Various Rh catalysts and cinchona-type modifiers were tested in the hydrogenation of ethyl pyruvate, ethyl 3-methyl-2-oxobutyrate, and ketopantolactone. The experiments were completed with the study of the nonlinear behavior of modifier mixtures, and UV and NMR analysis of hydrogenation of the modifiers. From this study, beta-isocinchonine emerged as an outstanding modifier of Rh/Al2O3 that gave up to 68% ee in the hydrogenation of ketopantolactone to (R)-pantolactone in toluene, at full conversion and without the formation of any detectable byproducts. Careful prereduction of the catalyst at elevated temperature is critical to achieve good enantioselectivity. The loss of ee, or even the formation of the opposite enantiomer in small excess, in protic solvents is attributed to the formation of solvent-substrate and solvent-modifier complexes that disturb the enantioselection on cinchona-modified Rh. In the weakly interacting solvent toluene, only a few ppm of beta-isocinchonine related to ketopantolactone was sufficient to induce enantioselection. This unique feature of the conformationally rigid isocinchona alkaloid is attributed to the stronger adsorption on Rh and weaker adsorption on Al2O3, and to the higher resistance against hydrogenation of its quinoline ring "anchoring moiety" compared with the corresponding values of cinchonine and cinchonidine. (C) 2007 Elsevier Inc. All rights reserved.