One-Electron Photooxidation of N-Methionyl Peptides. Mechanism of Sulfoxide and Azasulfonium Diastereomer Formation through Reaction of Sulfide Radical Cation Complexes with Oxygen or Superoxide

Abstract

We have characterized and quantified pathways by which sulfide radical cation complexes of N-methionyl peptides (Met-Met, Met-Met-Ala, and Met-Leu) transform into various products through the reaction with superoxide or oxygen. Sulfide radical cations were generated photolytically by the reaction of the peptides with either triplet carboxybenzophenone (3CB) or hydroxyl radicals (HO•). Sulfide radical cations of Met-Met and Met-Met-Ala, generated through 3CB, formed intramolecularly sulfur−sulfur three-electron-bonded radical cation complexes, [R2S∴SR2]+, which efficiently reacted with superoxide to yield the respective disulfoxides Met(O)-Met(O) and Met(O)-Met(O)-Ala. Competitively, monomeric sulfide radical cations and [R2S∴SR2]+ converted intramolecularly into sulfur−nitrogen three-electron-bonded complexes, [R2S∴N(R)H2]+, which reacted with both superoxide and molecular oxygen to yield azasulfonium derivatives. Among these azasulfonium derivatives the C(S),S(R) diastereomers (AS II) were generally formed in about 1.5−3.8-fold excess over the C(S),S(S) diastereomers (AS I), indicating some diastereoselectivity in the reaction mechanism. Representative quantum mechanical calculations for the azasulfonium diastereomers of l-Met showed that the energy difference between both diastereomers was small, 1.9 kcal/mol (electronic energy) or 1.3 kcal/mol (gas-phase free energy). In complementary experiments, complex [R2S∴N(R)H2]+ was generated through the reaction of the peptides with HO•. Here, the azasulfonium diastereomers were generated predominantly by the reaction of [R2S∴N(R)H2]+ with molecular oxygen. The diastereomeric ratios [AS II]/[AS I] were generally higher when the azasulfonium products were formed via the reaction of [R2S∴N(R)H2]+ with superoxide instead of with molecular oxygen. The reaction of superoxide with the sulfur radical cation complexes most likely proceeded via an inner-sphere mechanism, i.e. radical−radical combination where the addition of superoxide to [R2S∴SR2]+ yielded an intermediary persulfoxide, R2S(+)−O−O(-), and the addition of superoxide to [R2S∴N(R)H2]+ gave an intermediary hydroperoxysulfurane, R(H)N−S(R2)OOH.