Synergistic Catalusis Of Divalent Nickel And Phosphine Ligands For The Construction Of Chiral Tertiary Alcohols

Chiral tertiary alcohol structures play an important role in organic synthesis.This structure is commonly found in the structures of natural products and chiral drugs,especially those containing heterocyclic compounds（tetrahydrofuran,indole,pyrrolidine）are very large.Bacterial antibiotics such as anisomycin and nicotine both contain chiral tertiary alcohols and pyrrolidine skeletons,so more economical and efficient methods for synthesizing chiral tertiary alcohols have always been the direction of continuous research in the field of organic chemistry.Most of the early catalyzed intramolecular reactions of alkynones to synthesize chiral tertiary alcohols used precious metals（such as Pd,Ru,Ir,etc.）,but due to the high value of precious metals,they could not be applied in large-scale industrial production.So how to replace precious metals with inexpensive and more environmentally friendly cheap metals（such as Fe,Co,Ni,etc.）to synthesize chiral tertiary alcohols is the focus of our research.In this work,we developed a structure containing chiral tertiary alcohols by co-catalyzed asymmetric reductive cyclization between bivalent nickel metal and phosphine ligands.The first part of the work reported the intramolecular cyclization of Ni（Ⅱ）and BI-DIME-catalyzed reduction of N-alkynones with boron reagents,and generated multiple pyrrolidine derivatives with chiral tertiary alcohols.We synthesized 16N-alkynone substrates by changing the aryl substituent,using HBpin as the reducing agent for the reaction,and bivalent nickel co-catalyzed with the P-chiral ligand BI-DIME to give high yields（95%）,pyrrolidine derivatives of chiral tertiary alcohols with extremely high E/Z selectivity（>99%）and er value（>99:1 er）.Afterwards,we scaled up the reaction to the gram scale and obtained good experimental results,proving that the reaction has broad prospects for industrial application.Based on the analysis of the work in the first part,we tried the same method for O-alkynones and obtained high yield（91%）,very high E/Z selectivity（>99%）and er value（> 99:1 er）chiral tertiary alcohol tetrahydrofuran derivatives.In order to obtain the practicability of this reaction,we scaled up the reaction to the gram level,and obtained very good reaction results,which proved that the reaction has certain industrialization prospects.Because these two reactions are relatively similar,we jointly studied the reaction mechanism of this type of reaction.The chiral phosphine ligand BI-DIME plays an important role,which provides a large steric interaction for the reaction,making the reaction have Excellent isolated yield,excellent E/Z selectivity and enantioselectivity.In conclusion,the method in this paper provides a better and more convenient method for the synthesis of chiral tertiary alcohols.Compared with the traditional synthesis method,the method of this paper can be synthesized outside the glove box,which makes the reaction construction more convenient,and reduces the cost of the reaction on the basis of one-step reduction to generate a chiral tertiary alcohol.This methodology has great possibility to be applied in industrial production.