Design of asymmetric catalysts generally involves time- and resource-intensive heuristic endeavors. In view of the steady increase in interest toward efficient catalytic asymmetric reactions and the rapid growth in the field of machine learning (ML) in recent years, we envisaged dovetailing these two important domains. We selected a set of quantum chemically derived molecular descriptors from five different asymmetric binaphthyl-derived catalyst families with the propensity to impact the enantioselectivity of asymmetric hydrogenation of alkenes and imines. The predictive power of the random forest (RF) built using the molecular parameters of a set of 368 substrate–catalyst combinations is found to be impressive, with a root-mean-square error (rmse) in the predicted enantiomeric excess (%ee) of about 8.4 ± 1.8 compared to the experimentally known values. The accuracy of RF is found to be superior to other ML methods such as convolutional neural network, decision tree, and eXtreme gradient boosting as well as stepwise linear regression. The proposed method is expected to provide a leap forward in the design of catalysts for asymmetric transformations.

N-heterocyclic carbenes (NHCs) belong to the popular family of organocatalysts used in a wide range of reactions, including that for the synthesis of complex natural products and biologically active compounds....

A catalytic system for intramolecular C(sp2)–H and C(sp3)–H amination of substituted tetrazolopyridines has been successfully developed. The amination reactions are developed using an iron-porphyrin based catalytic system. It has been...

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.

The mechanism and origin of stereoinduction in a chiral N-heterocyclic carbene (NHC) catalyzed C-C bond activation of cyclobutenone has been established using B3LYP-D3 density functional theory computations. The activation of cyclobutenone as an NHC-bound vinyl enolate and subsequent reaction with the electrophilic sulfonyl imine leads to the lactam product. The most preferred stereocontrolling transition state exhibits a number of noncovalent interactions rendering additional stabilization. The computed enantio- and diastereoselectivities are in good agreement with the previous experimental observations.

The enantioselective cross-coupling reactions that transform a racemic mixture into an enantio-enriched product are in high contemporary demand. Elucidation of mechanism involving catalytic enantioselective transformation with racemic substrates is often challenging. Herein, we provide mechanistic insights derived through a comprehensive density functional theory (B3LYP-D3) investigation, on the origin of stereoinduction in a Rh-catalyzed asymmetric allylic arylation of racemic 3-chlorocyclohex-1-ene by using arylboronic acid. Energetically most preferred pathway is found to proceed through (a) a transmetalation wherein aryl group gets transferred from the boron of arylboronic acid to the Rh center of the catalyst, (b) an oxidative addition (OA) of Rh to the C–Cl bond of cyclohexenyl chloride, and (c) a reductive elimination (RE) leading to the bond formation between the Rh-bound phenyl and cyclohexenyl moiety to furnish the final arylated product. We note that each enantiomer of the substrate follows different OA modes, which is highly suggestive of a dynamic kinetic asymmetric transformation (DYKAT). Although the likelihood of DYKAT has been routinely invoked in the literature, quantitative energetic details, as well as mechanistic underpinnings such as the identity of the common intermediate, generally remain scarce. The R enantiomer of cyclohexenyl chloride is found to undergo an anti-SN2′ OA, whereas the S enantiomer prefers an anti-SN2 route to the common prochiral η3-Rh-π-allyl intermediate. High enantioselectivity in the ensuing RE, favoring the S enantiomer of the product, is traced to the lower activation barrier, which, in turn, arises from the lower distortion energy in the RE transition state when the si face of Rh-bound cyclohexenyl forms the bond with the phenyl group than when the re face is involved. The mechanistic insights presented herein are expected to be valuable toward understanding the DYKAT mechanism of conversion of racemic substrates to an enantiopure product.

The origin of high enantioselectivity in the formation of quaternary stereogenic carbon.

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