Periodic Reporting for period 1 - SYNPHOCAT (Synthetic Bimodal Photoredox Catalysis: Unlocking New Sustainable Light-Driven Reactivity)
Reporting period: 2022-09-01 to 2025-02-28
Solar light is an inexhaustible, abundant, and free reactant that can promote the construction and transformation of molecules. The chemistry community is particularly interested in photocatalysis, which uses light energy to promote a chemical transformation. Photocatalysts (PCs) play a key role in transformative light-driven processes by donating or receiving electrons to or from the target substrate. The selection and structural refinement of PCs can channel reactivity to diverse mechanistic pathways, but often proceeds via trial and error. Here, I will use structure-property relationships to: 1) define novel bimodal organic PCs able to catalyse thermodynamically demanding and opposite photoredox events exploiting their electronically excited state; 2) explore the PCs’ reactivity by means of their radical ions, going beyond conventional photoredox approaches; 3) capitalise on the new reactivity and bimodal way of action of the PCs to implement novel selective transformations of biological targets under physiological conditions. These project core concepts will be accomplished by the rational evaluation and optimisation of the PCs physicochemical and structural properties as well as the careful analysis of the mechanistic features subtending the light-driven chemical events. Overall, SYNPHOCAT will deliver new conceptual and experimental tools for the sustainable light-driven construction and functionalisation of biorelevant molecules, opening the way to a new dimension of sustainable light-driven chemistry.
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.
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.
Several achievements from the SYNPHOCAT project are breakthroughs or significant advancements in their fields:
i) The photocatalytic construction of hybrid bioisosteres, with the development of CF2-BCAs as bioisosteric replacements for aryl ketones and ethers represents a breakthrough in synthetic and medicinal chemistry. This method offers broad substrate applicability and addresses critical needs for molecules with improved pharmacokinetic properties, significantly enhancing drug discovery potential. See publication 5.
ii) The development and use of novel highly reducing photocatalysts, with the introduction of 9ADA and 12ADBA scaffolds marks a major advancement in organic photocatalysis. Their ability to facilitate proton-coupled electron transfer (PCET) has enabled previously inaccessible transformations, including activation of redox-inert substrates and metal-free polymerizations, pushing sustainable synthesis forward. See publication 8.
iii) An additional major advancement is the use of key mechanistic information to design novel reaction manifold that have solved longstanding synthetic challenges. This approach has been used in diverse research projects allowing access to previously inaccessible scaffolds such as unconventional stereochemical variants of oxetoindolinic frameworks and highly functionalised azetidines. See publication 1 and 9.
i) The photocatalytic construction of hybrid bioisosteres, with the development of CF2-BCAs as bioisosteric replacements for aryl ketones and ethers represents a breakthrough in synthetic and medicinal chemistry. This method offers broad substrate applicability and addresses critical needs for molecules with improved pharmacokinetic properties, significantly enhancing drug discovery potential. See publication 5.
ii) The development and use of novel highly reducing photocatalysts, with the introduction of 9ADA and 12ADBA scaffolds marks a major advancement in organic photocatalysis. Their ability to facilitate proton-coupled electron transfer (PCET) has enabled previously inaccessible transformations, including activation of redox-inert substrates and metal-free polymerizations, pushing sustainable synthesis forward. See publication 8.
iii) An additional major advancement is the use of key mechanistic information to design novel reaction manifold that have solved longstanding synthetic challenges. This approach has been used in diverse research projects allowing access to previously inaccessible scaffolds such as unconventional stereochemical variants of oxetoindolinic frameworks and highly functionalised azetidines. See publication 1 and 9.