In asymmetric catalysis, a chiral catalyst bearing chiral center(s) is employed to impart chirality to developing stereogenic center(s). A rich and diverse set of chiral catalysts is now available in ...the repertoire of synthetic organic chemistry. The most recent trends point to the emergence of axially chiral catalysts based on binaphthyl motifs, in particular, BINOL-derived phosphoric acids and phosphoramidites. More fascinating ideas took shape in the form of cooperative multicatalysis wherein organo- and transition-metal catalysts are made to work in concert. At the heart of all such manifestations of asymmetric catalysis, classical or contemporary, is the stereodetermining transition state, which holds a perennial control over the stereochemical outcome of the catalytic process. Delving one step deeper, one would find that the origin of the stereoselectivity is delicately dependent on the relative stabilization of one transition state, responsible for the formation of the predominant stereoisomer, over the other transition state for the minor stereoisomer. The most frequently used working hypothesis to rationalize the experimentally observed stereoselectivity places an undue emphasis on steric factors and tends to regard the same as the origin of facial discrimination between the prochiral faces of the reacting partners. In light of the increasing number of asymmetric catalysts that rely on hydrogen bonding as well as other weak non-covalent interactions, it is important to take cognizance of the involvement of such interactions in the sterocontrolling transition states. Modern density functional theories offer a pragmatic and effective way to capture non-covalent interactions in transition states. Aided by the availability of such improved computational tools, it is quite timely that the molecular origin of stereoselectivity is subjected to more intelligible analysis. In this Account, we describe interesting molecular insights into the stereocontrolling transition states of five reaction types, three of which provide access to chiral quaternary carbon atoms. While each reaction has its own utility and interest, the focus of our research has been on the mechanism and the origin of the enantio- and diastereoselectivity. In all of the examples, such as asymmetric diamination, sulfoxidation, allylation, and Wacker-type ring expansion, the role played by non-covalent interactions in the stereocontrolling transition states has been identified as crucial. The transfer of the chiral information from the chiral catalyst to the product is identified as taking place through a series of non-covalent interactions between the catalyst and a given position/orientation of the substrate in the chiral environment offered by the axially chiral catalyst. The molecular insights enunciated herein allude to abundant opportunities for rational modifications of the present generation of catalysts and the choice of substrates in these as well as related families of reactions. It is our intent to propose that the domain of asymmetric catalysis could enjoy additional benefits by having knowledge of the vital stereoelectronic interactions in the stereocontrolling transition states.
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. In their organocatalytic manifestation, NHCs are known to impart umpolung reactivity to aldehydes and ketones, which are then exploited in the generation of homoenolate, acyl anion, and enolate equivalents suitable for a plethora of reactions such as annulation, benzoin, Stetter, Claisen rearrangement, cycloaddition, and C-C and C-H bond functionalization reactions and so on. A common thread that runs through these NHC catalyzed reactions is the proposed involvement of an enaminol, also known as the Breslow intermediate, formed by the nucleophilic addition of an NHC to a carbonyl group of a suitable electrophile. In the emerging years of NHC catalysis, enaminol remained elusive and was largely considered a putative intermediate owing to the difficulties encountered in its isolation and characterization. However, in the last decade, synergistic efforts utilizing an array of computational and experimental techniques have helped in gaining important insights into the formation and characterization of Breslow intermediates. Computational studies have suggested that a direct 1,2-proton transfer within the initial zwitterionic intermediate, generated by the action of an NHC on the carbonyl carbon, is energetically prohibitive and hence the participation of other species capable of promoting an assisted proton transfer is more likely. The proton transfer assisted by additives (such as acids, bases, other species, or even a solvent) was found to ease the kinetics of formation of Breslow intermediates. These important details on the formation,
in situ
detection, isolation, and characterization of the Breslow intermediate are scattered over a series of reports spanning well over a decade, and we intend to consolidate them in this review and provide a critical assessment of these developments. Given the central role of the Breslow intermediate in organocatalytic reactions, this treatise is expected to serve as a valuable source of knowledge on the same.
Molecular insights on the formation, detection, and even isolation of the Breslow intermediate, which is the most important species in N-heterocyclic carbene (NHC) catalysis, as obtained from experimental and computational studies, are presented.
Conspectus In the domain of reaction development, one aims to obtain higher efficacies as measured in terms of yield and/or selectivities. During the empirical cycles, an admixture of outcomes from ...low to high yields/selectivities is expected. While it is not easy to identify all of the factors that might impact the reaction efficiency, complex and nonlinear dependence on the nature of reactants, catalysts, solvents, etc. is quite likely. Developmental stages of newer reactions would typically offer a few hundreds of samples with variations in participating molecules and/or reaction conditions. These “observations” and their “output” can be harnessed as valuable labeled data for developing molecular machine learning (ML) models. Once a robust ML model is built for a specific reaction under development, it can predict the reaction outcome for any new choice of substrates/catalyst in a few seconds/minutes and thus can expedite the identification of promising candidates for experimental validation. Recent years have witnessed impressive applications of ML in the molecular world, most of them aimed at predicting important chemical or biological properties. We believe that an integration of effective ML workflows can be made richly beneficial to reaction discovery. As with any new technology, direct adaptation of ML as used in well-developed domains, such as natural language processing (NLP) and image recognition, is unlikely to succeed in reaction discovery. Some of the challenges stem from ineffective featurization of the molecular space, unavailability of quality data and its distribution, in making the right choice of ML model and its technically robust deployment. It shall be noted that there is no universal ML model suitable for an inherently high-dimensional problem such as chemical reactions. Given these backgrounds, rendering ML tools conducive for reactions is an exciting as well as challenging endeavor at the same time. With the increased availability of efficient ML algorithms, we focused on tapping their potential for small-data reaction discovery (a few hundreds to thousands of samples). In this Account, we describe both feature engineering and feature learning approaches for molecular ML as applied to diverse reactions of high contemporary interest. Among these, catalytic asymmetric hydrogenation of imines/alkenes, β-C(sp3)–H bond functionalization, and relay Heck reaction employed a feature engineering approach using the quantum-chemically derived physical organic descriptors as the molecular featuresall designed to predict the enantioselectivity. The selection of molecular features to customize it for a reaction of interest is described, along with emphasizing the chemical insights that could be gathered through the use of such features. Feature learning methods for predicting the yield of Buchwald–Hartwig cross-coupling, deoxyfluorination of alcohols, and enantioselectivity of N,S-acetal formation are found to offer excellent predictions. We propose a transfer learning protocol, wherein an ML model such as a language model is trained on a large number of molecules (105–106) and fine-tuned on a focused library of target task reactions, as an effective alternative for small-data reaction discovery (102–103 reactions). The exploitation of deep neural network latent space as a method for generative tasks to identify useful substrates for a reaction is demonstrated as a promising strategy.
Accomplishing high diastereo- and enantioselectivities simultaneously is a persistent challenge in asymmetric catalysis. The use of two chiral catalysts in one-pot conditions might offer new avenues ...to this end. Chirality transfer from a catalyst to product gets increasingly complex due to potential chiral match-mismatch issues. The origin of high enantio- and diastereoselectivities in the reaction between a racemic aldehyde and an allyl alcohol, catalyzed by using axially chiral iridium phosphoramidites P R/S –Ir and cinchona amine is established through transition-state modeling. The multipoint contact analysis of the stereocontrolling transition state revealed how the stereodivergence could be achieved by inverting the configuration of the chiral catalysts that are involved in the activation of the reacting partners. While the enantiocontrol is identified as being decided in the generation of P R/S –Ir−π-allyl intermediate from the allyl alcohol, the diastereocontrol arises due to the differential stabilizations in the C–C bond formation transition states. The analysis of the weak interactions in the transition states responsible for chiral induction revealed that the geometric disposition of the quinoline ring at the C8 chiral carbon of cinchona–enamine plays an anchoring role. The quinolone ring is noted as participating in a π-stacking interaction with the phenyl ring of the Ir−π-allyl moiety in the case of P R with the (8R,9R)-cinchona catalyst combination, whereas a series of C–H···π interactions is identified as vital to the relative stabilization of the stereocontrolling transition states when P R is used with (8S,9S)-cinchona.
Burgeoning developments in machine learning (ML) and its rapidly growing adaptations in chemistry are noteworthy. Motivated by the successful deployments of ML in the realm of molecular property ...prediction (MPP) and chemical reaction prediction (CRP), herein we highlight some of its most recent applications in predictive chemistry. We present a nonmathematical and concise overview of the progression of ML implementations, ranging from an ensemble-based random forest model to advanced graph neural network algorithms. Similarly, the prospects of various feature engineering and feature learning approaches that work in conjunction with ML models are described. Highly accurate predictions reported in MPP tasks (e.g., lipophilicity, solubility, distribution coefficient), using methods such as D-MPNN, MolCLR, SMILES-BERT, and MolBERT, offer promising avenues in molecular design and drug discovery. Whereas MPP pertains to a given molecule, ML applications in chemical reactions present a different level of challenge, primarily arising from the simultaneous involvement of multiple molecules and their diverse roles in a reaction setting. The reported RMSEs in MPP tasks range from 0.287 to 2.20, while those for yield predictions are well over 4.9 in the lower end, reaching thresholds of >10.0 in several examples. Our Review concludes with a set of persisting challenges in dealing with reaction data sets and an overall optimistic outlook on benefits of ML-driven workflows for various MPP as well as CRP tasks.
Controlling remote selectivity and delivering novel functionalities at distal positions in arenes are an important endeavor in contemporary organic synthesis. In this vein, template engineering and ...mechanistic understanding of new functionalization strategies are essential for enhancing the scope of such methods. Herein, meta-C–H allylation of arenes has been achieved with the aid of a palladium catalyst, pyrimidine-based auxiliary, and allyl phosphate. 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) was found as a critical solvent in this transformation. The role of HFIP throughout the catalytic cycle has been systematically studied. A broad substrate scope with phenethyl ether, phenol, benzylsulfonyl ester, phenethylsulfonyl ester, phenylacetic acid, hydrocinnamic acid, and 2-phenylbenzoic acid derivatives has been demonstrated. Interestingly, conformationally flexible arenes have also been selectively allylated at the meta-position using allyl phosphate. A combination of 1H NMR, 31P NMR, ESI-MS, kinetic experiments, and density functional theory (DFT) computations suggested that reaction proceeds through a ligand-assisted meta-C–H activation, allyl addition forming a Pd-π-allyl complex which is then followed by a turnover determining the C–C bond formation step leading to the meta-allylated product.
For catalytic asymmetric hydroformylation (AHF) of alkenes to chiral aldehydes, though a topic of high interest, the contemporary developments remain largely empirical owing to rather limited ...molecular insights on the origin of enantioselectivity. Given this gap, herein, we present the mechanistic details of Rh-(S,S)-YanPhos-catalyzed AHF of α-methylstyrene, as obtained through a comprehensive DFT (ω-B97XD and M06) study. The challenges with the double axially chiral YanPhos, bearing an N-benzyl BINOL-phosphoramidite and a BINAP-bis(3,5-t-Bu-aryl)phosphine, are addressed through exhaustive conformational sampling. The C–H···π, π···π, and lone pair···π noncovalent interactions (NCIs) between the N-benzyl and the rest of the chiral ligand limit the N-benzyl conformers. Similarly, the C–H···π and π···π NCIs between the chiral catalyst and α-methylstyrene render the si-face binding to the Rh-center more preferred over the re-face. The transition state (TS) for the regiocontrolling migratory insertion, triggered by the Rh-hydride addition to the alkene, to the more substituted α-carbon is 3.6 kcal/mol lower than that to the β-carbon, thus favoring the linear chiral aldehyde over the achiral branched alternative. In the linear pathway, the TS for the hydride addition to the si-face is 1.5 kcal/mol lower than that to the re-face, with a predicted ee of 85% for the S aldehyde (expt. 87%). The energetic span analysis reveals the reductive elimination as the turnover determining step for the preferred S linear aldehyde. These molecular insights could become valuable for exploiting AHF reactions for substituted alkenes and for eventual industrial implementation.
An increasing number of examples are now being reported that use chiral N-heterocyclic carbenes (NHCs) in conjunction with Lewis acids to enhance catalytic potential. Herein, we provide molecular ...insights into an NHC-catalyzed stereoselective annulation reaction between N-methylisatin and an enal leading to spirooxindole lactone in the presence of LiCl as the Lewis acid. Mechanistic features as well as the origin of enantio- and diastereoselectivities of the catalytic reaction have been unraveled using the density functional theory (B3LYP-D3) method. The key mechanistic steps of the reaction are identified to proceed through the formation of a Breslow intermediate between the chiral NHC catalyst and the enal, an enantioselective addition of the re face of this intermediate to the re face of the carbonyl group of N-methylisatin, and an intramolecular proton transfer and lactonization that eventually provide access to (2S,3R)-spirooxindole lactone as the final product. In the most preferred pathway, the Lewis acid is bound to the carbonyl group of the substrate in the form of LiCl(THF). We note that both DBU and LiCl(THF) employed in the reaction play crucial roles respectively in the formation of the initial Breslow intermediate (between the enal and NHC) and in the stereocontrolling C–C bond formation as well as in an ensuing intramolecular proton transfer. The explicit participation of LiCl(THF) is found to lower the activation barriers by 6.4 and 8 kcal/mol, respectively, for the stereoselective C–C bond formation and an ensuing intramolecular proton transfer, in comparison to the pathway devoid of the Lewis acid. The predicted enantio- and diastereoselectivities using the LiCl(THF)-bound transition state models have been in good agreement with the experimental observations. A number of weak interactions such as C–H···O, C–H···π, Cl···π, and lone pair···π have been identified as playing a vital role in offering additional stabilization to the transition state that corresponds to the major stereoisomer of the spirocyclic product.
-Hydroxylated cores are ubiquitous in natural products. Herein, we disclose the first template assisted
hydroxylation reaction. Experimental and
studies helped us to gain valuable mechanistic ...insights, including the role of the hexafluoroisopropanol (HFIP) solvent, during C-H hydroxylation. The reactive intermediates, prior to the C-H activation, have been detected by spectroscopic techniques. Additionally, the C-O bond formation has been extended to
-acetoxylation. The preparation of a phase II quinone reductase activity inducer and a resveratrol precursor illustrated the synthetic significance of the present strategy.
Insights into chiral induction for an asymmetric sulfoxidation reaction involving a single oxygen atom transfer are gained through analyzing the stereocontrolling transition states. The fitting of ...the substrate into the chiral cavity of a new class of imidodiphosphoric Brønsted acids, as well as weak CH⋅⋅⋅π and CH⋅⋅⋅O noncovalent interactions, are identified as responsible for the observed chiral induction.
Turn the stereo up: The first transition‐state (TS) model for a new class of axially chiral imidodiphosphoric acid catalysts in the title reaction is proposed using DFT(M06‐2X) calculations. The recognition of the substrate in the chiral pocket and a series of weak noncovalent interactions are responsible for stereoinduction. This stereoelectronic model differs from the commonly employed models which rely on steric interactions.
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