taxol total synthesis - university of delaware · •convergent synthesis •took two years from...
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Total Synthesis of Taxol
K.C. Nicolaou, Z. Yang, J.J. Liu, H. Ueno, P.G.Nantermet, R.K. Guy, C.F. Claiborne, J. Renaud,E.A. Couladouros, K. Paulvannan, E.J. Sorenson
Nature. 1994, 367, 630
K.C. Nicolaou• Kyriacos Costa Nicolaou born in
Cyprus 1946• B.Sc. 1969: Bedford College• Ph.D. 1972: University College
London under F. Sondheim and P.J.Garratt
• Post-doc 1973 with T.J. Katz(Columbia) and 1976 E.J. Corey(Harvard)
• 1976-1989: UPenn faculty• 1989-present: Faculty at UC San
Diego and The Scripps ResearchInstitute
http://www.scripps.edu/nicolaou/
Taxol
• Extracted from the bark of the Pacific Yew tree• Used for the treatment of ovarian, breast, lung and
melanoma cancer
OH
O
AcO O
HO OBzH OAc
OHN
O
Ph O
OHPh
Retrosynthetic Analysis
Forward Synthesis
OO
O B
O
EtO2C
Ph
[4+2]O
OO B
O
EtO2C
Ph
HO OH
OOH
HOH
HOEtO2C
OO
OHO
EtO
OH
CO2Et
HO O
OHO
PhB(OH)2, PhH
HO OH
+
OO
OHO
EtO
OH
Forward Synthesist-BuMe2SiOTf
2,6-lutidineDMAPCH2Cl2
O
OTBSO
EtO
OTBS
LiAlH4, Et2O
O
OTBS
HO
OTBS
O OO
O
OAcO
EtO
OH
CSACH2Cl2, MeOH
O
OH
OTBSO
OH
O
OH
OTBSO
TPSClimidazole
DMF
TPSOKH
PhCH2Brn-Bu4NI
Et2O
O
OBn
OTBSO
TPSO
Forward Synthesis
O
OBn
OTBSO
TPSO
LiAlH4Et2O
OBn
OH
TPSO
OHOH
MeO OMeCSA
CH2Cl2, Et2O
OBn
O
TPSO
OHO
TPAP, NMOCH3CN
OBn
O
TPSO
OO
Shapiro ReactionOBn
O
TPSO
OO
+
OTBS
NNHSO2Ar
n-BuLiTHF
TBSOOBn
OH H O
O
TPSO
OBnO
OOTBS
NNHSO2Ar
n-BuLiTHF
OTBS
Li
H
OLi
HH H
OTPS
NuRe face
Si face
Sharpless Epoxidation
TBSOOBn
OH H O
O
TPSO VO(acac)2t-BuOOHbenzene
TBSOOBn
OH H O
O
TPSO
O
LiAlH4, Et2O
TBSOOBn
OH H O
O
TPSO
HO
KHEt2O, HMPA
COCl2
TBSOOBn
H O
O
TPSO
O O
O
TBAF, THF
HOOBn
H O
O
HO
O O
O
McMurry CouplingHO
OBn
H O
O
HO
O O
O
TPAP, NMOCH3CN, CH2Cl2
OOBn
H O
O
O
O O
O
TiCl3 (DME)Zn-CuDME
OBn
H O
OO O
O
HO OH
Kinetic resolution
Ac2O, DMAPCH2Cl2
OBn
H O
OO O
O
AcO OH
TPAP, NMOCH3CN
OBn
H O
OO O
O
AcO O
Forward Synthesis
OBn
H O
OO O
O
AcO OOBn
H O
OO O
O
AcO OBH3 THF
H2O2, NaHCO3
OH
HCl, MeOHH2O
OBn
H OH
OHO O
O
AcO O
OH
OBn
H OH
OAcO O
O
AcO O
OH
Ac2O, DMAPCH2Cl2
H2, Pd(OH)2(C)EtOAc
OH
H OH
OAcO O
O
AcO O
OH
Forward Synthesis
OH
H OH
OAcO O
O
AcO O
OH
TESClpyridine
OTES
H OH
OAcO O
O
AcO O
OH
K2CO3MeOH
OTES
H OH
OHO O
O
AcO O
OH
TMSClpyridine
CH2Cl2
OTES
H OH
OTMSO O
O
AcO O
OH
OTES
H OH
OTMSO O
O
AcO O
OTf
Tf2Oi-PrNEtCH2Cl2
Forward Synthesis
OTES
H OH
OTMSO O
O
AcO O
OTf
CSAMeOH
OTES
HO O
O
AcO O
OOH
Ac2O, DMAPCH2Cl2
OTES
HO O
O
AcO O
OOAc
C6H5LiTHF
OTES
HHOBzO
AcO O
OOAc
OTES
HHOBzO
AcO O
OOAc
PCCNaOAcbenzene O
Forward Synthesis
OTES
HHOBzO
AcO O
OOAc
O
OTES
HHOBzO
AcO O
OOAc
NaBH4MeOH
HONBzO
PhTESO
NaN(SiMe3)2THF
OTES
HHOBzO
AcO O
OOAc
O
O
PhOTES
NHPh
O
HF pyridineTHF
OH
HHO HO
AcO O
OOAc
O
O
PhOH
NHPh
O
Taxol
Conclusion
“Offers a solution to formidable synthetic challenge”• Convergent synthesis• Took two years from conception to completion• “May enable researchers to devise more effective,
less toxic drugs of the taxol class” (C&EN, vol. 72,pp. 32-43)
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