Reaction-based mechanistic investigations were performed for the hetero-Diels-Alder (hDA) reactions of enones with isatins that werec atalyzed by an amine-based catalyst system composed of three molecules (an amine, an acid, and at hiourea). The results indicated that the hDA product obtained from the reaction between hept-3-en-2-one and isatin using the amine-based catalysts ystem was generated via ak inetically controlled [4+ +2] cycloaddition reaction of the in situ-generated enamineo ft he enone as the diene and isatin as the dienophile. The amine of the threecomponent catalysts ystem wase ssential fort he catalysis and stereocontrol, but the other components of the catalyst system also played important roles.B ased on the results, plausible transition states are discussed, and the system was furtheri mproved by alteringt he loadings of the catalyst components for faster reactions with high stereoselectivities. The three-component catalysts ystems are flexible and can be tuned to obtain better results.

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The development of concise methods for the synthesis of functionalized small molecules is important in the search for new bioactive molecules. To contribute to this, we have developed oxa-hetero-Diels-Alder reactions of enones with isatins catalyzed by amine-based catalyst systems. Various spirooxindole tetrahydropyranones were synthesized either in enantiomerically enriched forms or as racemic forms depending on the catalyst system. The reaction products were further transformed at the ketone carbonyl group and the indole nitrogen. Using these reactions, functionalized spirooxindole tetrahydropyran derivatives with functional groups in four directions in a three-dimensional space were concisely obtained. From these synthesized compounds, an inhibitor of human ion channel Nav1.7 with μM-level activity was identified, indicating that the developed reaction methods are useful for providing molecules for the discovery of new biofunctional molecules.

The decalin structure is found in bioactive molecules. We have developed catalytic enantioselective formal (4+2) cycloaddition reactions via aldol-aldol cascade reactions between pyruvate-derived diketoester derivatives and cyclohexane-1,3-dione derivatives that afford highly functionalized decalin derivatives. The reactions were performed using a quinidine-derived catalyst under mild conditions. Decalin derivatives bearing up to six chiral carbon centers including tetrasubstituted carbon centers were synthesized with high diastereo- and enantioselectivities. Five to six stereogenic centers were generated from achiral molecules with the formation of two C-C bonds in a single transformation resulting in the formation of the decalin system.

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The HKR of racemic syn- or anti- alkoxy- and azido epoxides catalyzed by Co(salen) complex affords a practical access to a series of enantioenriched syn- or anti- alkoxy- and azido epoxides and the corresponding 1,2-diols. This strategy has been successfully employed in the concise, enantioselective synthesis of bioactive molecules such as (S,S)-reboxetine and (+)-epi-cytoxazone.

Concise cascade reactions of pyruvates with aldehydes that generate functionalized dihydropyran derivatives in one pot have been developed. The products, dihydropyrans, were further concisely transformed to various molecules.

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