A central theme of SYNPHOCAT is the development of innovative photocatalytic strategies employing rationally designed organic photocatalysts. My group recently design and developed 9-aryl dihydroacridines and 12-aryl dihydrobenzoacridines. These photocatalysts unlock previously inaccessible transformations through proton-coupled electron transfer (PCET) mechanisms and under visible-light, and mild reaction conditions. These findings extend the scope of both reductive and polymerization processes, allowing efficient and selective activation of redox-challenging substrates. Building on this concept, significant advancements have been made in the synthesis of complex bioisosteric structures relevant to drug discovery. The innovative use of difluoroalkyl bicycloalkanes (CF2-BCAs) as hybrid bioisosteres demonstrates the utility of such new photocatalytic systems towards radical generation to achieve structural bioisosteric analogues with improved pharmacokinetic properties. These hybrid scaffolds were shown to retain bioactivity in medicinal contexts, as illustrated by the design of a Leukotriene A4 hydrolase inhibitor.
We also used visible-light photocatalysis for the rapid and efficient (3 + 2) cycloadditions of aziridines with a number of diverse dipolarophiles, providing a versatile route to diverse nitrogen-containing compounds, including pyrrole derivatives, with high atom economy and stereoselectivity. We next explored, radical strain-release mechanisms, that further highlights the potential of photocatalysis to construct complex molecular architectures. In fact, azetidines were synthesized via the photocatalytic activation of azabicyclo[1.1.0]butanes (ABBs), enabling double functionalization in a single step. This strategy was applied to generate functional derivatives of pharmaceuticals, showcasing its utility in expanding synthetic access to biologically relevant molecules.
Finally, the mechanistic investigation of stereochemical control in light-driven [2+2] heterocycloadditions revealed the ability to precisely manipulate reaction pathways using light and steric effects, yielding new stereoisomeric variants previously inaccessible by conventional means.
These findings overall showcase groundbreaking progress in the field of photocatalysis and synthetic organic chemistry, emphasizing the key role of the newly developed photocatalytic systems, as well as the impact of light on the stereochemical outcome of light-driven reactions.
