10.1021/co300125m.s001 Agustina La Venia Agustina La Venia Barbora Lemrová Barbora Lemrová Viktor Krchňák Viktor Krchňák Regioselective Incorporation of Backbone Constraints Compatible with Traditional Solid-Phase Peptide Synthesis American Chemical Society 2013 nucleophilic addition Regioselective Incorporation peptide amide nitrogen Backbone Constraints Compatible regioselective formation aldehyde cyclic iminiums nitrogen nucleophile peptide amides peptide backbone amide nitrogen 2013-01-14 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Regioselective_Incorporation_of_Backbone_Constraints_Compatible_with_Traditional_Solid_Phase_Peptide_Synthesis/2452678 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 <i>N</i>-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 <i>N</i>-acyliminium ion cyclization-nucleophilic addition. The outcome of this nucleophilic addition was dependent on the substituent on the nitrogen nucleophile.