Zinc-catalyzed oxidation of 5-S-cysteinyldopa to 2,2 '-bi(2H-1,4-benzothiazine): Tracking the biosynthetic pathway of trichochromes, the characteristic pigments of red hair

Trichochromes, the peculiar pigments of red human hair, featuring the Delta (2,2')-bi(2H-1,4-benzothiazine) skeleton, are known to arise from cysteiny ldopas, mainly the 5-S-isomer (5). However, the mode of formation and the d irect precursors have remained largely undefined. To fill this gap, we inve stigated the oxidation of 5 in air or with chemical and enzymatic agents un der biomimetic conditions. In the presence of zinc ions, which occur in epi dermal tissues at significant concentrations, the reaction course is divert ed toward the formation of a labile 3-carboxy-2H-1,4-benzothiazine intermed iate (11), which was identified by direct NMR analysis. Structural formulat ion was supported by characterization of the analogous compound 13 isolated from oxidation of the model 5-methyl-3-S-cysteinylcatechol (12) after meth ylation. In the further stages of the oxidation, diastereomeric 2,2'-bi(2H- 1,4-benzothiazine) 15 and 14 were obtained from 5 and 12, respectively, the reaction proceeding at a higher rate and to a greater extent in the presen ce of acids. The dimers were shown to readily convert to each other in the presence of acids. In the case of the methylated dimers 14, a 2,2'-bi(4H-1, 4-benzothiazine) intermediate (16) was isolated and characterized. In acidi c media, trichochrome C (1a), the most abundant in red human hair, was smoo thly formed from aerial oxidation of 15, and under similar conditions, tric hochrome-related products (17 and 18) were obtained from 14 prior to or aft er methylation. The presence of la and precursors 5 and 15 was investigated by HPLC analysis of red hair samples following mild proteolytic digestion. On the basis of these data, a likely biosynthetic route to trichochrome pi gments of red human hair is depicted.