Accessing Carbon-based S(VI) compounds via Sulfur-Fluorine (SuFEx) Exchange Reactions

Pomona College, Claremont CA

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Abstract

S(VI)-based compounds are a critical class of organic molecules with biomedical applications against inflammatory disorders, cancer, and bacterial infections. Approaches to making these carbon-based sulfur(VI) compounds are limited by the commercial availability of starting materials and harsh reactions preventing late-stage functionalization. Sulfur-fluorine exchange (SuFEx) chemistry is a new, promising pathway to synthesize sulfonylated products from sulfur(VI) fluorides and nucleophiles, but the unique stability of sulfur(VI) fluorides compared to other S(VI) halides introduces challenges for synthetic applications. We propose new (SuFEx) reactions to make carbon-based sulfonylated compounds using metals salt and sulfur(VI) fluorides. The proposed work is innovative because it seeks to develop attractive alternatives to induce sulfonylated moieties into organic molecules using affordable Lewis acid catalysts and easy-to-handle metal bases. Successful implementation of the research proposed herein will lead to novel, one-step SuFEx transformations toward S–N and S–C formation, enabling the development of new, diverse libraries for drug discovery. The first aim focuses on the development of calcium-catalyzed activation of sulfonyl, sulfonimidoyl, and sulfondiimidoyl fluorides to make sulfonamides as well as new chiral S(VI) compounds chiral bioisosteres sulfonimidamides, and sulfondiimidamides – critically underdeveloped classes of sulfonylated compounds with high potential as drug targets. The proposed transformations will represent a considerable advance over current methods that rely on starting materials that are challenging to synthesize or isolate. Additionally, these reactions would be the first Lewis acid-catalyzed SuFEx reaction. The second aim focuses on understanding the catalytic Lewis-acid activation mechanism of sulfur(VI) fluorides in SuFEx chemistry. These kinetic and computational studies will provide critical information for understanding key intermolecular interactions that govern the reaction, leading to a new generation of SuFEx reactions. The third aim will focus on developing a two- step, one-pot method to access sulfones and sulfonate esters from sulfonyl fluorides and fluorosulfates using metal enolates. The proposed SuFEx/decarboxylative method would establish the role of enolates as carbon nucleophiles to sulfonylated compounds. This would represent a new avenue in SuFEx chemistry and allow access to complex structures in sulfones and sulfonates esters key to their promise in drug discovery. The PI’s research has enhanced the research environment at Pomona College by engaging undergraduate students in biomedically relevant research with a significant impact on synthesis and medicinal chemistry.