epothilones thomas
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EpothilonesEpothilones
Th K i kiThomasKaminskiNovember 3,2008
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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
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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)( )
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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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