Taxol Semisynthesis: A Highly Enantio- and Diastereoselective Synthesis of the Side Chain and a New Method for Ester Formation at C-13 Using Thioesters
A very simple, new, and straightforward approach to the Paclitaxel (Taxol) and Docetaxel (Taxotere) side chains has been developed using the imine addition reaction of thioester-derived boron enolates bearing chiral ligands. The addition reaction was studied extensively, using a combination of diffe...
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| Published in: | Journal of organic chemistry Vol. 62; no. 14; pp. 4746 - 4755 |
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| Main Authors: | , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
American Chemical Society
11-07-1997
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| Online Access: | Get full text |
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| Summary: | A very simple, new, and straightforward approach to the Paclitaxel (Taxol) and Docetaxel (Taxotere) side chains has been developed using the imine addition reaction of thioester-derived boron enolates bearing chiral ligands. The addition reaction was studied extensively, using a combination of different thioesters (ROCH2COSPh, ROCH2COSt-Bu), oxygen protecting groups (R = Bn, TBDMS, COPh, EE, TMS), chiral boron ligands [derived from both (−) and (+)-menthone], imines (PhCHNSiMe3, PhCHNCOPh), and in the presence or in the absence of additional Lewis acids (BF3−OEt2, Et2AlCl, TiCl4). The side chain was assembled in a few steps with the correct relative (syn) and absolute stereochemistry (2R,3S). The stereochemical outcome of the boron-mediated reaction was rationalized using chair vs boat transition state structures. A new direct route for attachment of the side chains to the baccatin nucleus using thioester chemistry has also been developed. By treatment of a mixture of a thioester (8, 12, or 17) and protected baccatin III (2b, 2c) with LHMDS, the 13-O acylated compounds were obtained in high yield (up to 90%). Hydrolysis of 18b gave Paclitaxel (1a) in 80% yield. |
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| Bibliography: | ark:/67375/TPS-FHN2T4NZ-7 Abstract published in Advance ACS Abstracts, June 15, 1997. istex:42CF0DA508EF1B3423E9E3779D4D9548CEBF5E16 |
| ISSN: | 0022-3263 1520-6904 |
| DOI: | 10.1021/jo9703212 |