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To investigate the ability of 2-alkyl-2-carboxy-azetidines (Azx) to induce reverse turns when incorporated into peptides, RCO-Azx- l -Ala-NHMe dipeptide derivatives were selected as simplified tetrapeptide models, in which the azetidine residue is incorporated at the i + 1 position. Molecular modelling, 1 H NMR and FTIR studies showed the high tendency of the model tetrapeptides to adopt γ-turn conformations, indicating that these azetidine-containing amino acids could serve as general γ-turn promoters.

Reduction with diphenylsilane and catalytic amounts of tris(triphenylphosphine)rhodium(I) carbonyl hydride resulted in an efficient, chemoselective method for the transformation of amino-acid-derived β-lactams into the corresponding azetidines, which after removal of the p-methoxybenzyl group, afforded a new family of conformationally restricted amino acids. Phe-derived compounds were obtained in enantiopure form by combining HPLC resolution of the β-lactam precursor and the above-mentioned procedure.

Trp(Nps)-Lys-NH(2) derivatives, bearing alkyl or guanidine groups either at the N-terminus or on the Lys side-chain or at both positions were conveniently prepared on solid-phase and evaluated as TRPV1 channel antagonists.