Asymmetric hydrogenation of 4-hydroxy-6-methyl-2-pyrone: Role of acid-baseinteractions in the mechanism of enantiodifferentiation

Enantioselective hydrogenation of the pseudo-aromatic 4-hydroxy-6-methyl-2- pyrone to the corresponding 5,6-dihydropyrone has been studied over cinchon idine-modified Pd/Al2O3 and Pd/TiO2 catalysts. A mechanistic model for enan tiodifferentiation is proposed, involving two H-bond interactions (N-H . . .O and O-H . . .O) between the deprotonated reactant and the protonated chi ral modifier. The model can rationalize (i) the sense of enantiodifferentia tion, i.e., the formation of (S)-product in the presence of cinchonidine as modifier; (ii) the complete loss of enantioselectivity when the acidic OH group of the reactant is deprotonated by a base stronger than the quinuclid ine N of the alkaloid; and (iii) the poor enantiomeric excesses obtained in good H-bond donor or acceptor solvents. NMR and FTIR investigations, and a b initio calculations, of reactant-modifier interactions support the sugges ted model. Several factors, such as catalyst prereduction conditions, trace amounts of water, presence of strong bases and acids, and competing hydrog enation of acetonitrile to ethylamines, were found to affect the efficiency of this catalytic system. (C) 2001 Academic Press.