title: Development of atom-economical catalytic asymmetric reactions under proton transfer conditions: construction of tetrasubstituted stereogenic centers and their application to therapeutics.
abstract: The development of atom-economical catalytic asymmetric reactions based on two distinct sets of catalyst, a rare earth metal/amide-based ligand catalyst and a soft Lewis acid/hard Brønsted base catalyst, is reviewed. These catalytic systems exhibit high catalytic activity and stereoselectivity by harnessing a cooperative catalysis through hydrogen bond/metal coordination and soft-soft interactions/hard-hard interactions, respectively. The effectiveness of these cooperative catalysts is clearly delineated by the high stereoselectivity in reactions with highly coordinative substrates, and the specific activation of otherwise low-reactive pronucleophiles under proton transfer conditions. The rare earth metal/amide-based ligand catalyst was successfully applied to catalytic asymmetric aminations, nitroaldol (Henry) reactions, Mannich-type reactions, and conjugate addition reactions, generating stereogenic tetrasubstituted centers. Catalytic asymmetric amination and anti-selective catalytic asymmetric nitroaldol reactions were successfully applied to the efficient enantioselective synthesis of therapeutic candidates, such as AS-3201 and the β(3)-adrenoreceptor agonist, showcasing the practical utility of the present protocols. The soft Lewis acid/hard Brønsted base cooperative catalyst was specifically developed for the chemoselective activation of soft Lewis basic allylic cyanides and thioamides, which are otherwise low-reactive pronucleophiles. The cooperative action of the catalyst allowed for efficient catalytic generation of active carbon nucleophiles in situ, which were integrated into subsequent enantioselective additions to carbonyl-type electrophiles.
authors.affiliation: The University of TokyoBunko-ku, Tokyo, Japan. nkumagai@bikaken.or.jp
authors.forename: Naoya
authors.initials: N
authors.lastname: Kumagai
mesh_terms: D000577:Amides / Q000737:chemistry*; D002384:Catalysis; D058116:Lewis Acids / Q000737:chemistry; D008674:Metals, Rare Earth / Q000737:chemistry*; D011522:Protons; D013237:Stereoisomerism
chemical_list: D000577:Amides; D058116:Lewis Acids; D008674:Metals, Rare Earth; D011522:Protons