TETRAHEDRON: ASYMMETRY Tetrahedron: Asymmetry 14 (2003) 3111–3115 Pergamon Resolution of -methylene--hydroxy esters catalyzed by free and immobilized Pseudomonas sp. lipase M. G. Nascimento,* Sandra P. Zanotto, Sı ´lvia P. Melegari, Luciano Fernandes and Marcus Mandolesi Sa ´ Departamento de Quı ´mica, Universidade Federal de Santa Catarina, Trindade, Floriano ´polis, SC, Brazil 88040 -900 Received 7 May 2003; accepted 7 August 2003 Abstract—Kinetic resolutions of -methylene--hydroxy esters (Baylis–Hillman products) have been performed via enzymatic enantioselective transesterification with Pseudomonas sp. lipase (PSL), free or immobilized in poly(ethylene) oxide (PEO), silica gel and montmorillonite K10, under different reaction conditions. The corresponding (R )-(+)-acetates from alkyl-substituted racemic alcohols were obtained with e.e. >99% and excellent to moderate conversions using the PSL/PEO system and vinyl acetate as acylating agent, in hexane. A naphthyl-substituted hydroxy ester was inert under these experimental conditions. © 2003 Elsevier Ltd. All rights reserved. 1. Introduction -Methylene--hydroxy esters 1 are versatile building blocks for the synthesis of many important compounds such as natural products (kijanolide, 1 mycestericin E, 2 terpenticin, 3 necic acids, 4 terpenoids, 5 insect pheromones), 6,7 nitrogen-containing heterocycles 8–10 and other biologically-active molecules. 11,12 These mul- tifunctional compounds 1 are readily available by a unique synthetic transformation involving a nucleo- phile-catalyzed reaction of ,-unsaturated esters with aldehydes, the Baylis–Hillman reaction (Eq. (1)). 13–15 A convenient access to optically-active -methylene-- hydroxy esters 1, however, represents a challenging issue that has received increasing interest. 2,16 Asymmet- ric versions of the Baylis–Hillman reaction using either chiral auxiliaries or chiral catalysts have been devel- oped, but only in a few cases were the chemical yields and enantiomeric excess high. 17–20 In addition, these methodologies usually employ rather expensive chiral sources and difficult experimental protocols with multi- step transformations that restrict their use. Racemic -methylene--hydroxy esters 1 are easily prepared from inexpensive reagents, and therefore they are good candidates for kinetic resolution. Although chemical resolution carried out by selective hydrogenation or epoxidation of the C=C double bond present in racemic 1 have been reported, these methods also present restrictions concerning the availability of the resolving reagents, multi-step synthesis, and low yields. 20–23 (1) Lipases (glycerol ester hydrolases E.C. 3.1.1.3) are established catalysts for the stereoselective resolution of synthetic or semi-synthetic chiral alcohols. 24,25 They accept a wide range of substrates, which are usually converted with high enantioselectivity. These enzymes also exhibit high stability in non-aqueous solvents. In most cases, enantiomerically pure alcohols are prepared from racemic or pro-stereogenic precursors and reac- tions are often performed via transesterification in organic solvents. To increase the reaction rate and to shift the equilibrium towards product synthesis, acti- vated esters such as vinyl acetate are routinely employed. 26 Among the available lipases, those from Pseudomonas sp. have been used to enhance kinetic resolutions of ferrocene derivatives and starting materi- als for the synthesis of terpenoids and carotenoids, as well as in the stereoselective preparation of polyesters 27 and polycarbonates. 28 * Corresponding author. Tel.: +55-48-3319219; fax: +55-48-3319711; e-mail: graca@qmc.ufsc.br 0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2003.08.015