Merging polar chemistry and photocatalysis: a multistep approach to enhance the sp³ fraction in organic molecules

Considering the “escape from flatland” concept, novel methodologies for increasing the Fsp3 fraction in organic molecules are highly sought-after in medchem campaign. This thesis explores the use of modern light-mediated processes for the generation of transient carbon radicals, followed by polar functionalization of the resulting intermediates. Specifically, the design of tailored radical acceptors bearing electron-withdrawing groups was pivotal to direct the first radical addition and facilitating the follow-up polar transformations to the desired end-products. This logic was applied to the development of novel strategies for building C(sp³)−C(sp³) frameworks from the coupling of abundant and inexpensive starting materials, such as C(sp³)–H bonds, carboxylic acids, aldehydes or amides. In the first part (Chapter 2-4), a photocatalytic radical addition was combined with a subsequent polar derivatization. Here, the design of tailored alkenes or imine-derivatives containing key electron-withdrawing groups was leveraged to fulfill the requirements for both the radical and polar elementary steps. In the second part (Chapter 5), the electrophilic activation of abundant amides was harnessed to access radical-sensitive iminium ion species, meeting the demands for the following radical addition.
In conclusion, the synergistic combination of polar and radical logics resulted in the development of four strategies to build C(sp³)−C(sp³) fragments. Specifically, these methods were designed with a focus on operational practicability, availability of starting materials and scalability, facilitated by the implementation of continuous-flow technology. Taken together, the radical-polar platform introduced here should open new avenues in organic synthesis, stimulating the design of novel radical acceptors to uncover unprecedent disconnections.