Synthesis of Taxol

Structure of Taxol

C47H51NO14

Principal investigator	Kyriacos C. Nicolaou
Publication year	1994
Synthesis type	Total
Number of steps	40 (3 parts)
References	Nature 1994, 367, 630. J. Am. Chem. Soc. 1994, 116, 591. J. Chem. Soc., Chem. Commun. 1993, 1024. J. Chem. Soc., Chem. Commun. 1992, 1117. J. Chem. Soc., Chem. Commun. 1992, 1118.

Part 1 of 3

intermediate structure

2-Chloroacrylonitrile

Sealed tube

PhH

130 °C, 72 h, 85%

See the Diels-Alder Reaction

intermediate structure

KOH

t-BuOH

65 °C, 3 h, 50%

intermediate structure

TBSCl

CH2Cl2

RT, 60 min, 100%

intermediate structure

+

intermediate structure

THF

RT, 3 h, 80%

intermediate structure

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Part 2 of 3

intermediate structure

+

intermediate structure

Neopentyl glycol, PhB(OH)2

Dean-Stark

PhH

RT to Reflux, 48.5 h, 61%

See the Diels-Alder Reaction

intermediate structure

TBSOTf, DMAP, 2,6-Lutidine

CH2Cl2

0 °C, 4 h, 95%

intermediate structure

LiAlH4

Et2O

0 °C, 60 min, 94%

intermediate structure

Camphorsulfonic acid

MeOH

RT, 60 min, 90%

intermediate structure

TBDPSCl, Imidazole

DMF

RT, 6 h, 92%

intermediate structure

n-Bu4N+ I-, KH, BnBr

Et2O

RT, 2 h, 87%

See the Williamson Ether Synthesis

intermediate structure

LiAlH4

Et2O

RT, 12 h, 80%

intermediate structure

2,2-Dimethoxypropane, Camphorsulfonic acid

CH2Cl2

RT, 7 h, 82%

intermediate structure

NMO, n-Pr4N+ RuO4-

MeCN

RT, 2 h, 95%

See the Ley-Griffith Oxidation

intermediate structure

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Part 3 of 3

intermediate structure

+

intermediate structure

n-BuLi

THF

-78 °C to RT, 30 min, 82%

See the Shapiro Reaction

intermediate structure

VO(acac)2, t-BuOOH

4 Å MS

PhH

RT, 12 h, 87%

intermediate structure

LiAlH4

Et2O

RT, 7 h, 76%

intermediate structure

KH, Phosgene

Et2O, HMPA

RT, 2 h, 48%

intermediate structure

n-Bu4N+ F-

THF

RT, 7 h, 80%

intermediate structure

n-Pr4N+ RuO4-, NMO

CH2Cl2, MeCN

RT, 2 h, 82%

See the Ley-Griffith Oxidation

intermediate structure

Zn-Cu, (TiCl3)2.2DME

DME

70 °C, 60 min, 23%

See the Pinacol Coupling

intermediate structure

+

intermediate structure

43%

"Also isolated was the correponding diastereoisomer (43% yield)."

intermediate structure

K2CO3

MeOH

90%

intermediate structure

DMAP, Ac2O

CH2Cl2

RT, 2 h, 95%

intermediate structure

n-Pr4N+ RuO4-, NMO

MeCN

RT, 2 h, 93%

See the Ley-Griffith Oxidation

intermediate structure

BH3.THF
H2O , H2O2

THF

0 °C, 2.5 h, 55%

intermediate structure

HCl

H2O, MeOH

RT, 5 h, 80%

intermediate structure

DMAP, Ac2O

CH2Cl2

RT, 30 min, 95%

intermediate structure

Pd/C, H2

EtOAc

RT, 30 min, 97%

intermediate structure

TESCl

Pyr

RT, 12 h, 85%

intermediate structure

K2CO3

MeOH

0 °C, 15 min, 95%

intermediate structure

TMSCl, Pyr

CH2Cl2

0 °C, 15 min, 96%

intermediate structure

Tf2O, i-Pr2NEt

CH2Cl2

RT, 30 min, 70%

intermediate structure

Camphorsulfonic acid

MeOH

10 min

intermediate structure

SiO2

CH2Cl2

4 h, 60% (2 steps)

intermediate structure

DMAP, Ac2O

CH2Cl2

RT, 4 h, 94%

intermediate structure

PhLi

THF

-78 °C, 10 min, 80%

intermediate structure

Celite, HCrO3Cl.Pyr, NaOAc

PhH

Reflux, 60 min, 75%

intermediate structure

NaBH4

MeOH

RT, 5 h, 83%

intermediate structure

+

intermediate structure

TMS2NNa

THF

0 °C, 78%

"87 % yield at 90 % conversion."

intermediate structure

Pyr.HF

THF

RT, 90 min, 80%

intermediate structure

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