Synthesis and Oxidation Chemistry of 8-S-Cysteinyl Conjugates of Salsolinol

Oxidation of the tetrahydroisoquinoline alkaloid salsolinol gives an ortho-quinone (1) as the proximate product. This o-quinone reacts avidly with L-cysteine or L-cysteine methyl ester to give 8-S-cysteinyl-salsalinol (9) or 8-S-cysteinyl-salsolinol methyl ester (10), respectively. The electrochemically driven oxidations of 9 and 10 have been studied at physiological pH. The initial step in these oxidations is 2e-2H+ reactions that give o-quinone intermediates which very rapidly cyclize to give tricyclic quinone imines. These quinone imines are relatively strong oxidizing agents and can oxidize the 8-S-cysteinyl conjugates from which they are derived, forming 3,4,7,8,9,10-hexahydro-5-hydroxy-10-methyl-2H-pyrido[4,3-h]-l,4-benzothiazine-3-carboxylic acid (from 9) or the corresponding methyl ester from 10. Alternatively, the tricyclic quinone imine intermediate derived from 10 can undergo intramolecular rearrangement to give the 7,8,9,10-tetrahydro-5-hydroxy-l0-methyl-2H-pyrido[4,3-h]-1,4-benzothiazine-3-carboxylic acid methyl ester. The tricyclic quinone imine derived from 9 is oxidatively decarboxylated. The possible formation and reactions of 8-S-cysteinyl salsolinol (9) in the brain as a result of chronic, excess consumption of ethanol are discussed.