Predictive computational methods and experimental studies for the discovery of carbohydrate-based catalysts and directing protecting groups

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Molecular discovery is often a long, inefficient and expensive process. Our research integrates organic, computational and medicinal chemistry in order to increase the output rates in both synthetic catalysis and drug discovery as well as to efficiently develop novel catalysts and potential drugs. Continuing this trend, we will take advantage of our program ACE, which accurately predicts the stereoselectivity of asymmetric reactions and proposes accurate three-dimensional models of transition states and ground states, to guide the design and synthesis of novel asymmetric catalysts and directing/protecting groups with a focus on carbohydrates. In a first part, further developments of ACE are proposed to produce a versatile and more user-friendly tool. In a second part, computer-aided design, synthesis and evaluation of novel asymmetric catalysts is proposed. As an experimental validation of the accuracy of ACE, proline mimetics will be the starting point for ACE-based design, synthesis and evaluation of efficient proline-like catalysts. Then, using the same strategy, carbohydrate-based catalysts will be designed, synthesized and evaluated as asymmetric catalysts for reduction and addition to carbonyls. Examples of potential stereoselective asymmetric carbohydrate-based catalysts for Luche reduction and Grignard addition are given. Our expertise in both computational chemistry and carbohydrate scaffolding will be an asset. In the past years, we have also developed a novel concept of directing/protecting groups (DPG). A DPG is a protecting group that is involved in additional interactions (i.e., hydrogen bonds) with the molecule it protects, hence increasing or decreasing the reactivity of other functional groups of the molecule. We have already shown that the use of a specifically designed DPG enables the regioselective manipulations of glucopyrannosides and can therefore be used in the preparation of carbohydrate-based catalysts, drugs and oligosaccharides. In a third part we will present the ACE-guided development of novel DPGs for not only hexoses (to date DPGs have been developed for glucopyrannosides) but also nucleotides.