Unanticipated stereoselectivity in the reaction of primaquine α-aminoamides with substituted benzaldehydes:  A computational and experimental study†

• Autor(a) principal: Ferraz, Ricardo
• Data de Publicação: 2007
• Outros Autores: Gomes, José R. B., Oliveira, Eliandre de, Moreira, Rui, Gomes, Paula
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.22/18746
• topic: Imidazolidin-4-ones; N-terminal aminoacid; α-aminoamide moiety

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 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 o-carboxyl or o-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 CO oxygen of the o-substituent play a crucial role.