Unanticipated Stereoselectivity in the Reaction of Primaquine α-Aminoamides with Substituted Benzaldehydes: A Computational and Experimental Study†
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Centro de Investigação em Química (UP), Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua Campo Alegre, 687, P-4169-007 Porto, Portugal, Escola Superior de Tecnologias de Saúde do Porto, Instituto Politécnico do Porto, Rua João Oliveira Ramos, 87, P-4000-294 Porto, Portugal, Plataforma de Proteòmica, Parc Cientìfic de Barcelona, Universitat de Barcelona, Carrer Josep Samitier, 1−5, E-08028 Barcelona, Spain, and Centro de Estudos de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade de Lisboa, Avenida Professor Gama Pinto, P-1649-003 Lisboa, Portugal
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 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 C
O oxygen of the o-substituent play a crucial role.
†
Dedicated to Professor Carlos M. M. S. Corrêa, Professor Emeritus of the University of Porto.
‡
Centro de Investigação em Química.
§
Escola Superior de Tecnologias de Saúde do Porto.
‖
Plataforma de Proteòmica.
⊥
Centro de Estudos de Ciências Farmacêuticas.
*
In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.
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