On the Mechanism of an Asymmetric alpha,beta-Unsaturated Carboxylic Acid Hydrogenation: Application to the Synthesis of a PGD_2 Receptor Antagonist

摘要

Ruthenium complexes employing axially chiral ligands were found to be effective asymmetric hydrogenation catalysts for the reduction of alpha,beta-unsaturated ene acid 1-E to give 2,a prostaglandin D_2 (PGD_2) receptor antagonist.With [(S-BINAP)Ru(p-cymene)Cl_2]_2 (3,S-BINAP = (S)-(+)-2,2'-bis(diphe-nylphospino)-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.