Lipase-catalyzed resolution and desymmetrization of 2-hydroxymethylaziridines

Abstract

The Amano PS lipase-catalyzed acetylation of 2-hydroxymethylaziridines 1a–e has been investigated in order to evaluate the effect of ring substituents on the enantioselectivity of the reaction and to assess the stereochemical preference of the enzyme. N-Benzyl-3-substituted cis-aziridines displayed high enantioselectivity and higher E values were found when the bulkiness of the substituent in position 3 was increased. In contrast, the corresponding trans isomers showed only poor enantioselectivity, regardless of the steric hindrance of the substituent at C₃. Removal of the N-benzyl group proved to be detrimental to the enantioselectivity. In addition, desymmetrization of meso dimethanolic cis-aziridine 1f was successfully accomplished, and the corresponding monoacetylated product 2f, which is related to a key intermediate used in the total synthesis of the mitomycin antibiotic FR-900482, was obtained in excellent yield and nearly enantiomerically pure form. Moreover, the absolute configuration of enantiomerically pure cis-aziridines was determined by chemical correlation and/or chiroptical techniques, thus showing the stereochemical preference of Amano PS lipase for the 2S enantiomer.