Highly Efficient Asymmetric Catalytic Synthesis Of Functional Tetrahydrofuran With Chiral Tertiary Alcohol

Chiral tertiary alcohols are key building blocks in organic synthesis.The tetrapurefuran structure with chiral tertiary alcohols is widely present in various biologically active natural products and artificially synthesized drugs.Much attention has been paid on methods for efficient construction of these structures.In the past,there have been many studies on using precious metals(such as Pd,Ru,Ir,etc.)as catalysts to catalyze the intramolecular reductive cyclization of alkyne-ketones to construct this structure.However,the use of base metals(such as Fe,Co,Ni,etc.)as catalysts,which are more abundant in the earth's crust,cheaper and more environmentally friendly,is still in the ascendant stage.Therefore,the use of base metals to catalyze the intramolecular reductive cyclization of alkyne-ketones to construct chiral tertiary alcohol tetrahydrofuran is of great significance and value.This paper reports an efficient Ni-catalyzed alkyne-ketone stereoselective asymmetric intramolecular reductive cyclization method to synthesize functional tetrahydrofuran with chiral tertiary alcohols.Using Et₃Si H as a reducing agent and P-chiral bisphosphine ligand DI-BIDIME can construct this target structure with high yield(99%),excellent stereoselectivity(>99%E/Z)and enantioselectivity(>99%er).We synthesized 20 different alkyne-ketone substrates and successfully used them in this reaction to achieve a more universal substrate range.The reaction can be scaled up to a gram scale without reducing its enantioselectivity,which proves that the reaction has a certain practicability.Ligand effects and reaction mechanism are detailed investigated.while ligand DI-BIDIME played an important role for providing a large?-conjugated system or steric interactions,thus processed excellent stereoselectivity and enantioselectivity of the product.Control experiments were set up to confirmed our estimation of its mechanism.In addition,we also found that using different metal catalyst precursors,the reaction also has good yield and enantioselectivity.Finally,we initially tried Ni-catalyzed reductive coupling reaction of alkyne-imine.Still,the activity of this type of reaction remains to be explored.