Fujie Tanaka

Enantioselective Mannich reactions of ketones, including functionalized ketones, with N-unprotected ketimines of isatin derivatives are reported. These reactions are catalyzed by amine-based catalysts and afford highly enantiomerically enriched 3-substituted 3-aminooxindole derivatives as single regioisomers under mild conditions. The use of N-unprotected imines minimizes the need for protection and deprotection steps. The reactions enabled the enantioselective construction of tetrasubstituted carbon centers and generated unprotected primary amine groups upon C–C bond formation with the N-unprotected ketimines. The primary amine groups generated in the products did not interfere with the aminocatalysis. The reactions did not require either a decarboxylative strategy (i.e., the use of β-ketoacid derivatives as reactants) or preformed enol ether derivatives to obtain the Mannich reaction products with high regio- and enantioselectivities.

Catalytic formal aldol condensation reactions between β‐ketophosphonates and arylaldehydes, in which the C−C double bond formation occurs at the γ‐position of the β‐ketophosphonate, are reported. The reactions were performed in the presence of a catalyst system composed of p‐anisidine and trifluoroacetic acid under mild conditions. Mechanistic investigations suggest that a Mannich reaction followed by elimination results in the formation of the γ,δ‐unsaturated β‐ketophosphonate. Although the β‐ketophosphonate has an active methylene group, the bond formation occurred selectively at the γ‐position of the β‐ketophosphonate.

In molecules with central chiral centers functionalized with aryl groups, the rotation of the single bond between the aryl group and the central chiral center may be hindered. Enantioconvergent alkylation reactions of racemic diastereomers to construct all‐carbon quaternary stereocenters resulting in easing of the rotation around the axes are described. We demonstrated that the rotation of the bond between a central chiral carbon center and a dihydrobenzofuranone can be tuned by selection of either a tertiary carbon bearing a hydrogen or a quaternary carbon at the central chiral center. The products have the benefits of a central chiral center and a flexibly rotatable bond, which can facilitate interactions with other molecules.

Reactions of pyruvates as nucleophiles under catalytic conditions are difficult to control without the use of enzymes as catalysts. Here, enantioselective aldol reactions of pyruvates with chlorinated and fluorinated aldehydes and ketones under organocatalytic conditions, in which pyruvates act as nucleophiles, are reported. Based on analyses of self-aldol reactions of pyruvates in the presence of model catalysts, catalysts of the desired cross aldol reactions were developed. Using the primary amine-derived catalyst, the desired aldol products, i.e., γ-chlorinated alkyl or γ-fluorinated alkyl group-substituted γ-hydroxy α-ketoesters, were obtained in good to high yields with high enantioselectivities.

Catalytic asymmetric Mannich reactions and kinetic resolutions via retro-Mannich reactions were developed. The combination of these reactions afforded tetrasubstituted α-amino acid derivatives with er >99 : 1.

1,3-Diamine-derived catalysts were designed, synthesized, and used in asymmetric Mannich reactions of ketones. The reactions catalyzed by one of the 1,3-diamine derivatives in the presence of acids afforded the Mannich products with high enantioselectivities under mild conditions. In most cases, bond formation occurred at the less-substituted α-position of the ketone carbonyl group. Our results indicate that the primary and the tertiary amines of the 1,3-diamine derivative cooperatively act for the catalysis.

We demonstrated that the loading amounts and concentrations of reactant 1,3-cyclohexanedione affect reaction rates and outcomes. In certain cases, reactions with higher concentrations of 1,3-cyclohexanedione were slower than those with lower concentrations. By minimizing the use of the cyclic 1,3-dione derivatives and by tuning the reaction concentration, the acid catalyst was reduced to 0.1 mol % to afford the desired products in high yields, and the reaction scope was expanded.

Methods for chemical modification of proteins and peptides at certain positions are required for the preparation of antibody‐drug conjugates, protein‐ or peptide‐biotin conjugates, and conjugates used as therapeutics or as tools in biomedical research. We have developed chemical modification methods that use spirooxindole oxirane derivatives for the synthesis of protein‐ and peptide‐conjugates. In most cases, the epoxide group of the spirooxindole oxirane derivatives reacted to form a covalent bond with certain histidine residues and/or the N‐terminal amino group of peptides and proteins. The modification reactions of various proteins resulted in the formation of proteins modified at only one or two positions.

The development of regioselective aldol reactions of β‐methyl‐substituted cyclic enone derivatives with isatins to afford the aldol products with the bond formation at the methyl group of the β‐methyl‐substituted cyclic enone derivatives is described. Catalyst systems composed of DBU and pyrrolidine with DMSO were identified that resulted in the aldol reactions with almost perfect regioselectivities. DBU, pyrrolidine, and DMSO were all required to selectively afford the γ‐position‐reacted aldol products. With the use of this method, the scope of the 3‐substituted 3‐hydroxyoxindole derivatives that can be concisely synthesized was expanded.