Oxidative Polymerization of the Pheomelanin Precursor 5-Hydroxy-1,4-benzothiazinylalanine: A New Hint to the Pigment Structure

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Abstract
Biosynthetic studies have shown that pheomelanins, the distinctive pigments of red human hair, arise from oxidative polymerization of cysteinyldopas via 1,4-benzothiazinylalanine intermediates. However, the mode of formation of the pigment polymer remains controversial. To address this point, we have investigated the conversion of the major biosynthetic precursor 5-S-cysteinyldopa (2a) to pheomelanin under biomimetic conditions. Peroxidase/H2O2 oxidation of 2a was shown to lead in the early stages to the 1,4-benzothiazinylalanine 8a, which rapidly declines with concomitant formation of a distinct pattern of oligomeric products. Reduction of the reaction mixture at this stage allowed the isolation of dimer 17 in 10% yield, along with trimers 18 and 19 in smaller amounts. A restricted rotation about the ethereal C−O bond of 17 was apparent by the presence of two NMR-detectable conformational isomers, separated by an activation energy barrier of 17.83 ± 0.03 kcal mol-1. Under similar oxidation conditions, the model catechol 2b gave the related dimers 15 and 16. The structure of oligomers 17−19, all characterized by C−C and C−O bonds between the benzothiazine units, would suggest that the peroxidase-promoted polymerization proceeds by phenol-type coupling of an aryloxy radical generated by initial one-electron oxidation of 8a. Overall, these results point to a structural model for the pheomelanin polymer which is basically different from that proposed on the basis of degradative studies.

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