Transition State Models for Proline-Catalyzed Reactions

Transition State Models for Proline-Catalyzed Reactions 

Limitations of Hydrogen-Bonding Guided Transition State Models 

The important aspect of their study relates to the stereochemical mode of addition in the most preferred transition state in (a) and (b). In model-(a). Re-face addition of enamine carboxylic acid on the Re-face of the aldehyde is the lowest energy addition leading to an enantiomeric excess of about 99% in favor of (2S,3S) stereoisomer and anti-diastereomer as the major product In model-(b), on the other hand, anti-face addition involving the Si-Re mode respectively between enamine carboxylate and aldehyde is of the lowest energy. This approach predicts 

These two examples, of aldol and a-amination, evidently illustrate that a generalized transition state model demands additional refinements, taking the reaction conditions as well into account While the hydrogen bonding transition state models remained successful for many prohne atalyzed reactions, the apphcabihty of the same to specialized reaction conditions tends to surest the need for more investigations. Similarly, with a different series of pyrroUdine catalysts devoid of a-carboxylic acid, the need for alternative transition state models to the general hypothesis of carboxylic acid directed approach of the electrophile, is more readily evident. For example, one of the most popular pyrroUdine catalysts in use today carries bulkier a-substituents. 

With a-substituted pyrrolidine catalysts, there are a few mechanistic issues that deserve to be mentioned. Firstly, the formation of pyrrolidine enamine with the nucleophilic partner could encounter increased steric encumbrance near the amino nitrogen that can result in reduced efficiency. Secondly, alternative mechanisms without the involvement of enamines could also be operating [40]. However, among the limited set of available computational studies on a-substituted pyrrolidines, the enamine pathway has been effective towards rationalizing the stereochemical outcome of the reaction. In most of these, a steric control driven transition state model has been invoked wherein the incoming electrophile is guided towards the enamine double bond from the face opposite to that of the bulky a-substituent. 

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