Development of Sulfur-Based Reactions with Translational Applications

Project Summary/Abstract Cross-coupling reactions provide the most reliable and modular means to diverse chemical space, enabling the discovery of novel pharmaceuticals and elucidation of critical biological pathways. Seminal efforts spanning the last century have led to the development of a variety of metal-catalyzed cross-coupling reactions that allow efficient chemical bonds formation. However, these powerful chemical transformations still have shortcomings. Endeavors in developing novel coupling methodologies could address the identified challenges in the chemical literature. More importantly, they can be deployed to rapidly synthesize structurally and topologically complex compounds from accessible starting materials. Our research laboratory is seeking to invent new synthetic approaches to address this identified gap in the cross-coupling literature, specifically focusing on methodology development with the nonmetal element sulfur, one of the most abundant and inexpensive starting materials with versatile oxidation states (–2 to +6). We propose high valent sulfur complexes can enable diverse coupling modes in either stoichiometric or catalytic fashions. This proposal is organized into three sections with the goal of addressing current limitations in synthetic methodology and affording the ability to rapidly generate diverse and complex small molecule libraries. The first portion of this proposal illustrates a plan for sulfurane-mediated hindered C(sp2) and C(sp3) coupling via S(IV) to S(II) reduction. The second section illustrates how nonmetal sulfur (S(VI) to S(IV)) can provide a general and practical solution to alkyl boronate synthesis, especially for unprotected alkyl boronic acids. The last part of this proposal argues that persulfuranes have the potential to mediate synthetically valuable C–F bond formation, even possibly in a catalytic manner (S(VI) ↔ S(IV)). These described methods will enable facile access to scaffolds of interest for medicinal chemistry and biological evaluation. The biological properties of several families of compounds will be further investigated through our already established collaborations. Taken together, these innovative new synthetic modes could address the synthesis of challenging and medicinally relevant chemical scaffolds.