On the Mechanism of an Asymmetric α,β-Unsaturated Carboxylic Acid Hydrogenation:  Application to the Synthesis of a PGD₂ Receptor Antagonist

Ruthenium complexes employing axially chiral ligands were found to be effective asymmetric hydrogenation catalysts for the reduction of α,β-unsaturated ene acid 1-E to give 2, a prostaglandin D₂ (PGD₂) receptor antagonist. With [(S-BINAP)Ru(p-cymene)Cl₂]₂ (3, S-BINAP = (S)-(+)-2,2‘-bis(diphenylphospino)-1,1‘-binapthyl), it was discovered that low hydrogen pressures (<30 psi) were essential to achieve high enantioselectivities (92% ee). A detailed mechanistic study was undertaken to elucidate this pressure dependence. It was determined that compound 1-E is in a ruthenium-catalyzed equilibrium with endocylic isomer 1-Endo and in photochemical equilibrium with Z isomer 1-Z. Each isomer could be hydrogenated to give 2, albeit with different rates and enantioselectivities. Hydrogenation of 1-Endo with 3 was found to give 2 in high enantiomeric excess, regardless of pressure and at a rate substantially faster than that of hydrogenation of 1-E and 1-Z. In contrast, isomers 1-E and 1-Z exhibited pressure-dependent enantioselectivities, with higher enantiomeric excesses obtained at lower pressures. A rationale for this pressure dependence is described. Deuterium labeling studies with 1-Endo and tiglic acid were used to elucidate the mechanism of hydride insertion and product release from ruthenium. Under neutral conditions, protonolysis was the major pathway for metal−carbon cleavage, while under basic conditions, hydrogenolysis of the metal−carbon bond was predominant.