Integrating organic chemistry and computational chemistry for efficient molecular discovery

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Background Several organic chemistry-oriented research programs require long, iterative, inefficient and cost-ineffective discovery and development processes. Over 2 decades ago, NMR spectroscopy and other techniques were integrated into the organic chemist's toolbox to significantly improve this process. In contrast, only a handful of organic chemistry groups in Canada truly integrate computational chemistry to get more insights into their organic molecules or synthetic methodologies while some routine experiments could be carried out directly by experimentalists with major benefits. Our research programs focuses on the integration of synthetic organic, computational and medicinal chemistry in order to increase the success rates in synthetic catalysis, biocatalysis and drug discovery. To do so, we develop and apply computational user-friendly and accurate predictive tools such as our software packages VIRTUAL CHEMIST for asymmetric catalyst design and FORECASTER for drug design. Continuing this trend, we will further develop tools for organic chemists and demonstrate that their integration in the organic chemistry lab is not only possible but also valuable. Research program and objectives 1. I propose to enhance the computer-aided design, synthesis and evaluation of novel asymmetric catalysts. We have developed synthetic strategies to prepare proline-like mono- and bicyclic scaffolds, which will now be used as a starting point for VIRTUAL CHEMIST-based virtual screening and design of organocatalysts. Through this process, a selection of catalysts will be synthesized and experimentally evaluated. 2. ACE accurately predicts the stereoselectivity of asymmetric reactions and more specifically organocatalysed reactions. Further major developments including the development of a force field for metals to study metal catalysis and validations are proposed. Among the challenges are the various coordination geometries that a metal can adopt (e.g., copper can be square planar, tetrahedral or in between). Previously, ACE was validated on literature data, throughout this research program the validations will now be experimental. 3. In the past years, we have developed novel concepts of directing/protecting groups (DPGs) and transient DPGs (TDPGs) which enable the regioselective functionalization of glucose derivatives with no need for protecting groups. Labile covalent bonds and non-bonded interactions modulate the reactivity of other functional groups of the molecule enabling regioselective transformations. We will expand the concept of TDPGs to nucleotides and polyols through computer-aided design and synthesis of novel TDPGs, their experimental validation of the predicted additional non-bonded interactions between the TDPGs and the polar groups of the molecule and their application to regioselective manipulation of polyol including carbohydrates.