Amino acid based phosphoramidite ligands for the rhodium-catalyzed asymmetric hydrogenation

Two sets of amino acid based phosphoramidite ligands with either a BINOL backbone (S-b-1a-e and Rb-1a) or a flexible biphenol backbone (2a-c and 2f) were synthesized and evaluated in the rhodium-catalyzed hydrogenation of different functionalized alkenes: dimethyl itaconate (3), methyl 2-acetamidoacrylate (4), methyl alpha-acetamidocinnamate (5) and N-(3,4-dihydro-2-naphthalenyl)acetamide (6). The amino acid fragment can be modified at three positions (R-1-R-3) giving rise to modular ligands. Initial experiments varying the R-1 position of the amino acid fragment, showed that the valine-based phosphoramidite ligand S-b-1b forms the most selective rhodium catalyst for three of the four substrates of the current study. The modifications at the other positions (R-2 and R-3) tweaked the ligand structure such that enhanced selectivities were obtained; up to 97% ee is obtained for the asymmetric hydrogenation of 4 with S-b-1e. For ligands with two sources of chirality match/mismatch effects are observed, the diastereoisomer S-b-1b giving higher selectivity than the diastereoisomer R-b-1b for most of the substrates, The set of phosphoramidite ligands having the flexible and cheap biphenol backbone is developed to study the ability of the amino acid derivatives as the sole source of chirality in the ligand to steer enantio selectivity in rhodium-catalyzed hydrogenation. This study shows their capacity to compete with their BINOL-based analogues and even to outclass them depending on the substrate evaluated.