Stereoselective Synthesis of aza-Sulfur(VI) Motifs as Design Elements for Drug Discovery

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The incorporation of "unusual" functional groups in medicinal chemistry provides access to new areas of biologically relevant chemical and intellectual property space. This is particularly attractive for groups that can provide improved physicochemical properties or novel replacement groups. In this context, aza-sulfur (VI) motifs (containing an S=N group) have emerged as offering an attractive balance of properties and controlled three-dimensional frameworks, as well as acting as bioisosteres for other important functionality. This is most notable in sulfoximines, which feature in AstraZeneca's ATR inhibitor AZD6738 (Ceralasertib), in clinical trials for various advanced cancers. This project will develop new stereocontrolled methods to generate aza-sulfur (VI) motifs that are predicted to provide valuable design options in medicinal chemistry. Methods will be developed that provide more facile access to these underexplored motifs and control the absolute 3-D shape to enable medicinal chemists to readily incorporate these into discovery programmes. New stereocontrolled processes will be developed for sulfoximines, sulfonimidamides, and sulfondiimine groups. Furthermore functionalisation of the respective nitrogen atoms will be developed to demonstrate tunability of the global properties, and the preparation of cyclic derivatives. This project fits with the EPSRC priority of transforming healthcare. We will develop facile access to new replacement groups for use in drugs and chemical probes, and expand the design options for medicinal chemists. The project will take two approaches to the asymmetric synthesis of the targeted structures by S-N and S-C bond formation, to maximise flexibility to incorporate these derivatives in a drug discovery programme, and to directly access to either configuration at the sulfur atom. Fundamental studies on the intermediates in these processes will provide new mechanistic insights. Finally we will explore the properties of the generated compounds.