An Organophotoredox Strategy to Mono- and Difluoroalkyl Bicyclo[1.1.1]pentanes: Towards Double Bioisosteric Replacements

The bioisosteric replacement is a fundamental strategy in modern medicinal chemistry to modulate the physicochemical and biological properties of a drug. This practice is based on the substitution of a chemical motif with another functionality, without altering the key aspects of molecular recognition of the parent compound in the specific biological environment. In this regard, the difluoromethylene group (-CF2-) is a suitable replacement of carbonyl groups (C=O) or oxygen atoms, conferring to the new modified molecule an increased lipophilicity and metabolic stability. On the other hand, bicyclopentanes (BCPs) have emerged as another class of valuable bioisosteric replacements for para-substituted phenyl rings and alkynes. The aim of the thesis is to combine these molecular entities and access unprecedented difluoroalkyl-BCPs, thus unveiling a new class of bioisosteres. To achieve this goal, we have developed a mild and general visible-light-driven method for the difluoroalkylation of [1.1.1]-propellanes using bromide derivatives as radical precursors. The process is triggered by a single electron transfer (SET) reduction of the starting bromide substrate from a photo-excited organic catalyst. The radical addition of difluoroalkyl radical intermediate to [1.1.1]-propellane, followed by an atom transfer radical addition (ATRA) process give access to a wide variety of synthetically versatile difluorinated BCP products, which can be further derivatized to access other relevant drug-like compounds.