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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
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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
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http://www.scripps.edu/nicolaou/
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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
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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 HO
O
TPSO
OBnO
OOTBS
NNHSO2Ar
n-BuLiTHF
OTBS
Li
H
OLi
HH H
OTPS
NuRe face
Si face
-
Sharpless Epoxidation
TBSOOBn
OH HO
O
TPSO VO(acac)2t-BuOOHbenzene
TBSOOBn
OH HO
O
TPSO
O
LiAlH4, Et2O
TBSOOBn
OH HO
O
TPSO
HO
KHEt2O, HMPA
COCl2
TBSOOBn
H O
O
TPSO
O O
O
TBAF, THF
HOOBn
H O
O
HO
O O
O
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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
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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
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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
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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
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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
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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)
