The enantioselective hydrogenation of ketopantolactone to R-(-)-pantolactone was investigated on 5 wt% Pt/Al2O3 chirally modified with cinchonidine The influence of catalyst pretreatment conditions, hydrogen pressure, temperature, solvent polarity, and catalyst, reactant, and modifier concentrations was studied in a slurry reactor. An enantiomeric excess (ee) of 79% at full conversion was achieved in toluene after optimization of pressure, temperature, and amount of modifier. Good ee could be obtained only after rigorous removal of traces of oxygen and water during catalyst pretreatment and from the hydrogenation reaction mixture. Molecular modeling studies (performed using molecular mechanics, semiempirical, and ab initio methods) provided a feasible structure for the diastereomeric transition complex formed between cinchonidine and ketopantolactone and an explanation for the observed enantiodifferentiation in apolar medium. The calculations indicate that formation of the complex affording R-(-)-pantolactone is energetically favored with cinchonidine, whereas the near enantiomer cinchonine favors S-pantolactone, in agreement with experimental observations. Interestingly, in apolar solvents, where the alkaloid modifier is not protonated, the modeling suggests similar structures for the diastereomeric transition complexes for the hydrogenation of ketopantolactone and methyl pyruvate.