Efficient Synthesis in Solid-Phase of Freidinger-like Lactams by Microwave Irradiation

Abstract

Introduction Among the numerous strategies toward the conformational restriction of peptides, incorporating the backbone into a “Freidinger” lactam structure has proven useful in the design of a variety of medicinally relevant targets, especially peptidase/protease inhibitors [1]. Such cyclization of the peptide backbone fixes the amide bond in the trans rotameric form, places severe limitations on ψ1 rotation, and would be expected to bias neighboring φ1 and φ2 torsional angles. Several different synthetic strategies have been developed toward Freidinger lactams, including some stereoselective methods that allow control over the C-3 center (amino substituent) or the glycyl side chain (R1 in Fig. 1) [2]. However, no one method has proved completely facile for the stereoselective synthesis of Freidinger lactams of various ring sizes containing a spectrum of C-terminal amino acid residues. Here we report a new synthetic methodology to perform Freidinger lactams, developed under microwave irradiation. The structures were synthesized starting from iodine derivative of Asp opportunely protected that was reacted with an amino acid linked on Wang resin (Fig. 2). The iodine derivative of Asp was prepared as previously reported in literature. In this preliminary study, Gly, Phe, Lys, and Asp were used as amino acids loaded on Wang resin.