Refined Transition-State Models for Proline-Catalyzed Asymmetric Michael Reactions under Basic and Base-Free Conditions

摘要

The stereocontrolling transition state (TS) models for C−Cnbond formation relying on hydrogen bonding have generally been successful innproline-catalyzed aldol, Mannich, α-amination, and α-aminoxylation reactions.nHowever, the suitability of the hydrogen-bonding model in protic and aproticnconditions as well as under basic and base-free conditions has not been wellnestablished for Michael reactions. Through a comprehensive density functionalntheory investigation, we herein analyze different TS models for thenstereocontrolling C−C bond formation, both in the presence and absencenof a base in an aprotic solvent (THF). A refined stereocontrolling TS for thenMichael reaction between cyclohexanone and nitrostyrene is proposed. Thennew TS devoid of hydrogen bonding between the nitro group of nitrostyrenenand carboxylic acid of proline, under base-free conditions, is found to be morenpreferred over the conventional hydrogen-bonding model besides being ablento reproduce the experimentally observed stereochemical outcome. A DBU-bound TS is identified as more suitable fornrationalizing the origin of asymmetric induction under basic reaction conditions. In both cases, the most preferred approach ofnnitrostyrene is identified as occurring from the face anti to the carboxylic acid of proline−enamine. The predicted enantio- andndiastereoselectivities are in very good agreement with the experimental observations.