TETRAHEDRON: ASYMMETRY Tetrahedron: Asymmetry 12 (2001) 1025–1034 Pergamon Asymmetric reduction of ketones via whole cell bioconversions and transfer hydrogenation: complementary approaches Annemarie Hage, a,c, * Danie¨lle G. I. Petra, c Jim A. Field, b Dick Schipper, f Joannes B.P. A. Wijnberg, d Paul C. J. Kamer, c Joost N. H. Reek, c Piet W. N. M. van Leeuwen, c Ron Wever c and Hans E.Schoemaker c,e a Division of Industrial Microbiology, Department of Agrotechnology and Food Sciences, Wageningen University and Research Centre, PO Box 8129 , 6700 EV Wageningen, The Netherlands b Department of Chemical and Environmental Engineering, University of Arizona, PO Box 210011 , Tucson, AZ 85721 - 0011 , USA c Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 166 , 1018 WV Amsterdam, The Netherlands d Laboratory of Organic Chemistry, Wageningen University and Research Centre, Dreijenplein 8 , 6703 HB Wageningen, The Netherlands e DSM Research, Life Science Products, PO Box 18 , 6160 MD Geleen, The Netherlands f DSM Research, postpoint 624 - 305 , PO Box 1 , 2600 MA Delft, The Netherlands Received 5 March 2001; accepted 11 April 2001 Abstract—Prochiral aryl and dialkyl ketones were enantioselectively reduced to the corresponding alcohols using whole ce white-rot fungus Merulius tremellosus ono991 as a biocatalytic reduction system and ruthenium(II)–amino alcohol and iridiu amino sulfide complexes as metal catalysts in asymmetric transfer hydrogenation. Comparison ofthe results showed that the corresponding chiral alcohols could be obtained with moderate to high enantioselectivities (e.e.s of up to 98%). The biocatalytic and transfer hydrogenation approaches appear to be complementary. The biocatalytic approach is the most suitable for the enantioselective reduction of chloro-substituted (aryl) ketones, whereas in the reduction of a,b-unsaturated compounds excellent results were obtained using the catalytic hydrogenation protocol. © 2001 Elsevier Science Ltd. All rights reserved. 1.Introduction Enantiomerically pure alcohols are useful chiralbuild- ing blocks in organic synthesis that can be used as key intermediates in the synthesis of more complex enan- tiopure bioactivecompounds.Accordingly,there is considerable interest in highly efficient routes to chiral alcohols.They can be synthesized in enantiomerically pure form from prochiralketoneseitherbiologically, using a biocatalytic system, or chemically via stereose- lective reduction, using either a catalytic system or a stoichiometric amount of reducing agent. The enantioselective reduction of ketonesusing Me- CBS-oxazaborolidine, developed by Corey et al., 1,2 is an excellentexample ofthe lattermethod.Here we have used this methodology to establish the absolute configurations of some of the chiral alcohols obtained via the biocatalytic route. Many examples of enantioselective microbial reductions have been described in the literature. 3–8 Bernardiet al. described the reduction of (Z)-3-fluoro-4-phenyl-1-(p- tolylsulphonyl)but-3-en-2-oneusing the yeast Geotrichumcandidum to form (−)-(S)-3-fluoro-4- phenyl-1-(p-tolylsulphonyl)but-3-en-2-ol with 98% e.e. The oppositeenantiomer(+)-(R)-3-fluoro-4-phenyl-1- (p-tolylsulphonyl)but-3-en-2-ol could be formed in 95% e.e. using the white-rot fungus Phanerochaete chrysosporium. 5 White-rotfungi are lignin degrading basidiomycetes and contain an extensivereductive enzyme system. Recently,we described the biocatalytic properties of white-rot fungi in aryl acid reductions. 8 Ketone reduc- tion during lignin degradation has been suggested 9 and the de novo preparation ofboth chloro-substituted arylketonesand chiralchloro-substituted aryldiols by * Corresponding author. Tel.: +31-317-483754; fax: +31-317-484978; e-mail: annemarie.hage@imb.ftns.wau.nl 0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 9 5 7 - 4 1 6 6 ( 0 1 ) 0 0 1 7 2 - 0