Organocatalytic Mitsunobu Activation for Streamlined Pharmaceutical Synthesis

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One of the major challenges facing scientists today is the need to produce essential organic molecules such as pharmaceuticals and agrochemicals in an energy efficient and non-polluting fashion. Inherent in this problem is the necessity to form new chemical bonds predictably and under environmentally benign conditions. Unfortunately, at present many of the methods used by synthesis chemists are inherently wasteful and produce one (or more) molecules of waste along with every molecule of product. This proposal focusses on one such chemical reaction - the Mitsunobu reaction. Originally developed in the 1960s, the reaction is still being used in its original form, which involves the use of two stoichiometric chemical reagents - one of which is toxic and explosive. As a result, a typical reaction generates nearly twice as much waste as product. Despite this very poor level of efficiency, the reaction is carried out in laboratories around the world on a daily basis because it represents the state-of-the-art method for nucleophilic substitution of alcohols with inversion of configuration. For this reason a catalytic Mitsunobu reaction, in which no stoichiometric reagents are required, would have a major impact on the field of chemical synthesis. However, there remain fundamental chemical challenges to overcome and no general solution has been described to date.In this proposal we describe unprecedented catalytic Mitsunobu reactions that are mediated by a new family of organocatalysts. Most significantly, our new catalytic reactions do not require any additional chemical reagents, generate water as the sole by-product and occur with the same predictable stereochemical outcome as the conventional stoichiometric reactions. Therefore, they represent very powerful alternatives to existing methods. Furthermore, we also describe catalytic enantioconvergent Mitsunobu reactions that allow resolution of racemic alcohols without sacrificing the unwanted enantiomer. This represents a new approach to the kinetic resolution of alcohols for the production of high value enantiomerically enriched products. Finally, we demonstrate how the new catalytic reactions can be applied in very short and efficient syntheses of valuable active pharmaceutical ingredients and intermediates. This highly ambitious project is based upon exciting preliminary results that clearly demonstrate chemical feasibility of the new catalysis manifold. Pharmaceutical manufacturers have been asking for catalytic reactions of this type for over a decade and the potential commercial applications of this project have been recognised by GlaxoSmithKline. For this reason, this application is made with their full support in collaboration with Dr Helen Sneddon (Head of GSK Green Chemistry) as a project partner. The applicant has been working in the this area for over five years and his previous experience in phosphorus catalysis makes him uniquely placed to deliver this project. With EPSRC support now we can open up a new area of organocatalysis for future research and enhance the competitiveness of the UK pharmaceutical industry, which is responsible for £17bn of exports and 16% of the world's best selling drugs.