Enantioselective synthesis of ethyl nipecotinate using cinchona modified heterogeneous catalysts

Ethyl nicotinate was hydrogenated to ethyl nipecotinate in two steps. In the first step, the starting material was converted to the 1,4,5,6-tetrahydro derivative with Pd/C and hydrogen in 76% yield. The hydrogenation of this intermediate was investigated with both unmodified and 10,11 -dihydrocinchonidine modified noble metal catalysts and the influence of the catalyst metal, support, solvent and modifier concentration was tested. Catalyst activity was low in all cases, probably because the C=C double bond is part of a vinylogeous carbamate. The highest activity was observed with Rh and Rh/Pt catalysts. Highest ee's were obtained at relatively low conversions with Pd/C in DMF (19% ee, 12% conversion) and Pd/TiO2 in a DMF/H2O/AcOH system (24% ee, 10% conversion). This is the first successful example of an enantioselection in the hydrogenation of an alpha,beta-unsaturated ester with a modified heterogeneous catalyst. With the addition of 10,11 -dihydrocinchonidine, catalyst activity usually decreased. Ee and activity were strongly influenced by the catalyst metal, the carrier and the solvent. Due to the empiric nature of the study and the low ee's obtained, a mechanistic interpretation of the results is not warranted. (C) 1999 Elsevier Science B.V. All rights reserved.