Pergamon TetrahedronLetters, Vol. 38, No. 42, pp. 7459-7462, 1997 © 1997 ElsevierScience Ltd All rights reserved.Printed in Great Britain ~ru-~An_nrY~arce'TXCtl~,:.,~ 0040-4039/97 $17.00 + 0.00 PII: L.1UU"tU "f'UJT~,71]U I IJU J Enantioselective Introduction of a Benzenesulfonylmethyl Substituent at an Unactivated Carbon Atom via Chemoenzymatic Methods Anita R. Maguire* and Leonard L. Kelleher Department of Chemistry, University College Cork, Ireland Abstract: Introduction of a benzenesulfonylmethyl group at the unactivated y-carbon of carboxylic acid derivatives has been achieved through a combination of rhodium acetate catalysed carbenoid C-H insertion and baker's yeast mediated kinetic resolution. Access to the two complementary enantiomeric series of 6 with excellent enantiocontrol is possible. © 1997 Elsevier Science Ltd. Advances in the development of new methodology for enantioselective synthesis in recent years have been extensive; for example, enantioselective functionalisation at positions or [~ to a carboxylic acid moiety can be readily achieved by existing methods, the former by enantioselective enolate alkylation I and the latter by asymmetric conjugate addition, 2 among other methods. However, functionalisation at an unactivated 7-carbon of carboxylic acid derivatives in an enantioselective manner is much less readily achieved using existing synthetic methods. 3 We report here enantioselective introduction of benzenesulfonylmethyl groups at the unactivated 7-position of carboxylic acids, achieved through a synthetically powerful combination of a transition metal catalysed process and a kinetic resolution via biocatalysis. 4 Regiospecific activation of the unactivated C-H bond at the ~-carbon was achieved under mild conditions via rhodium acetate catalysed carbenoid insertion 5 as illustrated in Scheme 1. Transformation of the carboxylic acids 1, under standard conditions, via esters to 13-keto sulfones 2, followed by diazo transfer 6 led to the tx-diazo-[~-keto sulfones 3. Rhodium(II) acetate catalysed decomposition of 3 resulted in essentially quantitative C-H insertion to form the o~-benzenesulfonylcyclopentanones 4. The carbenoid insertions were complete in just a few hours in refluxing dichloromethane. While the crude product in some reactions contained a mixture of cis and trans isomers of 4, equilibration to form exclusively the thermodynamically more stable trans isomers was readily achieved. With the racemic cyclopentanone derivatives in hand, the next challenge was to develop a method to obtain these compounds in enantiomerically pure (or enriched) form. Application of biocatalysis 7 leading to a kinetic resolution of the enantiomers of 4 was identified as an appropriate strategy. One of the micro-organisms which has been widely investigated in organic synthesis is baker's yeast, Saccharomyces cerevisiae, largely due to its ready availability, ease of use and the wide range of substrates which it accepts. 8 While 7459