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Enzymatic resolution to (−)‐ormeloxifene intermediates from their racemates using immobilized Candida rugosa lipase
Author(s) -
Lehmann Søren Vig,
Breinholt Jens,
Bury Paul Stanley,
Nielsen Thomas Eiland
Publication year - 2000
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/1520-636x(2000)12:7<568::aid-chir4>3.0.co;2-u
Subject(s) - candida rugosa , chemistry , lipase , triacylglycerol lipase , substrate (aquarium) , diisopropyl ether , hydrolysis , chromatography , candida antarctica , organic chemistry , acetonitrile , immobilized enzyme , rhizomucor miehei , ether , enzyme , oceanography , geology
In the synthesis of (−)‐ormeloxifene, a drug candidate recently under development, enzymatic resolution of potential intermediates can be carried out using a simple, practical method. Five commercially available lipases, Candida rugosa lipase, Candida antarctica lipase B, Mucor miehei lipase, Pseudomonas cepacia lipase, and Humicola lanuginosa lipase, all immobilized on Accurel®, were initially screened in combination with four different substrates belonging to the class of phenyl esters. Excellent stereoselectivity was observed using C. rugosa lipase with an acetate as substrate, but low reaction rates were observed in scale‐up experiments. However, by changing the acyl part of the ester into a hexanoyl moiety and subjecting this substrate 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 more than 95% ee that could be converted to the target molecule, (−)‐ormeloxifene, in two synthetic steps. Simple recovery of the immobilized enzyme by filtration allowed multiple recycling of the catalyst without significant loss of enzymatic activity. Capillary electrophoresis with sulfobutyl ether β‐cyclodextrin as a chiral buffer additive and acetonitrile as an organic modifier was demonstrated to provide an excellent chiral analytical tool for monitoring the enzymatic reactions. Chirality 12:568–573, 2000. © 2000 Wiley‐Liss, Inc.