Reagents and methodologies for the introduction of thiofluoroalkyl and fluorosulfur motifs

Identifier:  TDX:4711

Handle: https://hdl.handle.net/20.500.11797/TDX4711

Authors:  Bernús Pérez, Miguel

Abstract:
This thesis focuses on the development of reagents and methodologies for incorporating thiofluoroalkyl and fluorosulfur motifs. The work is divided in six chapters: The first chapter introduces the significance of organic synthesis and exposes the importance of sulfur and fluorinated motifs in chemical space exploration. The second chapter outlines the objectives of the thesis. Chapter III presents a systematic investigation of the medicinal chemistry properties of thiofluoroalkyl fragments. The logP and pKa values of a family of 2-SCH3 and 2-SCH2CH3 fluorinated pyridines are determined. Isosteric relationships among different fluorinated patterns are identified as key findings. Chapter IV focuses on the development of two saccharin-based reagents for the electrophilic introduction of -SCF2CF2H and -SCF2CF3 fragments. These reagents, synthesized from readily available starting materials, demonstrate the direct introduction of thiofluoroalkyl chains in various nucleophiles, including blockbuster drugs and natural products. Chapter VI introduces a modular flow platform for the introduction of -SO2F handles in phenol and amino derivatives via click reaction. The microfluidic system generates gaseous SO2F2 on demand which is then reacted it in a second module. The rapid SuFEx ligation allows the derivatization of therapeutically relevant small molecules, peptides, and proteins. The system can be coupled with other modules for telescoped transformations. Chapter V presents an improved preparation method for [SF5O-] complexes, which serves as a source for introducing -OSF5 fragments into organic molecules. The developed methodology overcomes limitations of existing methods by using readily available chemicals and laboratoryware, eliminating the need for expensive and specialized equipment. The optimization of complex preparation and mechanistic experiments are discussed, along with the functionalization of a primary alkyl triflate.