Resolution of 1-Benzamido-4-Carboxymethyl-Cyclopent-2-Ene Using Pig Liver Esterase

Abstract 1- R -benzamido-4S-carboxymethyl-cyclopent-2-ene (Ia) is a useful intermediate in the production of carbocyclic nucleosides. Resolution of racemic I (ie Ia + Ib) has been attempted using pig liver esterase (PLE). The methyl ester was readily hydrolysed:hydrolysis of the 1S, 4 R -ester (Ib) being 3-4 times faster than the 1 R , 4 S -ester (Ia) as judged by chiral HPLC. This is in contrast to the work of Sicsic et al. (1) who found the 1 R , 4 S enantiomer of the closely related substrate 1-acetamido-4-carboxymethyl-cyclopent-2-ene to be preferentially hydrolysed. Solvents are well known to affect the stereochemical course of esterase reactions (2, 3). Eleven solvents with a range of log P values were tested for their effect on the rate and enantioselectivity of the PLE-catalysed hydrolysis of racemic I. There appeared to be no systematic relationship between log P and the effect of the solvent on the reaction. The most interesting effects were found with dimethylsulphoxide (DMSO) and methanol. DMSO was found to decrease the relative rate of hydrolysis of Ib/Ia in a concentration dependent manner. Indeed, at 50% (v/v) DMSO, Ia was preferentially hydrolysed. Methanol, on the other hand, significantly increased the enantioselectivity of the reaction. At 10% (v/v) methanol, the ratio of the hydrolysis rates of Ib/Ia was approximately doubled. Although absolute enantiospecificity was not obtained under any of the reaction conditions tested here, the residual ester (Ia) of correct conformation for synthesis of ‘natural’ carbocyclic nucleosides, could be obtained in high optical purity. For example, Ia could be obtained in 90% ee (65% yield) by allowing the reaction to proceed to 65% conversion, or 95% ee (58% yield) at 69% conversion. Higher optical purities, albeit with lower yield, could be obtained by allowing the reaction to proceed further.