Enantioselective Reduction of Pyridines via Brønsted Acid Catalysis

Key words

organocatalysis - Brønsted acids - piperidines - reduction

Significance

An organocatalytic enantioselective reduction of 2-substituted simple and fused pyridines is reported. The reaction is designed to undergo catalytic protonation by Brønsted acid 1, followed by reduction by hydride transfer from the Hantzsch dihydropyridine 2. The hexahydroquinolinone and tetrahydropyridine products are formed in moderate to good yields with good enantioselectivities. The scope of the reaction was modestly investigated.

Comment

The chiral piperidine moiety is prevalent in the large class of piperidine plant and animal natural products, for example the dendrobatid alkaloid pumiliotoxin C, a noncompetitive blocker of nicotinic receptors (see book and review below). A previous synthesis of hexahydroquino­linones involves a multistep process and use of stoichiometric amounts of a chiral auxiliary (H. M. Sklenicka et al. J. Am. Chem. Soc. 2002, 124, 10435). The present methodology establishes the first direct and efficient organocatalytic route for the synthesis of such compounds.

Book

J. W. Daly, H. M. Garraffo, T. F. Spande In Alkaloids: Chemical and Biological Perspectives, Vol. 13; S. W. Pelletier, Ed.; Pergamon: New York, 1999, 1-161.

Review

J. W. Daly, T. F. Spande, H. M. Garraffo J. Nat. Prod. 2005, 68, 1556.