Preparation of isoxazolidinyl nucleoside enantiomers by lipase-catalysed kinetic resolution

Abstract An efficient biocatalytic procedure to obtain chiral N,O-nucleoside derivatives consisting of a lipase-catalysed resolution of the corresponding racemates in organic solvent has been developed. Enantioselective esterification of thymine and cytosine derivatives, (±)- 9a and (±)- 9b , has been investigated by comparing the efficiency of different lipases and acyl donors. Since esterification of (±)- 9a and (±)- 9b , occurred with low enantioselectivity ( E  ⩽ 14) in the presence of the lipases considered, for preparative purposes we resorted, with success, to a double sequential kinetic resolution, using Lipozyme IM as the best catalyst. This approach enables us to obtain all the enantiomers with ee ⩾ 95%. The absolute configuration of the new chiral N -acetyl cytosine derivative 9b was established by circular dichroism spectroscopy.