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. Such cyclization of the peptide backbone fixes the amide bond in the trans rotameric form, places severe limitations on psi_1 rotation, and would be expected to bias neighboring phi_1 and phi_2 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 (R_1 in Fig. 1). 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.
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