Cu(Ⅱ)-catalyzed Asymmetric1,4-reduction For The Synthesis Of Chiral β-alky-β-aryl Propanoate And Weinreb Amides

One of the most powerful and direct strategy for the construction of enantiomerically enriched esters or Weinreb amides bearing β-stereocenters, which are valuable immediates for the synthesis of some structurally interesting compounds and natural products, is the catalytic asymmetric reduction of corresponding a,β-unsaturated esters or Weinreb amides. Copper hydrides (Cu-H) ligated by nonracemic ligands have been demonstrated to be the active species for effecting the asymmetric hydrosilylation of various α,β-unsaturated carbonyl compouds, owing to the use of less-expensive metal catalysts, the mild reaction conditions and the operational simplicities.This study focused on the developlepment of the effective and pratical copper mediated asymmetric hydrosilylation systems for the synthesis of optically enriched esters or Weinreb amides bearing β-stereocenters and the research results are summarized as followes:(1) Twenty-three α,β-unsaturated esters, and fourteen α,β-unsaturated Weinreb amides have been synthesized and characterized by1H NMR and13C NMR analysis. Meanwhile, the the racemic forms of the corresponding reduced esters and Weinreb amides were prepared and characterized by1H NMR and13C NMR analysis. The chiral analytical methods of these racemic products were established as well.(2) Systematic investigations, various modifications and fine-tunings have been made on chiral ligands, counterions of copper salts, additives as well as reaction conditions as to establish a novel chiral catalyst system with utility and praticality. In consideration of the pratical application, Cu(OAc)2·H2O, an air and moisture stable as well as substantially less expensive copper precursor, was utilized as copper source. In the presence of certain amounts of t-BuONa and t-AmOH as additives, the combination of Cu(OAc)2·H2O, enantiomeric Xyl-P-Phos and an inexpensive and innocuous hydride donor PMHS generated in situ an efficient catalyst system in normal atmosphere.(3) Furthermore, the developed air-stable catalyst system has been applied in the conjugated reduction of a range of β-alkyl-β-aryl α,β-unsaturated esters with high activitiy and moderate to excellent ee’s (up to98%ee).(4) An efficient and practical chiral non-precious copper catalyst system has been established for the first time for the synthesis of Weinreb amides bearing β-stereocenters in high enantioselectivities, which are versatile building blocks in the manufacture of many biologically active compounds. After a systematic investigation of the influences of the chiral ligands, metal precursor, and additives on the activitity and enantioselectivity, an optimized catalyst system has been established, and the reactions proceeded smoothly at room temperature to give moderate to good yields and ee’s (up to97%) in air.