Divergent synthesis of chiral amines via Ni-catalyzed chemo-and enantioselective hydrogenation of alkynone imines

Ligand-mediated nickel-catalyzed asymmetric hydrogenation of alkynone imines has been achieved. By using Ni(OAc)_2·4H_2O/(S,S)-Ph-BPE complex as a catalyst, the chemo-and enantioselective hydrogenation of alkynone imines occurred efficiently to afford chiral propargyl amines with high yields and excellent enantioselectivities(up to 99% yield, >99% ee), leaving the readily reducible alkynyl group intact. Both the C=N and C≡C bonds of alkynone imines were hydrogenated efficiently in the presence of Ni(OAc)_2·4H_2O and Josiphos SL-J011-1, furnishing unfunctionalized chiral imines efficiently(up to 99% yield, >99% ee).The(Z)-allylamines and(E)-allylamines were also efficiently prepared from alkynone imines by the combination of the different catalytic systems. The preliminary mechanism study revealed that the reduction of alkynone imines was a stepwise process and the C=N bonds were preferably hydrogenated in the complete reduction of alkynone imines. The synthetic utility of this method was demonstrated by its application in the late-stage modification of the antiviral drug Zidovudine and the concise synthesis of chiral dibenzoazepine.

Access to N-a-quaternary chiral morpholines via Cu-catalyzed asymmetric propargylic amination/desymmetrization strategy

Morpholines are widespread in many biologically and catalytically active agents,thus being an important aim of pharmaceutical and synthetic chemists.However,efficient strategies for the catalytic asymmetric synthesis of chiral morpholines bearing crowded stereogenic centers still remain elusive.Herein,we disclose a Cu-catalyzed asymmetric propargylic amination/desymmetrization strategy to help resolve this challenge.As a result,two kinds of structurally various chiral morpholines bearing rich functional groups and N-a-quaternary stereocenters were produced with high efficiency and selectivity(42 examples,up to91%yield,97:3 er and>19:1 dr).In addition,a series of transformations were performed to demonstrate the synthetic utility of this methodology.In particular,a hit compound for new antitumor drugs was identified through cellular evaluation.Furthermore,mechanistic investigations reveal that,hydrogen bonding in the key copper-allenylidene intermediate together withπ-πstacking aids remote enantioinduction.