Catalytic Enantioselective Alkylation Of 2-Alkoxytetrahydrofurans

Enantiopure tetrahydrofurans(THFs)bearing diverse ?-alkyl substitution patterns are highly privileged building blocks featured in numerous bioactive natural products and synthetic pharmaceuticals.Existing catalytic enantioselective approaches predominantly relied on THF construction strategy involving cyclization of pre-functionalized olefin substrates,such as intramolecular alkene alkoxylation,Prins cyclization,and[3+2]cycloaddition.On the other hand,catalytic asymmetric addition to in situ generated cyclic oxocarbenium ions represents a straightforward strategy for preparing a-substituted oxygen heterocycles.Despite excellent innovation,the predominant majority of existing examples are limited to the employment of resonance-stabilized oxocarbenium ions within a six-membered ring.In contrast,catalytic enantioselective addition to non-resonance-stabilized,five-membered oxocarbenium ions has remained a formidable challenge.The high electrophilicity of non-resonance-stabilized species often results in degradation of chiral catalyst,and their small size and the lack of any Lewis basic site or ?-surface for substrate-catalyst interactions makes enantiodifferentiation particularly difficult to achieve.In 2017,List reported the first example of asymmetric alkylation of 2-acetoxy-THFs with ketene acetals catalyzed by confined imidodiphosphorimidates with excellent enantioselectivity.In 2019,our group developed a catalytic enantioselective oxidative C-H alkylation of THF with carboxylic acid derivatives.While high efficiency and excellent enantiocontrol were achieved for reactions in small scale,the use of stoichiometric and explosive tBuOOH at high temperature hampered the large-scale synthesis in terms of safefy and economy issues.Considering that 2-alkoxy THFs can be efficiently prepared through simple alkyoxylation of 2,3-dihydrofurans with diverse alcohols,we herein reported a catalytic enantioselective alkylation of 2-alkoxy THFs with a broad range of carboxylic acid derivatives.The reaction can be conducted in a gram scale in high efficiency with excellent enantioselectivity,thus providing a practical and robust synthetic method for enantiopure a-alkyl substituted THFs.The specific operation is as follows:First,we selected 2-alkoxytetrahydrofuran as the substrate for the reaction condition screening,and determined the best stereoselectivity and yield of the diphosphine ligand through the screening of the ligand.Ni(OTf)2 as a nickel salts,BF3·OEt2 and 2,4,6-collidine as additives,this combination is critical for reactivity and selectivity.Subsequently,the reaction solvent was screened and found to be the most effective in the mixed solvent of THF and CH2Cl2,thereby determining the optimal reaction conditions.With the optimized conditions in hand,the scope of catalytic asymmetric alkylation of 2-alkoxy THFs was explored.A variety of acetyloxazolidinethiones bearing electronically varied aryl groups with diverse substituent patterns participated in the asymmetric alkylation smoothly,providing respective a-alkylated THFs in good yields with excellent ee and moderate diastereocontrol.Asides from cyclic,aliphatic oxocarbenium ions,acyclic ones were also compatible with the alkylation conditions,and all have good excellent enantiocontrol.Finally,we explore the synthetic application of the method.And proposed a reaction mechanism of catalytic asymmetric alkylation.In summary,a nickel(?)-catalyzed asymmetric alkylation of non-resonance-stabilized,five-membered oxocarbenium ions generated in situ from 2-alkoxy THFs with a broad range of carboxylic acid derivatives has been disclosed.The reaction performed in a large scale exhibits high efficiency,excellent enantioselectivity,and good functional group tolerance.Asides from five-membered oxocarbenium ions,six-membered and acyclic aliphatic species were also well tolerated with excellent enantiocontrol,thus providing a practical and robust method to access enantiopure a-alkyl substituted saturated ethers.