Toward Biomimetic Synthesis of Dityrosine-Containing Peptides

Dityrosine cross-links is found in large variety of peptides and proteins. It occurs naturally in fungal cell wall proteins, invertebrate egg, as well as in vertebrate proteins, and believed to impart a wide range of properties, ranging from stabilization against degradation to conformational restriction of cyclic peptides.

A synthetic protocol for the preparation of dityrosine cross-linked peptides based on biomimetic oxidative coupling reactions is under development. In order to overcome the known low reactivity of tyrosine toward oxidative dimerization, a tert-butyl group, which facilitates the homocoupling, was introduced on the phenolic ortho-position of the amino acid. The acid-sensitive tert-butyl group has number of roles: a) it reduces the tyrosine oxidation potential, b) it directs the spin-density distribution of the readily formed phenoxyl radical to the second ortho-position, and c) it prevents further oligomerization of the dityrosine product. Indeed, oxidative dimerization of Cbz-Tyr(2-t-Bu)OMe (Fe[TPP]Cl (1 mol %), H₂O₂ urea complex, HFIP, rt, 5 min.) afforded the corresponding dityrosine peptide in 97% yield. While removal of the t-Bu group under acidic conditions affords the desired dityrosine dimer, under oxidation conditions [FeCl₃ (30 mol %), t-BuOOH, HFIP, rt] a selective oxidative cleavage of one of the t-butyl groups is taking place affording Tyr-Dopa cross-linked dipeptide in 57% yield.