The dawn of the 21st century has brought with it a surge of research related to computer-guided approaches to catalyst design. In the past two decades, chemoinformatics, the application of informatics to solve problems in chemistry, has increasingly influenced prediction of activity and mechanistic investigations of organic reactions. The advent of advanced statistical and machine learning methods, as well as dramatic increases in computational speed and memory, has contributed to this emerging field of study. This review summarizes strategies to employ quantitative structure−selectivity relationships (QSSR) in asymmetric catalytic reactions. The coverage is structured by initially introducing the basic features of these methods. Subsequent topics are discussed according to increasing complexity of molecular representations. As the most applied subfield of QSSR in enantioselective catalysis, the application of local parametrization approaches and linear free energy relationships (LFERs) along with multivariate modeling techniques is described first. This section is followed by a description of global parametrization methods, the first of which is continuous chirality measures (CCM) because it is a single parameter derived from the global structure of a molecule. Chirality codes, global, multivariate descriptors, are then introduced followed by molecular interaction fields (MIFs), a global descriptor class that typically has the highest dimensionality. To highlight the current reach of QSSR in enantioselective transformations, a comprehensive collection of examples is presented. When combined with traditional experimental approaches, chemoinformatics holds great promise to predict new catalyst structures, rationalize mechanistic behavior, and profoundly change the way chemists discover and optimize reactions.1644 3.3. Perspective on CCM 1649 4. Chirality Codes 1649 4.1. Introduction to Chirality Codes 1649 4.2. Application of CICC 1649 4.3. Other Chirality Codes 1654 4.4. Conclusion and Perspective 1654 5. Molecular Interaction Field (MIF) Based Methods 1655 5.1. Alignment Dependent MIF Methods 1655 5.1.1. Background to Alignment Dependent MIF Methods 1655 5.1.2. Applications of Alignment Dependent MIF-Based Methods in Asymmetric Catalysis 1656 5.1.3.

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Cellular RNA labeling strategies based on bioorthogonal chemical reactions are much less developed in comparison to glycan, protein and DNA due to its inherent instability and lack of effective methods to introduce bioorthogonal reactive functionalities (e.g. azide) into RNA. Here we report the development of a simple and modular posttranscriptional chemical labeling and imaging technique for RNA by using a novel toolbox comprised of azide-modified UTP analogs. These analogs facilitate the enzymatic incorporation of azide groups into RNA, which can be posttranscriptionally labeled with a variety of probes by click and Staudinger reactions. Importantly, we show for the first time the specific incorporation of azide groups into cellular RNA by endogenous RNA polymerases, which enabled the imaging of newly transcribing RNA in fixed and in live cells by click reactions. This labeling method is practical and provides a new platform to study RNA in vitro and in cells.

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The Soai reaction has profoundly impacted chemists’ perspective of chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Herein, we describe the unprecedented observation of asymmetry amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc. Kinetic studies with a surrogate substrate and spectroscopic analysis of a series of zinc-alkoxides that incorporate specific structural mutations reveal a ‘pyridine-assisted cube escape’. The new tetrameric cluster functions as a catalyst that activates the substrate through a two point binding mode and poises a coordinated diisopropylzinc moiety for alkyl group transfer. Transition-state models leading to both the homochiral and heterochiral products were validated by density functional theory calculations. Moreover, experimental and computational analysis of the heterochiral complex provides a definitive explanation for the non-linear behavior of this system. Our deconstruction of the Soai system reveals the structural logic for autocatalyst evolution, function and substrate compatibility – a central mechanistic aspect of this iconic transformation.

Propargyl amines are versatile synthetic intermediates with numerous applications in the pharmaceutical industry. An attractive strategy for efficient preparation of these compounds is nitrene propargylic C(sp 3 )-H insertion. However, achieving this reaction with good chemo-, regio-, and enantioselective control has proven to be challenging. Here, we report an enzymatic platform for the enantioselective propargylic amination of alkynes using a hydroxylamine derivative as the nitrene precursor. Cytochrome P450 variant PA-G8 catalyzing this transformation was identified after eight rounds of directed evolution. A variety of 1-aryl-2-alkyl alkynes are accepted by PA-G8, including those bearing heteroaromatic rings. This biocatalytic process is

Selective functionalization of aliphatic C–H bonds, ubiquitous in molecular structures, could allow ready access to diverse chemical products. While enzymatic oxygenation of C–H bonds is well established, the analogous enzymatic nitrogen functionalization is still unknown; nature is reliant on preoxidized compounds for nitrogen incorporation. Likewise, synthetic methods for selective nitrogen derivatization of unbiased C–H bonds remain elusive. In this work, new-to-nature heme-containing nitrene transferases were used as starting points for the directed evolution of enzymes to selectively aminate and amidate unactivated C­(sp3)–H sites. The desymmetrization of methyl- and ethylcyclohexane with divergent site selectivity is offered as demonstration. The evolved enzymes in these lineages are highly promiscuous and show activity toward a wide array of substrates, providing a foundation for further evolution of nitrene transferase function. Computational studies and kinetic isotope effects (KIEs) are consistent with a stepwise radical pathway involving an irreversible, enantiodetermining hydrogen atom transfer (HAT), followed by a lower-barrier diastereoselectivity-determining radical rebound step. In-enzyme molecular dynamics (MD) simulations reveal a predominantly hydrophobic pocket with favorable dispersion interactions with the substrate. By offering a direct path from saturated precursors, these enzymes present a new biochemical logic for accessing nitrogen-containing compounds.

Diisopropylzinc alkylation of pyrimidine aldehydesthe Soai reaction, with its astonishing attribute of amplifying asymmetric auto­catalysisoccupies a unique position in organic chemistry and stands as an eminent challenge for mechanistic elucidation. A new paradigm of “mixed catalyst–substrate” experiments with pyrimidine and pyridine systems allows a disconnection of catalysis from auto­catalysis, providing insights into the role played by reactant and alkoxide structure. The alkynyl substituent favorably tunes catalyst solubility, aggregation, and conformation while modulating substrate reactivity and selectivity. The alkyl groups and the hetero­aromatic core play further complementary roles in catalyst aggregation and substrate binding. In the study of these structure–activity relationships, novel pyridine substrates demonstrating amplifying auto­catalysis were identified. Comparison of three auto­catalytic systems representing a continuum of nitrogen Lewis basicity strength suggests how the strength of N–Zn binding events is a predominant contributor toward the rate of auto­catalytic progression.