Sustainable Phosphorus Chemistry: Catalytic Asymmetric SN2 Reactions

This proposal describes innovative new chemistry that will transform phosphorus-mediated substitution reactions by rendering them catalytic in the phosphorus component and, therefore, devoid of phosphorus waste. This will substantially reduce the economic and environmental footprint of phosphorus-mediated processes that are used by academic and industrial chemists on a daily basis and allow the full commercial potential of the chemistry to be realized. Furthermore, the world's supply of phosphate rock, the material from which most organophosphorus compounds are derived, is running out and the new catalytic reactions represent a sustainable alternative to current methods.

Despite over one hundred years of progress many of the transformations that underpin chemical synthesis, e.g SN2 reactions of activated alcohols, are inherently wasteful. Since the 1960s organic chemists have used phosphorus-mediated reactions, such as the Mitsunobu reaction, for the synthesis of important fine chemicals including pharmaceuticals. However, at present, this chemistry generates at least one molecule of phosphorus waste for every molecule of product produced. This impacts heavily on the environmental and economic footprint of the chemistry and for over a decade industry has been asking for a solution to this problem. For example, a recent report authored by process chemists from GlaxoSmithKline, Pfizer, Merck, Lilly, Schering-Plough and AstraZeneca stated that "the ideal Mitsunobu reaction would be catalytic in nature" and, most significantly, "future research towards making this transformation green is required to realize its full potential in commercial applications". To meet these demands new sustainable phosphorus chemistry is urgently required. This adventurous programme, that is aligned with the "Dial-a-Molecule" grand challenge, will deliver highly sought after substitution reactions that are catalytic in phosphorus. This will dramatically reduce downstream waste and open up a range of new applications in pharmaceutical and agrochemical synthesis that will benefit UK industry. Moreover, new fundamental chemistry of phosphine oxides, incorrectly assumed by many to be unreactive compounds, will be explored. Finally, the new strategy described is applicable to many other important phosphorus-mediated reactions and, therefore, forms a new platform for catalysis.

This proposal benefits from: (a) exciting preliminary results that indicate the chemistry proposed is deliverable; (b) a collaborative experimental, theoretical and mechanistic approach and (c) the PI's reduced teaching load (as a new academic) allowing him to closely monitor progress and drive the project forward.

Synthetic Organic Chemistry funded by the EPSRC has made a substantial contribution to the success of the pharmaceutical industry that in turn has made a major contribution to UK plc. The recent announcement of the "Dial-a-molecule" Grand Challenge Network underscores the need for continued investment in Organic Chemistry research to ensure that new fundamental chemistry is developed to allow industrial researchers to realise their molecular designs in a safe, cost-effective and environmentally benign fashion. The demand for the catalytic Mitsunobu chemistry outlined in this proposal has been well articulated by the pharmaceutical industry. For example, a recent report authored by process chemists from GlaxoSmithKline, Pfizer, Merck, Lilly, Schering-Plough and AstraZeneca stated that "the ideal Mitsunobu reaction would be catalytic in nature" and, most significantly, "future research towards making this transformation green is required to realize its full potential in commercial applications". The demand for this research and the potential beneficiaries are therefore clear: the chemistry will benefit all scientists involved in the synthesis of small organic molecules. The potential industrial beneficiaries will be made aware of the research through (a) the high profile publications generated; (b) talks given at conferences and at industrial sites by the PDRA / PI and (c) specific consultations to foster collaborations that will take place once the new catalytic reactions have been developed.

In terms of academic impact the research will open up a new field of catalysis in the area of organophosphorus chemistry and is therefore of fundamental importance. It is very likely that, following the publication of the work described in the proposal, other investigators will apply the strategy developed for the catalysis of other important phosphorus-mediated reactions.