Applications of the Hofmann-Löffler reaction for C-H functionalization in Total Synthesis

Identifier:  TDX:3265

Handle: https://hdl.handle.net/20.500.11797/TDX3265

Authors:  Del Castillo Fernández, Estefanía

Abstract:
This doctoral Thesis summarizes advances in the field of C-H functionalization of aliphatic bonds. Methods for remote functionalization are necessary to expand the transformations available in the organic molecules. For this transformation, nitrogen-centered radicals are the perfect candidates to promote selective C-X bond formation over unactivated and distal C-H bonds. Nitrogen-centered radicals have been widely used as reactive intermediates in synthetic chemistry in the last decades, carrying out hydrogen atom transfer chemistry, where the well-known Hofmann-Löffler reaction was pioneering. The first research project is based on the concept of ‘interrupted Hofmann-Löffler’ reaction to the selective halogenation of organic molecules. For that, we employed sulfonamides or sulfamates esters as directing/protecting group of the transformation. These directing groups promote 1,5 or 1,6-hydrogen atom transfer generating the carbon-centered radical at γ or δ-positions. This radical is trapped by the addition of a halogen atom at this position. This protocol provided access to multiple halogenated organic compounds, such as cyclic and acyclic structures. In some cases, vicinal and geminal halogenation is observed. The second and the third part of my doctoral Thesis is related to the application of the Hofmann-Löffler reaction for the formation of the pyrrolidine ring into some alkaloids. The combination of hypervalent iodine(III) species with catalytic amount of molecular iodine seemed to be a robust tool for late-stage amination in the enantioselective synthesis of nicotine. In this regard, in the last part of the Thesis we demonstrated that this methodology could be applied to more complex molecules being able to synthesize the enantioselective hasubanan core where the pyrrolidine formation occurred in the last steps of the synthesis.