Highly Enantioselective Organocatalytic Transfer Hydrogenation of Quinolines

Abstract

The highly enantioselective Brøn­sted acid catalyzed cascade transfer hydrogenation of 2-substituted quinoline derivatives 1 presented herein gives direct access to a variety of 2-aryl- and 2-alkyl-substituted tetrahydroquinolines 2 with good yields and excellent enantioselectivities. In this approach, sterically congested Brønsted acid 3 activates the quinoline 1 by catalytic protonation, which allows cascade hydrogenation in the presence of Hantzsch dihydropyridine 4 as cofactor. This first step is a 1,4-hydride addition, then an isomerization occurs, which is followed by a 1,2-hydride addition. Furthermore, this methodology (and subsequent N-methylation) was successfully applied to the synthesis of biologically active tetrahydroquinoline alkaloids: galipinine, cuspareine, and angustureine, which were obtained in good yields (79-89%) and excellent enantioselectivities (90-91%).