Enantioselective synthesis of hexahydrofuro[3,2-c] quinolines through a multicatalytic and multicomponent process. A new “aromatic sandwich” model for BINOL-phosphoric acid catalyzed reactions

• Published in: Chemical science (Cambridge) 2014, Vol.5 (3), p.996-1007
• Main Authors: Calleja, Jonás, González-Pérez, Adán B., de Lera, Ángel R., Álvarez, Rosana, Fañanás, Francisco J., Rodríguez, Félix
• Format: Article
• Language: English
• Subjects: Aldehydes; Asymmetry; Chemical reactions; Cycloaddition; Organic compounds; Phosphoric acid; Reaction mechanisms; Synthesis (chemistry)
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/C3SC52891J

A new and straightforward metal-organo orthogonal-relay catalytic asymmetric reaction for the enantioselective synthesis of hexahydrofuro[3,2-c]quinolines is reported. The process involves a three-component coupling reaction between an alkynol, an aldehyde and an arylamine catalyzed by a gold complex and a chiral BINOL-derived phosphoric acid. Quantum chemical calculations of the reaction mechanism suggest that the involved acid-catalyzed Povarov reaction is better described as a sequential Mannich/intramolecular Friedel-Crafts process between the 5-phenyl-2,3-dihydrofuran and protonated N-phenylaldimine reactants generated in situ. Moreover, computations of the reaction mechanisms for the formation of the four stereoisomers of the hexahydrofuro[3,2-c]quinoline adduct using (R)-TRIP-suggested a rationale for the face selectivity of the asymmetric Povarov cycloaddition. With a single coordination mode by ion pairing of the chiral phosphoric acid and the imine, the preferred approach of 5-phenyl-2,3-dihydrofuran to the iminium ion results from a combination of more favourable pi -stacking and reduced steric interactions in the Re-exo transition state relative to the alternative diastereoisomeric orientations.