Our Lewis acid-Brønsted base bifunctional catalysts promote many asymmetric reactions through simple proton transfer. "Direct" use of unmodified substrates significantly reduces waste. I believe our contribution conceptually changed reaction design to maximize atom economy. Furthermore, our Lewis acid-Lewis base bifunctional catalysts make possible the construction of chiral tetrasubstituted carbon stereocenters, which is currently one of the most important and difficult tasks in asymmetric catalysis.

When my research group began studying catalytic asymmetric carbon-carbon bond-forming reactions, some useful methods were available making use of chiral Lewis acids. However, these conventional methods typically required stoichiometric amounts of activated substrates. Since our first success in the direct use of nitroalkanes in Henry reactions more than 10 years ago, the number of related reactions has increased significantly. At the initial stage of research, only nucleophiles with relatively low pKa value, such as nitroalkane, malonate, and thiol, were used. By tuning Lewis acid-Brønsted base bifunctional catalysts, the substrate scope has broadened during the last decade. In-situ catalytic activation of ketones and carboxylic acid derivatives are possible at present. Catalysis based on the bifunctional concept is now widely studied not only by us, but also many research groups all over the world. For example, direct catalytic asymmetric aldol, Michael, and Mannich reactions are widely studied by many research groups. We are currently focusing on the construction of chiral tetrasubstituted carbon stereocenters based on the bifunctional concept. By altering the combination of functionalities that constitute the catalyst from Lewis acid + Brønsted base to Lewis acid + Lewis base, asymmetric cyanation of aldehydes and ketones, Strecker reactions of aldimines and ketoimines, and Reissert reactions of various heterocycles were achieved.

Despite spectacular recent achievements in asymmetric catalysis, there remain confounding problems to be tackled in future research. The construction of chiral tetrasubstituted carbon stereocenters, especially quaternary stereocenters, is one of the most important and difficult tasks in asymmetric catalysis. The number of asymmetric catalytic methods applicable in this regard is small, and the enantioselectivity of such reactions is still in need of improvement. Catalytic asymmetric hydrogenation, one of the most sophisticated and practical asymmetric catalyses, cannot afford quaternary carbon centers. Therefore, the development of new powerful and practical catalytic asymmetric carbon-carbon bond-forming reactions is of great importance. We are currently focusing on the construction of chiral tetrasubstituted carbon stereocenters based on the bifunctional concept. At the same time, atom economy in asymmetric reactions must be considered; to be useful, newly developed catalytic asymmetric reaction need to be environmentally benign. Research toward recovery and reuse of asymmetric catalysts is also important.

Currently, most asymmetric catalysts promote only one specific transformation. Sequential asymmetric catalysis, in which one asymmetric catalyst promotes more than one mechanistically distinct asymmetric reaction in one pot, is also desirable. Although there are several recent examples of sequential asymmetric catalysis, the reaction scopes are still limited. More powerful and sophisticated catalyst design is required in future research. Ideally, enantiomerically enriched complex molecules should be synthesized rapidly through the sequential asymmetric catalysis.

Our catalytic asymmetric Michael reaction using a heterobimetallic Al-Li-BINOL catalyst is performed on >50 kg scale for the synthesis of important optically pure pharmaceutical intermediates. Another rare-earth-BINOL complex is utilized for catalytic asymmetric epoxidation on >110 kg scale. Optically active alpha-amino phosphonic acids are synthesized using our rare-earth/alkali binaphthoxide complex (Hokko chemical) and are now commercially available from Aldrich. Some of our actual catalysts, including a Y-Li-BINOL complex and a La-linked-BINOL complex, are sold commercially (Strem).