Synlett 2002(10): 1665-1668
DOI: 10.1055/s-2002-34247
LETTER
© Georg Thieme Verlag Stuttgart · New York

Lipase-catalyzed Transesterification of Methyl 2-Substituted 3-Hydroxy-4-pentenoates and its Synthetic Application to the Taxol Side Chain

Tadakatsu Mandai*, Tetsuta Oshitari, Masafumi Susowake
Department of Chemistry and Bioscience, Kurashiki University of Science and the Arts, 2640 Nishinoura, Tsurajima, Kurashiki 712-8505, Japan
Fax: +81(86)4401062; e-Mail: ted@chem.kusa.ac.jp;
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Publikationsverlauf

Received 20 August 2002
Publikationsdatum:
23. September 2002 (online)

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Abstract

Syn-and anti-methyl 2-substituted 3-hydroxy-4-pentenoates were efficiently resolved in lipase-catalyzed transesterification. This protocol was successfully applied to the synthesis of the taxol side chain.

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For instance, compounds 1b and 4b were prepared as follows. A solution of methyl 4-methylvalerate (7.48 g, 57.5 mmol) in THF (20 mL) was added dropwise to a solution of LDA (60.3 mmol) in hexane (38.7 mL)/THF (50 mL) at
-78 °C and the mixture was stirred for 1 h. Then, acrolein (4.61 mL, 68.9 mmol) was added and the mixture was stirred at -78 °C for 2 min. After usual workup, the oil obtained was purified by medium-pressure column chromatography (Yamazen, Ultra PackTM,  50 × 300 mm, hexane/ethyl acetate = 6:1˜4:1 as eluent) to afford the less polar syn-racemate 1b (5.03 g, 27.0 mmol, 47% yield) and the more polar anti-racemate 4b (4.70 g, 25.2 mmol, 44% yield). Each compound can easily be discriminated by the chemical shifts of methine protons at 2- and 3-positions in 1H NMR spectra (CDCl3, 500 MHz) : δ 2.62-2.68 (m, 1 H, CHCOO) and 4.28-4.33 (m, 1 H, CHOH) for 1b, and δ 2.58-2.63 (m, 1 H, CHCOO) and 4.14-4.20 (m, 1 H, CHOH) for 4b. The chemical shifts of the methine protons at 2- and 3-positions of 1 are generally observed in the down field compared with those of 4. Additionally, syn-racemates 1 are generally less polar than anti-racemates 4 on TLC analysis (hexane/ethyl acetate = 5:1˜3:1).

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The quantity of the lipase was not optimized. The lipase collected was washed with ether, dried in air for 5 min and stored below 5 °C. The lipase retains full activity and can be reused at least three times.