DpenPhos/Rh(I) Catalyzed Asymmetric Hydrogenation of Dehydro-β-Amino Acid Esters

Enantiomerically pure beta-amino acids and their derivatives are very important chiral building blocks for the synthesis of beta-peptides, beta-lactams, and many important biologically active compounds. Among various methods developed for their synthesis, catalytic asymmetric hydrogenation of the corresponding dehydro-beta-amino acid esters represents one of the most efficient and environmentally benign approaches, in which the Rh(I) catalysts containing chiral phosphorous ligands play a central role. Although a variety of Rh(I) complexes of bidentate or monodentate ligands have been discovered for asymmetric hydrogenation of dehydro-beta-amino acid esters, some challenging issues still remain in terms of efficiency, enantioselectivity, and substrate scope. In the present work, a variety of Rh(I) complexes of modular monodentate phosphoramidite ligands, DpenPhos, have been systematically investigated for the asymmetric hydrogenation of (E)- or (Z)-beta-substituted dehydro-beta-amino acid esters. It was found that the presence of a N-H moiety in the phosphoramidite ligand is critically important for achieving high activity of the catalysis. Both (Z)- and (E)-geometrical isomers of the beta-acetamido acrylic acid esters can be hydrogenated in the presence of DpenPhos/Rh(I) catalysts to form the same enantiomers, albeit slightly different conditions were required to attain optimal enantioselectivities. (R,R)-3k/Rh(I) (1 mol%) was disclosed to be optimal for the hydrogenation of (E)-beta-alkyl substituted dehydro-beta-amino acid esters in dichloromethane under a relatively low pressure of hydrogen (0.5 MPa), affording the corresponding beta-amino acid esters with 92%-96% ee. The reaction still proceeded smoothly without significant sacrifice of activity or enantioselectivity either at a catalyst loading of 0.2 mol% or 0.1 MPa pressure of H-2. For the hydrogenation of more challenging (Z)-beta-alkyl or aryl substituted dehydro-beta-amino acid esters, (R,R)-3l/Rh(I) in combination with the dichloromethane/isopropanol (V/V=2/1) mixed solvent system turned out to be the best in terms of enantioselectivity and catalytic activity, giving a variety of beta-alkyl or aryl substituted beta-amino acid esters in >99% yields with excellent optical purities (92%-98% ee).