Regioselective incorporation of backbone constraints compatible with traditional solid-phase peptide synthesis.

A protected aldehyde was attached via a two-carbon spacer to a peptide backbone amide nitrogen during a traditional Merrifield solid-phase synthesis. Acid-mediated unmasking of the aldehyde triggered the regioselective formation of cyclic N-acyliminiums between the aldehyde and the neighboring peptide amide nitrogen. In the absence of an internal nucleophile, the cyclic iminiums formed dihydropyrazinones, a six-membered peptide backbone constraint between two peptide amides. In the presence of an internal nucleophile, tetrahydropyrazinopyrimidinediones or tetrahydroimidazopyrazinediones were formed via tandem N-acyliminium ion cyclization-nucleophilic addition. The outcome of this nucleophilic addition was dependent on the substituent on the nitrogen nucleophile.