Synthesis of Protected 3,4- and 2,3-Dimercaptophenylalanines as Building Blocks for Fmoc-Peptide Synthesis and Incorporation of the 3,4-Analogue in a Decapeptide Using Solid-Phase Synthesis.

Abstract

3,4-Dimercaptophenylalanines and 2,3-dimercaptophenylalanines have been synthesized for the first time by nucleophilic substitution of a protected aminomalonate on 3,4- and 2,3-dimercaptobenzyl bromide derivatives. The dithiol functions were protected as thioketals, and the key precursors, diphenylthioketal-protected dimercaptobenzyl bromides, were synthesized via two distinct routes from either dihydroxy benzoates or toluene-3,4-dithiol. Racemic mixtures of the fully protected amino acids were separated by chiral HPLC into the corresponding enantiomers. The absolute configuration of both 3,4- and 2,3-analogues could be assigned based on X-ray crystallography and VCD/DFT measurements. Thioketal groups were deprotected upon reaction with mercury oxide and aqueous tetrafluoroboric acid followed by treatment with H2S gas under an argon atmosphere to obtain the corresponding dimercapto amino acids. The optically pure l-Fmoc-protected 3,4-analogue (S- enantiomer) was successfully incorporated into a decapeptide using standard solid-phase peptide synthesis. Therefore, dithiolene-functionalized peptides are now accessible from a simple synthetic procedure, and this should afford new molecular tools for research into the catalysis, diagnostic, and nanotechnology fields.