Me-DuPHOS-Rh-catalyzed asymmetric synthesis of the pivotal glutarate intermediate for candoxatril

A greatly improved process has been developed for synthesis of the glutarat e derivative 2, a key intermediate required for Pfizer's drug candoxatril. The cationic (R,R)-Me-DuPHOS-Rh catalyst was found to allow highly efficien t and enantioselective hydrogenation of a unique carboxylate substrate (5) to afford the desired product in >99% ee and high yield (95%). The robust n ature of the process was validated on a 12 kg reaction scale. A novel mecha nism for the hydrogenation process is proposed. Through use of a labile eta (6)-benzene-Rh-Me-DuPHOS complex, the postulated catalytic intermediates ha ve been synthesized by independent means. Detailed spectroscopic analyses o f these intermediates corroborate the mechanistic hypotheses. Interconversi on of these key catalytic intermediates has been demonstrated.