A fundamental point in the mechanism of enantioselective hydrogenation over chirally modified metals is the nature of "chiral sites" developed by adsorption of the modifier on the metal surface. Despite considerable effort toward unraveling the adsorption mode of the modifier by surface science techniques, most of these spectroscopic measurements were done under conditions relatively far from those met under real reaction conditions. Here we applied a truly in situ "synthetic" approach, the systematic variation of the structure of the chiral modifier used for enantioselective hydrogenation over 5 wt% Pt/Al2O3. We have synthesized various O-alkyl, -aryl, and -silyl derivatives of cinchonidine (CD) and tested them in the enantioselective hydrogenation of ethyl pyruvate, ketopantolactone, 4,4,4-trifluoroacetoacetate, and 1,1,1-trifluoro-2,4-diketopentane. With increasing bulkiness of the ether group, the ee gradually decreased or even the opposite enantiomer formed in excess (up to 53% ee). We propose that the increasing bulkiness of the ether group prevents the strong, pi-bonded adsorption of the quinoline ring of CD close to parallel to the Pt surface. In this tilted position the modifier adsorbs weaker via the quinoline N and also the position of the interacting function, the quinuclidine N, is shifted. This shift results in a different shape and size of the "chiral pocket" available for adsorption of the activated ketone substrate. The weaker adsorption of the bulky ether derivatives was proved by UV-vis spectroscopy and by the nonlinear behavior of modifier mixtures. The tilted adsorption mode was corroborated by the lower hydrogenation rate of the quinoline ring of the ether derivatives, relative to that of CD. (C) 2004 Elsevier Inc. All rights reserved.