Approaches to the synthesis of retro-inverso peptides

Partial retro-inverso modification of biologically active peptides is described as a topochemical alteration of the backbone to prevent enzymatic degradation. The preparation of gem-diaminoalkyl residues from peptide amides using the reagent [bis(trifluoroacetoxy)iodo]benzene (TIB) is discussed. Treatment of N-t-butyloxycarbonyl tyrosine and N-t-butyloxycarbonyl tryptophan with this reagent led to decomposition of the protected amino acids. Protecting the tyrosine and tryptophan residues by t-butyl ether and Nin-formyl groups, respectively, prevented decomposition and led to good yields of the desired products. Racemic 2-alkylmalonyl diastereomers were found to be separable by HPLC. The chiral stability of peptides containing optically active malonyl residues was investigated under simulated physiological conditions. Synthetic considerations for the incorporation of gem-diaminoalkyl and 2-alkylmalonyl residues into larger peptides to yield partially modified retro-inverso peptide analogs are presented.