Preparation of Enantioenriched Sulfonimidoyl Fluorides

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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.