Estratégias fotocatalíticas para a síntese de moléculas fluoroalquiladas com potencial bioativo

Abstract

Fluorinated compounds are highly relevant in contemporary chemistry due to the unique properties imparted by fluorine and are widely employed in the development of molecules of pharmaceutical and agrochemical interest. In this context, the introduction of fluoroalkyl groups represents an important strategy for modulating the properties of organic molecules. Although numerous methodologies have been developed, many still require harsh reaction conditions, transition metals, or reagents that are difficult to handle. In light of these challenges, visible-light photocatalysis has emerged as an efficient and sustainable approach for the controlled generation of radical species under mild conditions. This thesis therefore focuses on the development of metal-free photocatalytic methodologies for the incorporation of fluoroalkyl groups into organic substrates, with the aim of functionalizing molecules with potential bioactivity. In this context, Chapter 1 describes the development of a protocol for the difluoroacetylation and difluoroacetamidation of peptides containing the amino acid tryptophan. The methodology showed good compatibility with di- to heptapeptide sequences, enabling the synthesis of 21 products in yields of up to 73%. Mechanistic studies were also conducted, providing insights into the nature of the species involved and the proposed mechanism of these transformations. Chapter 2 focuses on the difluoroacetylation of vinyl-C-glycosides, a class of sugar-derived olefins, for the synthesis of glycoamino acids and difluoroalkylated neoglycopeptides. The approach enabled the synthesis of 24 products in yields of up to 81%, demonstrating compatibility even with unprotected sugar derivatives. Mechanistic studies were also conducted to investigate the steps involved in the process. Finally, Chapter 3 describes the development of a domino synthetic strategy for the preparation of a new class of perfluoroalkyl- and difluoroalkylsubstituted 2-pyrazolin-5-ones. The methodology exhibited broad functional group tolerance, enabling the investigation of an extensive substrate scope comprising 44 examples, with isolated yields ranging from 17 to 90%, and was successfully translated to a continuous-flow photochemical system. Complementary mechanistic studies provided further insights into the transformation and supported the proposed reaction mechanism. Overall, the strategies developed in this thesis expand the possibilities for the synthesis of fluorinated compounds through efficient, mild, and sustainable photocatalytic methodologies.