An Extraordinary Photochemical Reaction of Pyrrole - A New Tool for Molecular Complexity

This proposal aims to explore a powerful photochemical reaction recently discovered in our laboratory. A variety of N-butenyl substituted pyrroles have been found to undergo an extraordinary photocycloaddition/rearrangement sequence to give tricyclic fused aziridines of high molecular complexity. Early studies have shown that as long as the pyrrole bears an electron withdrawing group on the 2-position the reaction sequence is highly tolerant of substitution. We will investigate the scope of the cycloaddition reaction by examining the effects of side chain substitution with a variety of cyclic and acyclic alkenes. The resulting aziridines will themselves be reactive species and should undergo a number of useful bond forming ring opening reactions. Once developed and understood the methodology will be applied as the key step in a very short synthesis of the alkaloid dendrobine. Overall the work in this proposal should serve to highlight the value of photochemistry and photochemical technology in modern chemical synthesis.

We hope that our work will encourage academics to consider a change of synthetic philosophy by adopting organic photochemistry for the construction of complex molecules. By providing enabling technology and demystifying the practical concerns of synthetic photochemistry we would hope that academics could consider this medium for generating powerful new synthetic methodologies that are the very definition of clean or green. As outlined in the proposal a powerful photochemical sequence can enable the synthesis of complex molecules such as dendrobine in very few steps without recourse to traditional protection-deprotection strategies. If academics adopt this philosophy in their synthetic planning then there would be a very positive impact in the creation of new complexity. Total synthesis would be become the engine for developing new methodologies rather than the slave to existing ones. Our flow-reactor has already had a major impact in the area of anti-malarial drugs: Seeburger has used our reactor in a stunning continuous-flow synthesis of the front-line anti-malaria drug Artemisinin. Seeburger's complete integrated flow system can now synthesize 800 g of this drug per day and an estimated 400 such reactor systems could provide the current world's supply of Artemisinin required to treat a disease which currently kills nearly a million people each year.

We also hope our work will encourage Pharma & Biotech to consider the complex polyheterocyclic structures developed in this proposal as viable templates for exploring new chemical space. The work outlined in this proposal will be attractive to Pharma & Biotech on three counts: (a) this previously unexplored molecular space is now very accessible; (b) flow-photochemistry as developed by us makes photochemical synthesis within the industry realistic for the first time and (c) our flow reactors enable the scale up of photochemistry (ours and others). Previously these molecules would have been considered too difficult and expensive to synthesize as potential drug candidates. If a UK company were able to synthesize complex drug like molecules based on the structures and philosophies outlined in this research, then the economic impact on that company could be enormous. For example they would have the IP rights to drug space that no competitor could match. This would apply equally at the discovery, process and manufacture stages of a drugs evolution to market. Thanks to the omnipresent lighting industry UV radiation has always been cheap and readily available, with powers ranging from a few milliwatts up to kilowatts. It is now time to exploit this by coupling modern technology with new chemistry to make high value molecules.

In a molecular context the UK's economic competitiveness has been seriously challenged in light of the economic downturn and serious levels of outsourcing to China and India. For example most of the large UK based Pharmaceutical companies now outsource significant stages of drug discovery to India and China, yet are doing this under the same, some would say, failed model of drug discovery. This has serious knock on effects for the UK economy, job market and academe. Much of this outsourcing is a direct consequence of the cost of the overall synthetic routes due to local labor, waste, safety, patent issues etc. Therefore, it seems logical to propose that if unique molecular complexity (and its IP) can be created in the UK and fed into drug discovery programs then there would be much less incentive to outsource which would have a very positive impact for UK plc.