Enantioselective S-oxygenation by flavin-containing and cytochrome P-450 monooxygenases

Abstract

The reaction of the modified Sharpless reagent, as well as microsomes and highly purified flavin-containing monooxygenase from hog liver, and cytochrome P-450IIB-1 from rat liver efficiently S-oxygenates 2-aryl-1,3-oxathiolanes with significant diastereoselectivity and enantioselectivity. The absolute configuration of the synthetic S-oxides and the enzyme-derived S-oxides was correlated by NMR analysis and by the sign of the Cotton effects obtained from circular dichroism studies. Of the sulfides studied, the trans-S-oxide was the major diastereomer produced from monooxygenase-catalyzed biotransformations. In all cases examined, enantioselective S-oxygenation was observed although enantiomeric excess varied from 7 to 100%. In contrast to previous reports, the enantioselectivity of S-oxygenation catalyzed by cytochrome P-450IIB-1 was not always opposite to that of hog liver flavin-containing monooxygenase activity. The presence of the minor S-oxide diastereomers in each case was due to incomplete chiral processing by each monooxygenase and not to a competing achiral nonenzymatic process. The results suggest that the active site of hog liver flavin-containing monooxygenase places greater constraints than that of cytochrome P-450IIB-1 on substrate orientation, but in both cases trans-S-oxide formation is strongly preferred possibly due to steric interactions of the substrate and the active site.