Enzymatic Oxygenation of Sulfides with Cytochrome P-450 from Rabbit Liver. Stereochemistry of Sulfoxide Formation

Abstract

Abstract Stereochemistry of enzymatic oxygenations of various diaryl, dialkyl and aryl alkyl sulfides to the corresponding sulfoxides with hepatic microsomes obtained from phenobarbital pretreated rabbit was investigated in comparison with those of nonenzymatic oxidations. Relative reactivity of the sulfides in the enzymatic oxygenation, based on the yields of the sulfoxides and the amount of oxygen absorption, depends upon the steric demand of the substituent in the oxygenation of 2-substituted thiochroman derivatives. However, such a trend was not observed in the enzymatic oxygenations of various acyclic sulfides. A substantial asymmetric induction on the sulfur atom was always observed (e.g., 54% e.e. for benzyl t-butyl sulfide). Formation of the sulfoxide with R-configuration predominated over that with S-configuration. The enzymatic oxygenation of all the unsymmetrical sulfides examined proceeded via the same steric course. Diastereomeric ratios of the sulfoxides formed in the enzymatic oxygenations of various racemic sulfides bearing alkyl substituents at α-position are markedly favoured more for the trans isomers than for the cis ones, while the ratio was nearly fifty-fifty in the nonenzymatic oxidations with both MCPBA and NaIO4. These results suggest that the enzymatic oxygenation takes place at the less hindered side of the sulfide. Both enzymatic and nonenzymatic oxidations of rigid six-membered cyclic sulfides, trans-thiadecalins and 4-(p-chlorophenyl)thiane, similarly occurred at the less hindered side to give mainly equatorial sulfoxides. The yields of the four stereoisomeric sulfoxides were nicely determined in the enzymatic oxygenation of racemic 2-methyl-2,3-dihydrobenzothiophene to elucidate the steric course of the oxygenation. Dependency of this microsomal oxygenation upon cytochrome P-450 enzyme was proved by several inhibition experiments and also by the identical stereochemical results of the oxygenation of a few selected sulfides to those with a reconstituted system with purified cytochrome P-450 and co-factors.