Unanticipated Stereoselectivity in the Reaction of Primaquine α-Aminoamides with Substituted Benzaldehydes:  A Computational and Experimental Study^†

Imidazolidin-4-ones are commonly employed as skeletal modifications in bioactive oligopeptides, either as proline surrogates or for protection of the <i>N</i>-terminal amino acid against aminopeptidase- and endopeptidase-catalyzed hydrolysis. Imidazolidin-4-one synthesis usually involves the reaction of an α-aminoamide moiety with a ketone or an aldehyde to yield an imine, followed by intramolecular cyclization. We have unexpectedly found that imidazolidin-4-one formation is stereoselective when benzaldehydes containing <i>o</i>-carboxyl or <i>o</i>-methoxycarbonyl substituents are reacted with α-aminoamide derivatives of the antimalarial drug primaquine. A systematic computational and experimental study on the stereoselectivity of imidazolidin-4-one formation from primaquine α-aminoamides and various substituted benzaldehydes has been carried out, and they have allowed us to conclude that intramolecular hydrogen-bonds involving the CO oxygen of the <i>o</i>-substituent play a crucial role.