Organocatalytic Mitsunobu Activation for Streamlined Pharmaceutical Synthesis

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.

Academic:
Catalytic activation of alcohols represents a major unsolved problem in the field of organic synthesis and, therefore, the work described in this proposal will have very significant academic impact resulting in a new area of organocatalysis.

Industry and society:
The project is of direct relevance to the UK pharmaceutical industry, which is the UK's most successful research-based industry and is responsible for approximately 10% of GDP. The sector is a major employer (>20,000 people in R+D, >70,000 total), has a trade surplus of over £3 billion and generates exports valued at over £20 billion. The competitiveness of the industry is based upon rapid discovery and development of new drugs, the majority of which are small organic molecules. The new synthesis methods that we will develop during this project will streamline the synthesis of chiral small organic molecules and will be applicable in drug discovery (small scale) and development (large scale) contexts. Our methods will result in cleaner and more economical syntheses of active pharmaceutical ingredients as well as drug candidates, which feeds into wealth creation. As legislation becomes increasingly stringent the demand for more complex chiral drug molecules is increased. Indeed, the Global Chiral Technology market is predicted to grow to $5.83 billion by 2017, with chiral synthesis accounting for ~80% of the total market share. For this reason fundamental research that delivers new methods for the synthesis of chiral molecules represents a strategic investment that will be linked to future wealth creation. In order to ensure that or methods are of direct relevance and benefit to the pharmaceutical industry we will collaborate with GlaxoSmithKline directly as a project partner. This will ensure that the new chemistry we develop is directly and immediately applicable in drug discovery and development. The Applicant also has strong links with AstraZeneca as well as the agrochemical industry (Syngenta) and, following development work at GlaxoSmithKline, a network of pharmaceutical and agrochemical companies will be established to further explore industrial applications.

The development of cleaner synthesis methods has broader societal value and results in the elimination of hazardous chemical reagents and waste streams. In the medium to long term the catalytic functionalisation and upgrading of renewable plant-derived alcohols may be possible using our chemistry. This will be particularly valuable as we begin to end our dependence upon crude oil-derived hydrocarbons as sources of feedstock chemicals.

The EPSRC portfolio and grand challenges:
Our fundamental studies on catalytic Mitsunobu reactions are aligned with the EPSRC portfolio (Physical Sciences: "Dial-a-molecule" Physical Science Grand Challenge; Chemical Biology and Biological Chemistry; Materials for Energy Applications. Healthcare Technologies: Diagnostics). Within the Dial-a-molecule grand challenge this work will impact upon the "Catalytic paradigms for 100% efficient synthesis" and "A step change in molecular synthesis" focus areas.

People:
The PDRA will gain significant expertise in the areas of synthetic organic chemistry, organocatalysis and organophosphorus chemistry. The PDRA will also benefit from a secondment at GlaxoSmithKline gaining insight into the chemistry used in the drug discovery and development process. This will place the PDRA in a very strong position with regard career progression in academia or the within the pharmaceutical, agrochemical or wider chemical industries.