The past few decades have seen tremendous progress in the synthesis and operation of molecular systems capable of controlled mechanical movement. Here we review the use of molecular machines as catalysts for controlling chemical reactions. We highlight the various catalyst designs with a focus on how the mechanical motion is used to control catalysis with varying degrees of success. This review discusses the current challenges of designing effective catalysts, the scope and limitations of various systems, as well as future potential and aims for the field. Although it is difficult to predict which concepts will become most important as so much work is at the proof of concept level, it seems clear that molecular machines have the potential to significantly impact the field of catalysis.We present an overview of innovations in using molecular machines as catalysts and discuss the concepts and principles emerging from the field. It is apparent that selectivity is a key challenge. 14 Perfectly selective switching of devices between 'on/off' states or between distinct catalytic functions has proven difficult to achieve. As with all catalysis, product chemo-and stereo-selectivity is also challenging. In addition, molecular machines must deal with kinetic factors that may Molecular machine: a system in which a stimulus triggers the controlled motion of one molecular or submolecular component relative to another and potentially results in a net task (or work) being done. 7 Chemoselectivity:The preferential reaction of one functional group over another in a chemical reaction. 15 Stereoselectivity:The preferential formation of one stereoisomer over another in a chemical reaction. If the stereoisomers are enantiomers, enantioselectivity applies (quantified by enantiomeric excess, e.e., or enantiomeric ratio, e.r.), if they are diastereomers, diastereoselectivity applies (quantified by diasteriomeric ratio, d.r.). 16

Photo-mediated 6p cyclization is avaluable method for the formation of fused heterocyclic systems.H ere we demonstrate that irradiation of cyclic 2-aryloxyketones with blue LED light in the presence of an Ir III complex leads to efficient and high yielding arylation across ap anoply of substrates by energy transfer.2 -Arylthioketones and 2-arylaminoketones also cyclizee ffectively under these conditions. Quantum calculation demonstrates that the reaction proceeds via conrotatory ring closure in the triplet excited state. Subsequent suprafacial 1,4-hydrogen shift and epimerization leads to the observed cis-fused products.

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Optimization of the catalyst structure to simultaneously improve multiple reaction objectives (e.g., yield, enantioselectivity, and regioselectivity) remains a formidable challenge. Herein, we describe a machine learning workflow for the multi-objective optimization of catalytic reactions that employ chiral bisphosphine ligands. This was demonstrated through the optimization of two sequential reactions required in the asymmetric synthesis of an active pharmaceutical ingredient. To accomplish this, a density functional theory-derived database of >550 bisphosphine ligands was constructed, and a designer chemical space mapping technique was established. The protocol used classification methods to identify active catalysts, followed by linear regression to model reaction selectivity. This led to the prediction and validation of significantly improved ligands for all reaction outputs, suggesting a general strategy that can be readily implemented for reaction optimizations where performance is controlled by bisphosphine ligands.

Stereodefined four-membered rings are common motifs in bioactive molecules and versatileintermediates in organic synthesis. However, the synthesis of complex, chiral cyclobutanes is a largely unsolved problem and there is a need for general and modular synthetic methods. Here we report a series of asymmetric cross-coupling reactions between cyclobutenes and arylboronic acids which are initiated by Rh-catalysed asymmetric carbometallation. After the initial carborhodation, Rh-cyclobutyl intermediates undergo chain-walking or C-H insertion so that overall a variety of additions such as reductive Heck reactions, 1,5-addition and homoallylic substitution are observed. The synthetic applicability of these highly stereoselective transformations is demonstrated in the concise syntheses of the drug candidates Belaperidone and PF-04862853. We anticipate this approach will be widely adapted by synthetic and medicinal chemists, and while the carbometallation approach is here exemplified with Rh and arylboronic acids, it is likely applicable to other metals and nucleophiles.