Enantioselective hydrogenation of N-acetyl dehydrophenylalanine methyl ester using cinchonine-modified Pd/Al2O3 catalysts

The enantioselective hydrogenation of (E)-N-acetyl dehydrophenylalanine methyl ester (NADPME) to N-acetyl phenylalanine methyl ester was investigated using cinchonine-modified Pd/Al2O3 catalysts. The catalysts were evaluated for this reaction using methanol as solvent with various cinchonine:NADPME molar ratios. Enantioselectivity was sensitive to this ratio as well as to the solvent, and in general, ee increased with the polarity of the solvent. The highest ee of 33% was observed with DMF/water as solvent, but attempts to improve upon this have been unsuccessful. We used combined structural modification of the reactant and alkaloid together with computer simulations to gain insight into why the low enantioselectivity persists. Using this approach, we propose a model in which NADPME interacts as a monomer with cinchonine via hydrogen bonding between the protonated quinuelidine-N of cinchonine and the hydrogen bond acceptor functional groups of NADPME, which induces enantioselection. DFT level calculations of these interactions show that N-H...O=C hydrogen bonding gives the most stable complexes and that the lowest pro-S and pro-R dimer forms are practically isoenergetic, although higher energy dimer pairs show discrimination, thereby helping to explain the disappointing ee obtained to date. (c) 2006 Elsevier Inc. All rights reserved.