Asymmetric Ion‐Pairing Catalysis of the Reversible Cyclization of 2′‐Hydroxychalcone to Flavanone: Asymmetric Catalysis of an Equilibrating Reaction

Abstract

AbstractThe asymmetric catalytic cyclization of the simple 2′‐hydroxychalcone (1) to flavanone (2), a model for the chalcone isomerase reaction, has been realized as a catalytic asymmetric ion‐pairing process with chiral quaternary ammonium salts (e.g., 9‐anthracenylmethlycinchoninium chloride; 9‐Am‐CN‐Cl) and NaH as small‐molecule co‐catalyst. In toluene/CHCl3 solution, the process reaches an intrinsic enantioselectivity of up to S = 14.4 (er = 93.5:6.5). The reversible reaction proceeds in two steps: A fast initial reaction approaches a quasi‐equilibrium with KR/S = 4.5, followed by a second, slow racemization phase approaching Krac = 9. A simple mechanistic model featuring a living ion‐pairing catalysis with full reversibility is proposed. Deuterium transfer from co‐solvent CDCl3 to product 2 and isolation of a Michael conjugate formed from 2 and 1 demonstrate the intermediacy of flavanone enolate ion pairs. A kinetic model shows good agreement with the experimentally observed, peculiar, time‐dependent evolution of the species concentrations and the enantiomeric excess of 2. The reaction is a chemical model of the chalcone isomerase enzymatic reaction. Furthermore, it is an ideal model for studying the characteristic behavior of reversible asymmetric catalyses close to their equilibria.