Cooperative Asymmetric Catalysis by N-Heterocyclic Carbenes and Brønsted Acid in γ-Lactam Formation: Insights into Mechanism and Stereoselectivity

Abstract

Current developments in the burgeoning area of cooperative asymmetric catalysis indicate the use of N-heterocyclic carbenes (NHCs) in conjunction with other catalysts such as a Brønsted acid. Herein, mechanistic insights derived through a comprehensive DFT (M06-2X) computational study on a dual catalytic reaction between an enal and an imine leading to trans-γ-lactams, catalyzed by a chiral NHC and benzoic acid, is presented. In the most preferred pathway, we note that the NHC catalyst activates one of the reactants (enal) in the form of a Breslow intermediate, whereas the electrophilic partner (imine) is activated by the benzoic acid through protonation of the imino nitrogen. In this article, we focus on the origin of cooperative action of both catalysts as well as on the stereoselectivity by identifying the stereocontrolling transition states. The explicit and cooperative participation of the Brønsted acid and NHC lowers the energetic barrier both in the Breslow intermediate formation and in the stereocontrolling step through a number of C–H···π, N–H···O, and π···π noncovalent interactions. The enantio- and diastereoselectivities computed using the transition state models with an explicit benzoic acid are in good agreement with the earlier experimental reports.

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…This can be attributed to the presence of additional stabilizing non- covalenti nteractions compared to the other conformations, as seen by comparing the corresponding NCI plots [57,93,94] in Figure 3b and through ac omparative AIM analysis (Figure 3c). [90,[95][96][97][98] More precisely,t he NCI plots show greater density of favorable non-covalent interactions (green patches) for Trans(re) comparedt oi ts counterpart. This is corroborated by the stronger (a, b, e, f, g, j) and additional (c, d) non-covalent contacts, successfully captured by AIM analysis.…”

“…An extensive conformational search for both atropisomers of alcohol 1 revealed that the Trans( re) orientation is strongly favored. This can be attributed to the presence of additional stabilizing non‐covalent interactions compared to the other conformations, as seen by comparing the corresponding NCI plots in Figure b and through a comparative AIM analysis (Figure c) . More precisely, the NCI plots show greater density of favorable non‐covalent interactions (green patches) for Trans( re) compared to its counterpart.…”

Recent Advances on Computational Investigations of N‐Heterocyclic Carbene Catalyzed Cycloaddition/Annulation Reactions: Mechanism and Origin of Selectivities

“…Based on Rovis's experimental report, Sunoj and co‐workers investigated the NHC and Brønsted acid cooperatively catalyzed [3+2] annulation reaction between enal 28 and imine 29 for the formation of γ‐lactam 30 at the SMD MeCN ‐M06‐2X/6‐31G(d, p) level in 2016 . As depicted in Scheme , the catalytic cycle begins with the nucleophilic addition of the chiral NHC to the electrophilic enal 28 , leading to the zwitterionic intermediate M49 .…”

A density functional theory study on mechanisms of [4 + 2] annulation of enal with α‐methylene cycloalkanone catalyzed by N‐heterocyclic carbene

“…[17][18][19][20][21][22][23][24][25] More recently, the Sunoj [26][27][28] group performed a theoretical study on mechanisms and enantioselectivity of NHC-catalyzed Stetter and annulation reactions of enals. Moreover, some teams [29][30][31] studied a series of reactions involving the proton transfer process and showed an interesting result that the in situ formed acid can be assisted, which has attracted our attention.…”