Counterions Influence Reactivity of Metal Ions with Cysteinyldopa Model Compounds

Cysteinyldopas are naturally occurring conjugates of cysteine and dopa (3,4-dihydroxy-l-phenylalanine) that are
precursors to red pheomelanin pigments. Metal ions are known to influence pheomelanogenesis in vitro and may
be regulatory factors in vivo. Cydo (3-[(2-amino-ethyl)sulfanyl]-4,6-di-tert-butylbenzene-1,2-diol) and CarboxyCydo
(2-amino-3-(4,6-di-tert-butyl-2,3-dihydroxyphenylsulfanyl)-propionic acid) are model compounds of cysteinyldopa that
retain its metal-binding functionalities but cannot polymerize due to the presence of blocking tert-butyl groups.
Cydo reacts readily with zinc(II) acetate or nickel(II) acetate to form a cyclized 1,4-benzothiazine (zine) intermediate
that undergoes ring contraction to form benzothiazole (zole) unless it is stabilized by coordination to a metal ion.
The crystal structure of [Ni(zine)2] is reported. The acetate counteranion is required for the zinc-promoted reactivity,
as neither zinc(II) sulfate nor zinc(II) chloride alone promotes the transformation. The counterion is less important
for redox-active copper and iron, which both readily promote the oxidation of Cydo to zine and zole species; Cu(II)
complexes of both zine and zole have been characterized by X-ray crystallography. In the case of CarboxyCydo,
a 3-carboxy-1,4-benzothiazine intermediate decarboxylates to form [Cu(zine)2] under basic conditions, but in the
absence of base forms a mixture of products that includes the carboxylated dimer 2,2‘-bibenzothiazine (bi-zine).
These products are consistent with species implicated in the pheomelanogenesis biosynthetic pathway and emphasize
how metal ions, their counteranions, and reaction conditions can alter pheomelanin product distribution.