Late-stage sulfonamidation, and sulfonimidamidation for drug discovery

This proposal delivers methods to install sulfonamide and sulfonimidamide groups into complex drug-like fragments and intermediates. A variety of catalytic methods will combine the drug fragments with RO-NSO reagents, which have been previously developed by the Willis laboratory. The methods will employ readily available reagents and be straightforward to perform. Sulfur(VI) functional groups, principally sulfonamides, have had an enormous impact on medicine. For example, there have been 72 FDA approvals of drugs that contain a sulfonamide, making up approximately 5% of all approved medicines. Although less developed, sulfonimidamides, the mono aza-analog of sulfonamides, have recently shown potential in medicinal applications (Scheme 1). This is mainly due to their potential for asymmetry at sulfur, basic nitrogen atom allowing further functionalisation and favourable balance of physicochemical properties. The Willis group have been exploring new approaches to these important functional groups, focusing on the development of high-oxidation state sulfur-linchpin reagents. For example, using the sulfinylamine reagent Tr-NSO, an approach to sulfonimidamides starting from pre-formed organometallics, such as Grignard reagents and organolithiums was reported. The next generation reagent, BiPhO-NSO, can be used for the direct synthesis of sulfonimidamides and sulfoximines, again starting from pre-formed organometallic reagents. More recently, t-BuO-NSO was discovered to deliver primary sulfonamides in a single-step transformation from pre-formed organometallics. These reagents have been developed in collaboration with UCB. These transformations work well, and allow straightforward access to these valuable S(VI)-derived functional groups. However, the need to use reactive organometallic reagents is a limitation, and in particular restricts functional group compatibility. The focus of this proposal is to develop catalytic methods that allow reagents such as t-BuO-NSO and ArO-NSO to be used in combination with complex, drug-like fragments, to introduce sulfonamides and sulfonimidamides at a "late-stage". The implementation of late-stage-functionalisation approaches such as that envisioned in this work in a high-throughput pharmaceutical setting, may aid in the quicker identification of lead medicinal candidates. Our initial approach will be to exploit sulfonium salt intermediates. These are attractive intermediates as they can be readily prepared using a variety of methods, and can similarly be further functionalised using several mechanistically-distinct chemistries. Importantly for this application, sulfonium salts have been shown to undergo classical 2-electron transition-metal-catalysed reactions, such as Pd(0)/(II) cycles, and also photoredox promoted 1-electron chemistries. In summary, this project focuses on the development of new catalytic methods to introduce medicinally relevant sulfonamide and sulfonimidamide groups into drug-like fragments. Approaches based on both transition metal catalysis (likely Pd and Ni), as well as photoredox chemistry, will be explored. There will be a strong focus on delivering molecules of value to medicinal chemists. Application to array chemistry can also be envisioned within this type of project. Importantly, the direct relevance, and targeting of medicinally relevant motifs, means that the close involvement of a pharmaceutical industry partner, such as UCB, would add enormously to what could be achieved in this project. The project falls within the EPSRC research areas of "The mathematical and physical sciences powerhouse", and "Transforming health and healthcare" and will be in collaboration with UCB.