Reaction‐Based Mechanistic Investigations of Asymmetric Hetero‐Diels–Alder Reactions of Enones with Isatins Catalyzed by Amine‐Based Three‐Component Catalyst Systems

Abstract

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.

Catalytic asymmetric hetero-Diels–Alder reactions of enones with isatins to access functionalized spirooxindole tetrahydropyrans: scope, derivatization, and discovery of bioactives

“…Selected results of the screening from our previous report 2,3 are shown in Table 1. 3 The diastereomers of 3aa were able to be obtained as single diastereomer by silica gel column purification, and the enantiomeric purity of the major enantiomer was able to be increased by crystallization. The reaction catalyzed by only amine A and acid B without thiourea C was slower than the reaction catalyzed by the combination of A, B, and C (entry 3).…”

“…4 Although a number of spirooxindole cores have been synthesized, 2-7 efficient methods for the synthesis of tetrahydropyran-derived spirooxindoles had not been reported until our recent communication. 2,3 This method should allow concise access to various hDA products when substituted enones and isatins are used as reactants. We designed and optimized hDA reactions of enones with isatins catalyzed by amine-based catalysts to concisely access to spirooxindole tetrahydropyranones (Scheme 1).…”

“…2 The catalyst system composed of amine A, acid B, thiourea C was identified as the best among those tested (Scheme 2). 2,3 When the loadings of acid B and thiourea C were increased, the reaction with a reduced loading of amine A also afforded product 3aa with high diastereoand enantioselectivities (entry 6). The enantioselectivity of 3aa was higher in the reaction using the three-component catalyst system composed of A, B, and C than in the reactions using only A and B or only A and C (entries 1, 2, and 5 versus entries 3 and 4).…”

“…The enantioselectivity of 3aa was higher in the reaction using the three-component catalyst system composed of A, B, and C than in the reactions using only A and B or only A and C (entries 1, 2, and 5 versus entries 3 and 4). 2,3 The major stereoisomer of the product obtained by the reaction catalyzed by amine A, acid B, thiourea C was determined to be (2'S,6'R)-3aa by the X-ray crystal structural analysis of the p-toluenesulfonohydrazide derivative. In addition, reaction in the presence of B and C without amine A did not afford 3aa.…”

“…1 The desired reaction methods for these purposes should accept a wide range of reactants to generate various product compounds, yet should provide the desired products with high selectivities. 3 Here we report expansion of the scope of the hDA reactions, derivatization of the hDA reaction products, and the use of the molecules synthesized by the hDA reaction methods for identification of biofunctional molecules. To address these points, we have recently developed hetero-Diels-Alder (hDA) reactions of enones with isatins catalyzed by amine-based catalyst systems that provide spirooxindole tetrahydropyranones under mild conditions (Scheme 1); the initial results have been reported as a communication.…”