Challenges in Mechanistic Investigation of a Flexible Aminocatalyst as Demonstrated through Enamine Formation

Asymmetric catalysis has become a prominent topic in synthesis over recent decades. Conformational changes in the catalyst core play a significant role in the reaction, determining both its rate and selectivity. This article presents computational studies of enamine formation from cyclohexanone and the tripeptide catalyst Phe-Lys-Phe and considers challenges related to conformational search and the selection of an appropriate level of theory for studying flexible catalysts. This also demonstrates the importance of selecting the initial model system and how reducing the system under study or including the entire system in the model can impact the study's outcome. Furthermore, incorporating a water molecule into the model system significantly reduces the energy of proton transfer. Finally, the catalyst's ability to reorganize plays an important role, since it allows the energy of the transition states to be reduced. Thus, this shows that an alternative reaction pathway is more favorable than the one initially found, and the catalyst's flexibility allows and contributes its conformations to vary at different stages of the reaction.