Tetrahedron Letters 41 (2000) 4729±4731
Stereospeci®c synthesis of the major human metabolite
of paclitaxel
Mark D. Wittman,* John F. Kadow and Dolatrai M. Vyas
Bristol-Myers Squibb Pharmaceutical Research Institute, Division of Chemistry, PO Box 5100, Wallingford,
CT 06492-7660, USA
Received 8 November 1999; revised 21 April 2000; accepted 24 April 2000
Abstract
The stereospeci®c synthesis of 6-a-hydroxy paclitaxel 10, the major human metabolite of paclitaxel, is
described. The 6,7-a-diol 4, obtained from paclitaxel, is converted to the 6,7-b-cyclic sulfate followed by
nitrate addition and reduction to aord the title compound. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: taxoids; diols; oxidation; nitrates; inversion reactions; metabolites.
The expanding clinical use of TAXOL1 in cancer chemotherapy has fueled an aggressive search
within the medicinal chemistry community for second-generation taxanes with improved safety,
ecacy, and pharmacokinetics. We required a supply of 6-a-hydroxy paclitaxel 10, the major
human metabolite of paclitaxel,1 to validate our in vitro assays for the human metabolism of
paclitaxel and to evaluate analogs for improved metabolic stability.
Initially, we focused on the epimerization of the silylated a-diol 1 (4, TESCl, imidazole,
CH2Cl2) (Scheme 1). Treatment with KHMDS at 0ꢀC gave a mixture of epimers at C-7, which
could not readily be separated. The mixture was then deprotected to give the desired 6-a-hydroxy
paclitaxel 3 in 9% yield with 26% of the deprotected a-diol 2. Due to the low yield of product
and poor recovery of 2, we did not pursue a base-induced epimerization of this substrate. King-
ston2 has reported the epimerization of the 20-OTBS ether derivative of diol 2 using DBU to
obtain the 20-OTBS 6-a-hydroxy paclitaxel in 15% yield along with recovered starting diol.
Alternatively, we found that if the 6-a-hydroxyl group of 4 was protected as a phenoxyacetate
or acetate, a silylative epimerization could be aected using TESCl and imidazole at elevated
temperatures to aord derivatives 5. This process is likely driven by the fact that the C-7-a
hydroxyl is too hindered to react with silylating agents so that any epimerization is quickly trapped
with silyl chloride. Various attempts to remove the esters (K2CO3, MeOH; KCN, MeOH; Ti(OEt)4,
EtOH) from 5 resulted in removal of both the protecting group and silyl group and re-epimerization
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00707-3