Cooperative Asymmetric Cation-Binding Catalysis

Conspectus Asymmetric cation-binding catalysis in principle enables the use of (alkali) metal salts, otherwise insoluble in organic solvents, as reagents and effectors in enantioselective reactions. However, this concept has been a formidable challenge due to the difficulties associated with creating a highly organized chiral environment for cations and anions simultaneously. Over the last four decades, various chiral crown ethers have been developed as cation-binding phase-transfer catalysts and examined in asymmetric catalysis. However, the limited ability of chiral crown ethers to generate soluble reactive anions in a confined chiral cage offers a restricted reaction scope and unsatisfactory chirality induction. To address the constraints of monofunctional chiral crown ethers as cation-binding catalysts, it is therefore desirable to develop a cooperative cation-binding catalyst possessing secondary binding sites for anions, which enables the generation of a reactive anion within a chiral cage of a catalyst. This account summarizes our design, development, and applications of chiral BINOL-based oligoethylene glycols (oligoEGs) as a new type of bifunctional cation-binding catalyst. We initially found that achiral oligoEGs were efficient promoters in nucleophilic fluorination with potassium fluoride. Thereby, we hypothesized that, by breaking the closed cyclic ether unit of chiral crown ethers, the free terminal −OH groups could activate the electrophiles by hydrogen bonding whereas the ether oxygens could act as the Lewis base to coordinate metal ions, thus generating soluble anions in a confined chiral cage. This hypothesis was realized by synthesizing a series of chiral variants of oligoEGs by connecting two 3,3′-disubstituted-BINOL units with glycol linkers. Readily available BINOL-based chiral oligoEGs enabled numerous asymmetric transformations out of the reach of chiral monofunctional crown ether catalysts. We have demonstrated that this new type of bifunctional cation-binding catalysts can generate a soluble fluoride anion from alkali metal fluorides, which can be a versatile chiral promoter for diverse asymmetric catalytic reactions, kinetic resolution (selectivity factor of up to ∼2300), asymmetric protonation, Mannich reactions, tandem cyclization reactions, and the isomerization of allylic alcohols and hemithioacetals. We have also successfully utilized our chiral oligoEG catalysts along with alkali metal salts of carbon- and heteroatom-based n