D,L-S-methyllipoic acid methyl ester, a kinetically viable model for S-protonated lipoic acid as the oxidizing agent in reductive acyl transfers catalyzed by the 2-oxoacid dehydrogenase multienzyme complexes.

D,L-S(6,8)-Methyllipoic acid methyl ester triflate salt (D,L-S-methyllipoic acid methyl ester) was synthesized as a model for S-protonated lipoic acid, suggested to be the active form of lipoic acid in the reductive acylation catalyzed by the E1 and E2 enzymes of the 2-oxoacid dehydrogenase multienzyme complexes by a previous model [Chiu, C. C., Chung, A., Barletta, G., and Jordan, F. (1996) J. Am. Chem. Soc. 118, 11026-11029]. While in that earlier study lipoic acid could only trap only the enamine/C2 alpha-carbanion intermediate in an intramolecular model, and with the assistance of mercury compound to shift the equilibrium to the products, D,L-S-methyllipoic acid methyl ester could trap the enamine derived from 2-alpha-methoxybenzyl-3,4,5-trimethylthiazolium salt in an intermolecular reaction in the absence of a mercury compound, and with a rate constant of 6.6 x 10(4) M-1 S-1. A tetrahedral adduct at the C2 alpha-position formed between the enamine and D,L-S-methyllipoic acid methyl ester was isolated and characterized. The reaction likely takes place by two-electron nucleophilic attack, since no evidence was found for C2 alpha-linked homodimers, expected from a free-radical mechanism. The results suggest that, in the reductive acyl transfer, there is nucleophilic attack by the enamine at one of the sulfur atoms of the lipoic acid [probably at S8, according to Frey, P. A., Flournoy, D. S., Gruys, K., and Yang, Y. S. (1989) Ann. N.Y. Acad. Sci. 373, 21-35], while there is concomitant electrophilic catalysis by a proton juxtaposed at S6 via a general acid catalyst located on the E1 enzyme. Oxidation of the enamine derived from C2 alpha-hydroxybenzyl-3,4,5-trimethylthiazolium salt by D,L-S-methyllipoic acid methyl ester was also deduced on the basis of the formation of 2-benzoylthiazolium ion as a major product; however, the tetrahedral intermediate could not be detected. Oxidation of the enamine by D,L-S-methyllipoic acid methyl ester can take place with either an ether or an alcohol at the C2 alpha position of the enamine.