Nickel-catalyzed asymmetric hydrogenation of α,β-unsaturated ester phosphonates.

Chiral α-substituted β-functionalized phosphonates are valuable motifs in bioactive molecules, yet their direct catalytic asymmetric synthesis from α,β-unsaturated ester phosphonates remains underdeveloped. These substrates combine a highly electron-deficient alkene with two strongly coordinating polar groups, features that have largely confined their asymmetric hydrogenation to noble-metal catalysis. Here an efficient and highly enantioselective nickel-catalyzed hydrogenation of α,β-unsaturated ester phosphonates is reported. This reaction delivers chiral α-substituted ester phosphonates in up to 99% yield and 99% ee (enantiomeric excess) and operates at a high substrate-to-catalyst ratio (S/C) of 1000, significantly exceeding the S/C values of approximately 100 typical of noble-metal catalysts. The chiral products serve as versatile building blocks for synthesizing bioactive molecules such as glutamic acid phosphonate analogues, fosmidomycin derivatives, and β-aminophosphonic acid derivatives. DFT (density functional theory) calculations reveal that weak attractive noncovalent interactions between the catalyst and substrate stabilize the key transition state, which is crucial for the excellent enantioselectivity and activity. Furthermore, combined experimental and computational studies demonstrate that the regioselectivity is primarily determined by the kinetic preference of Ni-H migratory insertion, in which steric effects at the transition state play an important role.