Synthesis of substituted mandelic acid derivatives via enantioselective hydrogenation:: Homogeneous versus heterogeneous catalysis

An extensive screening of both homogeneous and heterogeneous catalysts was carried out for the enantioselective hydrogenation of p-chlorophenylglyoxylic acid derivatives. For p-chlorophenylglyoxylic amides only homogeneous Rh-diphosphine complexes gave satisfactory results, ees up to 87% were observed for the cy-oxo-pronop ligand. For methyl p-chlorophenylglyoxylate both a homogeneous as well as a heterogeneous catalyst performed with ees > 90%. A Pt catalyst modified with cinchona derivatives achieved 93% ee for the (R)- and 87% ee for the (S)-methyl p-chloromandelate. A Ru-MeObi-phep catalyst also reached 93% ee with TONs up to 4000 and TOFs up to 210 h(-1). For all catalytic systems the effects of the metal, the nature of the chiral auxiliary and the solvent as well as of the reaction conditions were investigated. The homogeneous process was scaled up to the kg scale and the enantiomeric purity of the product was enhanced to > 99% ee by two recrystallizations of the free p-chlorophenylmandelic acid.