Changing the Synthesis Landscape with Boron at the Helm: from Chiral Organometallics to Assembly Line Synthesis

Chemistry is unique amongst the sciences in that it has the power to constantly rejuvenate itself since it has the ability to study what it also creates. Creating molecules is where the developments in chemistry begin, which ultimately leads to the advancements in society. Within this context, the synthesis of organic molecules is central to many research disciplines from medicine to materials. However, despite substantial progress, the problems and difficulties associated with chemical syntheses severely limit the rate of growth and development of these disciplines. These fields are constrained by what chemists can make easily, rather than by the imagination of the scientists. In order to meet the emerging challenges across new disciplinary boundaries in a rapidly changing scientific landscape we require a step-change in the development of more rapid and robust techniques in organic synthesis.

Our proposal is to essentially 'grow' a carbon chain with specific substituents attached at specific places and with specific stereochemistry, so that so that at the end of the sequence a complex target molecule which may be a natural product, pharmaceutical or synthetic material will be produced essentially in one step. This is a hugely ambitious goal. The 'growth' phase is conducted using a chiral carbanion with a good leaving group attached (a carbenoid) which reacts with a boronic ester to give a homologated (enlarged) boronic ester. Repeating this reaction, using a different carbanion on the new boronic ester enables a second growth step to take place. The growth steps can be likened to adding lego pieces until a model has been created. Such a process has resonance with the remarkable machinery nature has evolved [polyketide synthases (PKS)] in its biosynthesis of polyketides. Indeed, by variation of the carbenoid and its stereochemistry (lego pieces) a diverse range of molecules with specific shape should be accessible thus enabling rapid structure-activity studies on complex molecules.

The boronic ester intermediates are stable organometallic reagents which are easily accessible with control over their shape. We plan to embark on a novel method of activation of these intermediates so that they can be transformed into a much broader range of molecules bearing new functionality. Such novel methodology would significantly expand the landscape of readily available chiral organic molecules.

The (desired) properties of a molecule are defined by its shape and functionality. Being able to control these critical features lies at the heart of chemistry and is what drives much of biological and materials chemistry. We aim to create new tools to enable us to easily synthesise a broad array of molecules with control over their shape and functionality. Our proposed synthesis program will provide an additional new tool to enable science.

Outside the academic research community we can identify the following users and beneficiaries of the research:
Industry: Pharmaceutical, Agrochemical and Fine Chemicals Industries. These industries are interested in reactions and strategies that provide greater efficiency and selectivity in transformations. They are also interested in new reactions that expand the available chemical space that can be probed by novel molecules as this could lead to new products. Much of the industry is focussed on easily accessible targets and so the space that they fish in becomes increasingly crowded. This proposal aims to address all of these specific issues. The new methodologies will not only lead to a significantly expanded landscape of readily available chiral organic molecules but also greater efficiency and selectivity in the synthesis of complex molecules.
We have a track record in patenting our research discoveries and have filed 8 patents to date. In addition we recently developed a new and much more efficient way of making pharmaceutically relevant heterocycles e.g. morpholines, piperazines, diazepines etc. through the use of Ph2SCH2CH2BrOTf as an alternative to 1,2-dibromo-ethane. We recognised the potential of this work and through Aldrich, the reagent has now become commercially available, thus demonstrating the capability of our group to ensure that discoveries are exploited.
People Skills:
Another key output from the grant will be a cohort of highly skilled and accomplished young researchers, who will have had the opportunity to make contributions and gain expertise in a highly challenging and rewarding area of contemporary science and so support the needs of the academic and industrial sectors. The UK chemical and pharmaceutical industries, who are major contributors to UK wealth, rely on this output. Without support in synthesis training, industrial, academic and societal progress risks stalling in the face of a ferociously competitive global economy.
We take the training of students and post-docs in our group very seriously (this is the pathway towards this impact) and have a high success rate in placing them in industry, government and academia.
Knowledge
In this proposal we have put forward fundamentally new transformations and new concepts which have the potential to open up new fields of research. This could have a significant impact in the field which would result in attracting high quality of individuals from abroad to our research group. This is likely to benefit UK in having a greater pool of highly talented and highly trained scientists that UK plc can potentially recruit from. It will also enhance the quality of our research output.
Collaboration
The extent of collaborations cannot be predicted at this stage as they are dependent on the outcome of the research. We have an extensive track record of past collaborations and will collaborate in the future within Bristol where complementary expertise is required e.g. conformational analysis, DFT calculations (Prof. Jeremy Harvey), NMR (Dr. Craig Butts), and physical organic chemistry (Prof. Guy Lloyd-Jones). New collaborations within the University will be pursued during the course of the grant if they become appropriate e.g. Prof. Chris Willis/Prof. Tom Simpson in biosynthesis studies of certain natural products (alpha 1, mycolactone) and making hybrid natural products by using semi-synthesis and modified PKSs; Dr. Charles Faul, a materials chemist with expertise in the design and synthesis of functional and switchable nanostructured materials and novel liquid crystals and a member of the implementation team of the Bristol Centre for Functional Nanomaterials DTC (specifically managing and expanding industry contacts and applications for the BCFN); Prof Paula Booth (Biochemistry), on investigations of the effects of specific lipid stereoisomers (sulfolipid I) on membrane transport proteins.