Preparation of Enantioenriched Sulfonimidoyl Fluorides

This project falls within the EPSRC synthetic organic chemistry research area.
Sulfonyl fluorides (SFs) have attracted increasing attention in recent years, with their ability to act as covalent electrophiles reported widely in the literature. The development of "click-reactions" to SFs by Sharpless et al., facilitating substitution at sulphur readily i.e sulfur-fluoride exchange (SuFex), has enhanced interest for this functional group. Sulfonimidoyl fluorides (SIFs), nitrogen-containing analogues of SFs, were first reported in the 1980's by Johnson et al. However, they remain an underexplored class of compounds, with few reports of their synthesis and application. Importantly, SIFs have displayed improved hydrolytic stability compared to their SF counterparts without compromising reactivity - they were shown to label specific protein residues more rapidly. The tunable reactivity at nitrogen and chirality at the sulfur centre offers unique prospects of the SIF warhead as a tool for chemical biology and synthesis. Furthermore, derivatisation of SIFs is well established, thus a variety of medicinally relevant sulfur(VI) reagents can be obtained from SIFs in a facile manner.
To our knowledge the synthesis of enantioenriched SIFs has not yet been developed; thus a mild method that can facilitate their synthesis is highly desirable. Accordingly, the initial focus of this research will be to develop and optimise a route for synthesising SIFs in optically pure form. The use of chiral sulfinamides as starting materials for accessing optically pure sulfonimidamides and sulfoximines respectively has proven an attractive strategy in recent years. Chiral sulfinamides are typically bench stable and can be readily accessed using either stoichiometric chiral auxiliaries or via kinetic resolution of racemic sulfinamides. Therefore, we are initially interested in the synthesis of enantioenriched SIFs from chiral sulfinamides via the formation of a sulfur-fluorine bond. A divergent approach to both enantiomers of respective SIFs from a single enantioenriched sulfinamide is envisaged. In our preliminary work, we have successfully translated conditions for the oxidative halogenation of racemic sulfinamides for the synthesis of enantioenriched SIFs through the use of chiral sulfinamide precursors. Further optimisation to improve reaction yield and e.e is required. We will establish a library of SIFs in a racemic and enantioenriched manner by varying the substituents of our starting material at both carbon and nitrogen. This will provide some insight into the effect the substitution pattern may have on the chemical stability of these reagents. Another area of investigation would be alternative strategies to synthesise SIFs, exploring the use of milder set of reaction conditions.
We are interested in applying the developed methodologies to the synthesis of chemical probes, whereby the chemical stability of SIFs to a variety of reaction conditions will be examined. These compounds can then be directly compared to their SF counterparts, with the possibility of achieving selective reactivity based on the enantiomer of the reagent employed. In summary, the work proposed in this project will contribute a greater understanding to the SIF functional group. Through the first synthesis of optically pure SIFs we will gain an insight into their stereochemical fidelity and promising potential chemical probes, which will be of interest to the medicinal and agrochemical communities.

This programme is focused on a new cohort-driven approach to the training of next-generation doctoral scientists in the practice of novel and efficient chemical synthesis coupled with an in-depth appreciation of its application to biology and medicine.

This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.

We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.

The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.

We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.

We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).

Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.

The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.