Practical enantioselective process for a chiral phosphodiesterase-4 inhibitor

L-869298 is a potent and selective phosphodiesterase-4 (PDE4) inhibitor, which is potentially useful in the treatment of asthma and chronic obstructive pulmonary disorder. A catalytic asymmetric synthesis that is suitable for the preparation of kilogram quantities of L-869298, and which does not require the use of chromatography, has been developed to support the on-going drug development program of L-869298 at Merck Research Laboratories. The catalytic asymmetric hydrogenation of an aromatic heteroaromatic ketone afforded the corresponding alcohol in almost perfect enantioselectivity. Activation of the alcohol via formation of the 4-toluenesulfonate, followed by an unprecedented displacement of the tosylate via the lithium enolate of ethyl-3-pyridyl acetate N-oxide, generated the chiral tetra-substituted ethane. The displacement reaction proceeded with inversion of configuration and without loss of optical purity. Deprotection of the displacement adduct followed by decarboxylation, afforded L-869298 in excellent overall yield. The methodology developed could be readily extended to the synthesis of several other chiral PDE4 inhibitors.