title: Unanticipated stereoselectivity in the reaction of primaquine alpha-aminoamides with substituted benzaldehydes: a computational and experimental study.
abstract: Imidazolidin-4-ones are commonly employed as skeletal modifications in bioactive oligopeptides, either as proline surrogates or for protection of the N-terminal amino acid against aminopeptidase- and endopeptidase-catalyzed hydrolysis. Imidazolidin-4-one synthesis usually involves the reaction of an alpha-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 o-carboxyl or o-methoxycarbonyl substituents are reacted with alpha-aminoamide derivatives of the antimalarial drug primaquine. A systematic computational and experimental study on the stereoselectivity of imidazolidin-4-one formation from primaquine alpha-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 o-substituent play a crucial role.
authors.affiliation: Centro de Investigação em Química (UP), Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua Campo Alegre, 687, P-4169-007 Porto, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ferraz
authors.forename: José R B
authors.initials: JR
authors.lastname: Gomes
authors.forename: Eliandre de
authors.initials: Ed
authors.lastname: Oliveira
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Paula
authors.initials: P
authors.lastname: Gomes
mesh_terms: D000577:Amides / Q000737:chemistry*; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry*; D001547:Benzaldehydes / Q000737:chemistry*; D002384:Catalysis; D019295:Computational Biology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D011319:Primaquine / Q000138:chemical synthesis / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013237:Stereoisomerism
chemical_list: D000577:Amides; D000962:Antimalarials; D001547:Benzaldehydes; D011319:Primaquine