Chemical and Enzymatic Oxidation of 2-Aryl-1,3-oxathiolanes: Mechanism of the Hepatic Flavin-Containing Monooxygenase

Article abstract of DOI:10.1021/ja00195a041

The reaction of NaIO4, H2O2, and highly purified and microsomal hog and rat liver flavin-containing monooxygenase with 2-aryl-1,3-oxathiolanes was investigated.The ρ values determined from Hammett plots for the rate of S-oxygenation are consistent with substantial nucleophilic character for the chemical reaction but this does not preclude radical character in the reaction.For the biotransformation reactions, the data provide evidence for a minor role of cytochrome P-450 in the S-oxygenation of 2-aryl-1,3-oxathiolanes, but the flavin-containing monooxygenase represents by far the major pathway for S-oxide formation.The diastereochemical outcome of the S-oxygenation of 2-aryl-1,3-oxathiolanes was determined and, in general, hog liver flavin-containing monooxygenase demonstrated considerable S-oxygenation stereoselectivity while rat liver flavin-containing monooxygenase (FMO) was markedly less stereoselective.The presence of the minor cis S-oxide diastereomer in each case is due to incomplete diastereomeric processing by each enzyme (FMO and cytochrome P-450) and not to a competing, achiral nonenzymatic process. 2-Aryl-1,3-oxathiolane S-oxides are also oxygenated a second time by H2O2 or hog or rat liver microsomal and highly purified FMO.The immediate S,S-dioxygenated product is not stable and is rapidly converted to the corresponding benzaldehyde.That the chemical and enzymatic oxygenation of 2-aryl-1,3-oxathiolane S-oxides is much slower than its corresponding sulfide is quite apparent from the large dependence on the nature of the para substituent.The reactions of 2-aryl-1,3-oxathiolanes with H2O2 and FMO serve to demonstrate the electronic and stereochemical requirements for S-oxygenation of dialkyl sulfides and provide evidence that rat and hog liver FMO are two different forms of the same enzyme.