Development of Chiral Catalysts for Mukaiyama Aldol Reactions in Aqueous Media

Abstract

Since the discovery of the Mukaiyama aldol reaction in 1973, tremendous efforts have been made to develop a definitive catalyst that catalyzes asymmetric Mukaiyama aldol reactions under mild conditions with broad substrate tolerance. Forty years later, an exhaustive search for a water-compatible Lewis acid was able to uncover the hidden potential of iron(II) and bismuth(III), leading to the establishment of broadly applicable and versatile catalytic systems for asymmetric Mukaiyama aldol reactions in aqueous media. The ternary catalytic system was able to expand the substrate generality considerably as the most distinguished catalyst ever reported. The superiority of this methodology over conventional methods has also been demonstrated in terms of high catalytic activity, simplicity of experimental procedures, and a wide substrate range including aqueous aldehydes, for which the stereochemistry had been regarded as difficult to control. Furthermore, a facile synthesis of the chiral ligand underscores its versatility. The reaction did not proceed at all without use of water. In the postulated mechanism, water plays prominent roles in: (1) producing the active metal complexes with a high water-exchange rate constant (3.2 × 10(6)) to activate substrates effectively and to catalyze the reaction through a rapid proton transfer on the order of picoseconds; (2) facilitating the catalytic turnover with simultaneous desilylation as direct access to aldol adducts or facile recovery of active metal complexes; and (3) stabilizing rigid transition states composed of metal complexes and reactants through entropy-driven aggregation derived from the highest cohesive energy density.