Chemoenzymatic synthesis of highly enantiomerically enriched secondary alcohols with a thiazolic core Laura Pop a , Pierrik Lassalas b , László Csaba Bencze a , Monica Ioana Tos ßa a , Botond Nagy a , Florin Dan Irimie a,⇑ , Christophe Hoarau b,⇑ a Department of Biochemistry and Biochemical Engineering, University Babes ß-Bolyai Cluj-Napoca, Ro-400028 Cluj-Napoca, Arany János 11, Romania b Institut de Chimie Organique Fine (IRCOF) associé au CNRS (UMR 6014), INSA et Université de Rouen, BP08, 76131 Mont Saint Aignan, France article info Article history: Received 23 February 2012 Accepted 28 March 2012 abstract Stereoselective preparative enzymatic acylation and hydrolysis/methanolysis of various C-substituted rac-thiazol-2-yl-methanols were achieved for the preparation of enantiopure or enantiomerically enriched, naturally occurring 2-hydroxymethylthiazoles. The absolute configurations of the resulting sec- ondary alcohols were determined by a detailed 1 H NMR study of Mosher’s derivatives. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction 2-Hydroxymethylthiazoles are common clusters of a wide range of biologically active azole natural products including archazolid, tubulysin, lyngbyabellin and hectochlorin (Fig. 1). 1 They are also important as chiral building blocks for the synthe- sis of thiopeptide antibiotics. Current synthetic strategies for the preparation of the enantio- merically pure forms are mainly based upon the use of Ugi, Hantzsch or biomimetic thiazole forming reactions using chiral reagents, 2 tandem stereoselective Strecker/Hantzch sequences 2d and stereose- lective reduction, nucleophilic addition and hydroxylation reactions to give 2-formyl, 2-keto, 2-alkyl and 2-vinyl-thiazoles. 2d,3 The 4-car- boxylated and 4-brominated 2-hydroxymethylthiazole series have attracted the most attention as common natural product subunits as well as the direct precursors of highly valuable dipeptide thiazoles. 4 With regard to this, the ready access to 2-hydroxymethylthiaz- ole esters through non-stereoselective synthetic routes (Scheme 1) 2g,5 and on the basis of our recent successful investiga- tions in the enzymatic deracemisation of heteroaryl secondary alcohols, 6 we herein report the enzyme mediated preparation of enantiomerically enriched 4-carboxylated and 4-brominated 2-hydroxymethyl-thiazoles over two pathways: (1) the stereose- lective acylation of racemic alcohols and (2) the non-selective acyl- ation of racemic alcohols followed by stereoselective hydrolysis/ alcoholysis (Scheme 2). 2. Results and discussion 2.1. Chemical synthesis The tert-butyl 2-hydroxymethylthiazole-4-carboxylates and 4- bromo-2-hydroxymethylthiazoles 2a–h were prepared as race- mates by operating a magnesium-bromide exchange reaction using Knochel’s reagent, 5d from the tert-butyl 2-bromothiazole-4- carboxylate 1a and commercially available 2,4-dibromothiazole 1b, followed by an electrophilic quench with various aldehydes (Scheme 1, route A). Alternatively, the formylation reaction was also achieved using N-formyl-morpholine as an electrophile to give 2-formylated tert-butylthiazole-4-carboxylate 3a and 4-bromothi- azole 3b, which were then reacted with commercially available Grignard reagents (Scheme 1, route B) to give the corresponding racemic secondary alcohols rac-2i–k. By chemical acylation of racemic secondary alcohols rac-2a–k with an acyl chloride or anhydride in the presence of DMAP, the racemic esters were prepared. In order to investigate the stereose- lectivity of the enzymatic reaction and the activity of the enzymes, the chromatographic enantiomeric separation of racemic second- ary alcohols 2 and of their ester derivatives 4–6 were performed successfully using the appropriate HPLC Chiralcel or Chiralpak chiral columns (Table 2). 2.2. Enzymatic kinetic resolutions First the selective O-acylations of racemic alcohols rac-2a-k using a broad panel of hydrolases [lipases A and B from from Can- dida antartica strains (CaL A and CaL B), lipases from Candida rugosa (CRL), Candida cylindracea (CCL), Pseudomonas cepacia (LPS), Pseudo- monas fluorescens (LAK), Rhizopus oryzae (Lipase F), lipases from 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2012.03.014 ⇑ Corresponding authors. Tel.: +40 264 593 833; fax: +40 264 590 818. E-mail address: irimie@chem.ubbcluj.ro (F.D. Irimie). Tetrahedron: Asymmetry 23 (2012) 474–481 Contents lists available at SciVerse ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy