New chemo-enzymatic approaches for the synthesis of (R)- and (S)-bufuralol Botond Nagy, Norbert Dima, Csaba Paizs, Jürgen Brem, Florin Dan Irimie, Monica Ioana Tos ßa ⇑ Biocatalysis and Biotransformation Research Group, Babes ß-Bolyai University, Arany János 11, Cluj-Napoca Ro-400028, Romania article info Article history: Received 12 July 2014 Accepted 5 August 2014 Available online 10 September 2014 abstract Both enantiomers of bufuralol are pharmaceutically important molecules. While the (S)-isomer with a higher b-blocking activity is recommended for hypertension treatment, the (R)-enantiomer can be used as marker of hepatic activity. In this paper two new alternative approaches are described for their chemo- enzymatic synthesis, providing both highly enantiomerically enriched stereoisomers of the target mole- cule (ee 96–98%). One route is based on the baker’s yeast mediated stereoselective biotransformation of a-substituted ketones, and the other one on the lipase mediated kinetic resolution of the racemic bromoethanol. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction The preparation of enantiopure compounds has gained great importance since the enantiomers of pharmaceuticals often display different physiological properties or metabolic behaviors and may have their own effects on drug–ligand interactions. Amino alcohol moieties with a certain stereochemistry can lead to important biological activities showing antiarrhythmic, enzy- matic inhibitory, antihypertensive, and b-adrenoacceptor blocking activity. 1 Bufuralol, developed by Hoffman-La Roche, is a widely studied potent, nonselective, b-adrenergic receptor antagonist. 2 It is effi- cient in hypertension treatment, 3 acts as inhibitor of testosterone 6b-hydroxylase, 4 and it was also used in studies of cytochrome P450. Bufuralol is a chiral molecule with an asymmetric carbon in the ethanol amine side chain and its oxidative degradation takes place enantioselectively and regioselectively in the liver. 5 While the b-blocking potency resides mainly in (S)-bufuralol (100 times greater than that of the (R)-enantiomer), (R)-bufuralol is a commonly used marker of hepatic CYP 2D6 activity. 6 Various stereoselective procedures for the synthesis of both enantiomers of bufuralol have been already described in the literature. (S)-Bufuralol has been obtained with acceptable enantiomeric excess (ee 87%) from 3-ethyl-2-hydroxy-benzaldehyde, via the stereoselective reduction of 2-bromo-1-(7-ethylbenzofuran-2-yl) ethanone with ()-B-chlorodiisopino-campheylborane as the key step. 1a Lee et al. have described a similar method involving the asymmetric transfer hydrogenation of 1-(7-ethylbenzofuran- 2-yl)-2-mesyloxyethanol mediated by Cp / RhCl[ S, S-TsDPEN] using an azeotropic mixture of formic acid/triethylamine. 7 The (R)-enantiomer was successfully obtained from the corresponding chloro-ketone 8 or keto-imine 9 using a sequential transfer hydroge- nation–substitution procedure or through a combined ruthenium- enzyme-catalyzed dynamic kinetic resolution of chlorohydrin. 10 Recently, the stereoselective synthesis of (S)-bufuralol (95% yield, ee 98%) via the corresponding (S)-cyanohydrin, was reported. 11 The latest compound was prepared by a homochiral metal–organic catalyst mediated enantiotope selective cyanation of the corresponding aldehyde. Due to their generally large substrate tolerance, high stereose- lectivity, effective catalytic activity without cofactors, and good commercial availability, lipases (EC 3.1.1.3) are especially attrac- tive biocatalysts for synthetic purposes. A highly enantioselective lipase-catalyzed kinetic resolution affords both enantiomers simultaneously from a racemic mixture (one as the unreacted enantiomer and the other as a new reaction product). Consequently Turner et al. employed an enzymatic enantiomer selective acylation of rac-7-ethylbenzofuran-2-yl-chloro-alcohol. 12 It was shown that lipases from Pseudomonas and Candida species can lead to successful resolution of the racemic chloro-alcohol pro- viding (R)-bufuralol. Herein we present two new chemo-enzymatic approaches for the stereoselective synthesis of both enantiomers of bufuralol. The first route is based on a baker’s yeast catalyzed biotransforma- tion of 2-(7-ethylbenzofuran-2-yl)-2-oxoethyl acetate 5 and 1-(7-ethylbenzofuran-2-yl)-2-hydroxyethanone 6, affording both http://dx.doi.org/10.1016/j.tetasy.2014.08.002 0957-4166/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +40 264 593 833; fax: +40 264 590 818. E-mail address: mtosa@chem.ubbcluj.ro (M.I. Tos ßa). Tetrahedron: Asymmetry 25 (2014) 1316–1322 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy