S

TBSO

O

O

O O OTBS

1 : 1 mixture with 6S, 7RClCl

ClDMAP, Et3N

OOTBS

O

Nicolaou, K.C.; He, Y.; Vourloumis, D.; Vallberg, H.; Yang, Z. Angew. Chem., Int. Ed. 1996, 35, 2399.19

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NicolaouNicolaouMacrolactonization :Epothilone C&D

EpoC EpoASimilar synthesis forEpothilone D&B

Nicolaou, K.C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J.I. J. Am. Chem. Soc. 1997, 119, 7960.

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SchinzerSchinzer

The3rd tocomplete syntheses of

R

OH

SX

O

OO

OHN

OH OO OH

Epothilone A, R = H, X = H Epothilone C, R = H, X = H

Epothilone B, R = Me, X = H Epothilone D, R = Me, X = H

Schinzer, D.; Limberg, A.; Boehm, O.M. Chem.- Eur. J. 1996, 2, 1477.Schinzer, D.; Limberg, A.; Bauer, A.; Boehm, O.M.; Cordes, M. Angew. Chem., Int. Ed. 1997, 236, 523.

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SchinzerSchinzerSynthesis ofEpothilone A(+Epothilone C)RCM

HF, MeCN, Et2O(65%)

epoxidation

EpoC EpoA48% 22

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Others synthesesOthers syntheses

Schinzer:based onaZnmodificationofDanishefsky's BAlkylSuzukicoupling

AccesstoEpothilone B

Schinzer, D.; Bauer, A.; Boehm, O.M.; Limberg, A.; Cordes, M. Chem.- Eur. J. 1999, 5, 2483.23

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Others synthesesOthers synthesesFrstner 's RCMFrstner sRCM

Epothilone Csynthesis

Frstner, A.; Mathes, C.; Grela, K. Chem. Commun. 2001, 1057.Frstner, A.; Mathes, C.; Lehmann, C.W. Chem.-Eur. J. 2001, 7, 5299.

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Others synthesisOthers synthesis

Mulzer :3differents approaches Epothilone B&D

Mulzer, J.; Mantoulidis, A. Tetrahedron Lett. 1996, 37, 9179.Mulzer, J.; Mantoulidis, A.; hler, E. Tetrahedron Lett. 1997, 38, 7725.Mulzer, J.; Mantoulidis, A.; hler, E. Tetrahedron Lett. 1998, 39, 8633.Mulzer, J.; Mantoulidis, A.; hler, E. J. Org. Chem. 2000, 65, 7456.

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Others synthesisOthers synthesis

Carreira :Epothilone A&B

Bode, J.W.; Carreira, E.M. J. Org. Chem. 2001, 66, 6410.Bode J W ; Carreira E M J Am Chem Soc 2001 123 3611Bode, J.W.; Carreira, E.M. J. Am. Chem. Soc. 2001, 123, 3611.Blackman, B.; Georg, G.I. Chemtracts. 2003, 16, 97.

Sinha:Epothilone Bp

Sinha, S.C.; Barbas III, C.F.; Lerner, R.A. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 14603.Sinha, S.C.; Sun, J.; Miller, G.P.; Barbas III, C.F.; Lerner, R.A. Org. Lett. 1999, 1, 1623.Sinha, S.C.; Sun, J.; Miller, G.P.; Wartmann, M.; Lerner, R.A. Chem.-Eur. J. 2001, 7, 1691.S J Si h S C A Ch I t Ed 2002 41 1381Sun, J.; Sinha, S.C. Angew. Chem. Int. Ed. 2002, 41, 1381.

Shibasaki:Epothilone C

Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49, 511.Sawada, D.; Shibasaki, M. Angew. Chem. Int. Ed. 2000, 39, 209.Hamashima, Y.; Sawada, D.; Nagomi, H.; Kanai, M.; Shibasaki, M. Tetrahedron. 2001, 57, 805.Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 10521.

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Others synthesisOthers synthesis

E.J.Thomas:Epothilone D

Martin, N.; Thomas, E.J. Tetrahedron Lett. 2001, 42, 8373

Ley:Epothilone A&Cusing immobilized reagent andscavengers

Storer, R.J.; Takemoto, T.; Jackson, P.S.; Ley, S.V. Angew. Chem. Int. Ed. 2003, 42, 2521.Storer, R.J.; Takemoto, T.; Jackson, P.S.; Brown, D.S.; Baxendale, I.R.; Ley, S.V. Chem.-Eur. J. 2004, 10, 2529.

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AcknowledgementsAcknowledgements

M l J t l C R Chi 2008 X d i 10 1016/j i 2008 02 005Mulzer J.etal.C.R.Chim. 2008,X,doi:10.1016/j.crci.2008.02.005

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