Sv. Lehmann et al., Enzymatic resolution to (-)-ormeloxifene intermediates from their racemates using immobilized Candida rugosa lipase, CHIRALITY, 12(7), 2000, pp. 568-573
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.