Study On The Copper-Catalyzed Asymmetric Propargylic Amination And Alkylation Reactions

Propargylic substitution,especially asymmetric propargylic substitution,has emerged as an increasingly viable tool for the construction of C-C bond and C-X bond(X=N,O,S).Recently,the tremendous progress made in transition-metal catalyzed asymmetric propargylic substitution.Despite considerable advances,Copper catalysis has experienced significant growth with the cost-effective,nontoxic and various developed ligands.Neverthless,further exploring various nucleophiles and developing a new and efficient catalytic systems remain challenging in molecular syntheses.In this thesis,the asymmetric propargylic substitution reactions of amine hydrochloride salts and 9-(10H)-anthrone were realized.1.Although significant achievements have been made in Copper-catalyzed asymmetric propargylic amination,the amine source mainly focus on the primary amine and secondary amine.The chloride anion and the proton in the amine hydrochloride salts have certain toxic effect on the metals,thus they are often not compatible with transition-metal catalyzed reactions,thus,the asymmetric propargylic amination involving amine hydrochloride is challenge to be realized.Therefore,based on the advantages of amine hydrochloride,such as high stability,antioxidation,low cost and easy handing,we developed the first asymmetric propargylic amination reaction using amine hydrochloride salts as nucleophilic reagents.Here,5 mol%copper catalysis with P,N,N-ligand promoted a series of chiral propargylic amines(up to 98%yield,99%ee)in high yields and excellent enantioselectivities.It is worth mentioning that this reaction system has good tolerance of the primary amines and secondary amines.Given the novel mechanism study,this method was further applied to the late-stage modification of anti-depression pharmaceuticals.The late-stage modification of organic intermediate 2,3,4,6-tetra-O-acetyl-β-D-glucopyranose and anti-AIDS drug Zidovudine were realized respectively,providing an efficient method for discovery of the potential biological active molecules.2.9-(10H)-anthrone has foverd widespread application in sugar determination,organic synthesis,materials and dyeing industry.It is also the main structural unit of many natural products and active molecules.The asymmetric functionalization of 9-(10H)-anthrone at the 10-position is usually limited to organocatalyzed Michael addition or Diels-Alder reactions.However,the transition metals catalyzed asymmetric functionalization of 9-(10H)-anthrone at the 10 position is rarely reported.Here,the transition metal Copper-catalyzed asymmetric propargylic substitution of 9-(10H)-anthrone at the 10-position was realized for the first time with 5 mol%Cu/new designed P,N,N-ligands as catalyst,A series of anthrone derivertives with 10 position functionalization were synthesized with high yields and high enantioselectivities.The derivatization of the products further verified the practicability in organic synthesis.Thus this project further enriched the types of asymmetric functionalization of anthrones.