CHEMOENZYMATIC SYNTHESIS OF ACETYL (R)-(+)-CYCLOSERINE AND (S)-(-)-CYCLOSERINE

The two enantiomers of acetyl cycloserine 8, the immediate precursors of the chiral forms of cycloserine 1, were prepared in enantiomeric excess higher than 98% by means of lipase-catalyzed hydrolysis of 3-benzyloxy-4-hydroxy-DELTA2-isoxazoline butyrate (+/-)-5. Among the five lipases tested, lipase from Chromobacterium viscosum was by far the most selective catalyst. Since the enantiomeric ratio (E) of the reaction was higher than 100, the hydrolysis spontaneously stopped at 50% conversion to yield (R)-3-benzyloxy-4-hydroxy-DELTA2-isoxazoline [(R)-(+)-4] and (S)-3-benzyloxy-4-hydroxy-DELTA2-isoxazoline butyrate [(S)-(-)-5] in almost enantiomerically pure form. Intermediates (R)-(+)-4 and (S)-(-)-5 were transformed into the enantiomers of acetyl cycloserine through a four step sequence. This strategy constitutes a valid alternative to the previously reported procedures.