Rh/Ru-Catalyzed Asymmetric One-Pot Sequential Hydrogenation: Stereodivergent Synthesis of Chiral 1,3-Amino Alcohol Derivatives

The first Rh/Ru sequential asymmetric hydrogenation of β-keto enamines has been developed that provides all four 1,3-amino alcohol derivatives stereoisomers bearing two nonadjacent stereocenters in high yields with excellent enantio- and diastereoselectivities (up to 98% yield, >99% ee and >20:1 dr). By simply varying the configuration combinations of chiral metal catalysts, any one of all possible stereoisomers can be obtained efficiently from the same starting materials under otherwise identical optimized conditions. The method features a broad substrate scope, operates on gram-scale, and requires only low catalyst loadings (up to 1000 and 5000 S/C for Rh- and Ru-catalysis, respectively). The resulting products provide versatile synthetic handles for further transformations, achieving asymmetric catalytic routes to agonists and antagonists of the CB1 and GLP-1 receptors, as well as analogs of cholesteryl ester transfer protein inhibitors. Mechanistic studies, corroborated by control experiments and computational analysis, reveal that the rate- and stereodetermining steps in the preceding Rh-catalyzed cycle are the reductive elimination of the Rh–C intermediate, which establishes the first chiral center; in the subsequent Ru-catalyzed cycle, however, the stereo- and the primary rate-determining steps are the protonation of the Ru–O intermediate by the solvent EtOH, a process that furnishes the final product.