Enzymatic resolution to (-)-ormeloxifene intermediates from their racemates using immobilized Candida rugosa lipase

Citation
Sv. Lehmann et al., Enzymatic resolution to (-)-ormeloxifene intermediates from their racemates using immobilized Candida rugosa lipase, CHIRALITY, 12(7), 2000, pp. 568-573
Citations number
13
Categorie Soggetti
Chemistry & Analysis
Journal title
CHIRALITY
ISSN journal
08990042 → ACNP
Volume
12
Issue
7
Year of publication
2000
Pages
568 - 573
Database
ISI
SICI code
0899-0042(2000)12:7<568:ERT(IF>2.0.ZU;2-L
Abstract
In the synthesis of (-)-ormeloxifene, a drug candidate recently under devel opment, enzymatic resolution of potential intermediates can be carried out using a simple, practical method. Five commercially available lipases, Cand ida rugosa lipase, Candida antarctica lipase B, Mucor miehei lipase, Pseudo monas cepacia lipase, and Humicola lanuginosa lipase, all immobilized on Ac curel(R), were initially screened in combination with four different substr ates belonging to the class of phenyl esters. Excellent stereoselectivity w as observed using C. rugosa lipase with an acetate as substrate, but low re action rates were observed in scale-up experiments. However, by changing th e acyl part of the ester into a hexanoyl moiety and subjecting this substra te to enzymatic hydrolysis in aqueous acetonitrile at room temperature by C . rugosa lipase, it became possible to run the reaction to a 50% conversion on a 10 g scale within a period of 4 h, obtaining a phenolic product of mo re than 95% ee that could be converted to the target molecule, (-)-ormeloxi fene, in two synthetic steps. Simple recovery of the immobilized enzyme by filtration allowed multiple recycling of the catalyst without significant l oss of enzymatic activity. Capillary electrophoresis with sulfobutyl ether beta-cyclodextrin as a chiral buffer additive and acetonitrile as an organi c modifier was demonstrated to provide an excellent chiral analytical tool for monitoring the enzymatic reactions. (C) 2000 Wiley-Liss, Inc.