Application of acetamidomethyl and 9-fluorenylmethyl groups for efficient side protection of penicillamine in solid-phase peptide synthesis

Synthesis of S-acetamidomethyl and S-fluorenylmethyl derivatives of penicillamine is described. Both groups are completely stable to all the usual reagents in solid-phase peptide synthesis, including the HF cleavage step, and show an excellent degree of orthogonality to each other. Treatment of the protected peptides Ac-L-Pen(X)-L-Pro-D-Val-L-Cys(X)-NH2 with thallium (III) trifluoroacetate or iodine for X = Acm or piperidine/DMF (1:1) for X = Fm induced with good yield the formation of the intramolecular disulfide bridge. This cyclic peptide appears to assume a type II beta-turn conformation in d6-DMSO as evidenced by 1H-NMR spectra.