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 b b 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.

The Reformatsky analogous reaction for the synthesis of novel β-thioxoestersviausing aroyl isothiocyanates under solvent-free ball milling and conventional conditions

“…15,16 The efficiency with which the atoms in the starting components of a reaction are incorporated into the intended product is referred to as the AE 17 (i.e., how efficiently a reaction makes use of the reactant atoms). [18][19][20] However, because we employed two different reaction conditions to achieve identical target compounds, the AE values for the mechanochemical and traditional techniques were the same. The theoretical maximum efficiency of reactant usage is given by AE.…”

“…, how efficiently a reaction makes use of the reactant atoms). 18–20 However, because we employed two different reaction conditions to achieve identical target compounds, the AE values for the mechanochemical and traditional techniques were the same. The theoretical maximum efficiency of reactant usage is given by AE.…”

A Career in Catalysis: Masakatsu Shibasaki

“…Multimetallic RE complexes can also function in heterogeneous catalysis. An amide-based ligand 8 , , bearing two phenol functionalities on both sides of l -Leu by amide linkage, forms an insoluble heterobimetallic complex with NdO 1/5 (O i Pr) 13/5 and NaHMDS in THF via self-assembly (Scheme ). , High-resolution ESI-MS and ICP analyses indicated that the heterogeneous catalyst comprised 8 :Nd:Na = 2:1:2, and nitroethane, which is used for catalyst preparation, is also incorporated into the catalyst.…”