Periodic Reporting for period 1 - NAKED-C (New late-stage functionalization reagents for the construction of chiral centers to impact drug discoveryhis her)
Período documentado: 2024-08-01 hasta 2026-07-31
Resumen del contexto y de los objetivos generales del proyecto
Modern society depends on the rapid discovery of new molecules for health, materials and sustainable technologies. Yet building molecular complexity still often requires long synthetic sequences, and late-stage modification of advanced molecules remains a major challenge. This project addressed that problem through the development of new methods for single-carbon transfer or insertion, inspired by the unique reactivity of highly reactive carbon species but redesigned into practical, selective, laboratory-compatible reagents and processes. The overall ambition of the project was to open new routes for the late-stage functionalization of drug molecules for accelerating drug discovery and lead optimization.
The scientific vision of the project was to turn the idea of “naked” or atomic-carbon reactivity into a useful synthetic platform. Rather than relying on free atomic carbon, which is too reactive for practical use, the project sought to create tailored carbon-transfer reagents that could deliver one carbon atom selectively into complex organic frameworks. This strategy aimed to provide chemists with new ways to decorate existing molecules without rebuilding them from scratch. Such an approach is especially valuable in medicinal chemistry, where small structural changes can strongly affect biological activity, selectivity, or physicochemical properties. The original proposal was explicitly framed around the development of novel synthetic methodologies and their application to tailored compounds of potential relevance for drug design and development.
The pathway to impact was therefore clear: first, design new reagents and activation modes for single-carbon transfer; second, establish selective reactions on simple model substrates; third, demonstrate applicability in complex scaffolds, drug-like molecules, and late-stage diversification. The project was hosted at ICIQ, an institute whose research mission includes chemistry for health and advanced catalysis.
In this broader context, the project set out to deliver enabling chemistry rather than one single target molecule. Its objective was to expand the toolbox available for modern synthesis by providing methods that can reshape carbon skeletons, introduce complexity at a late stage, and access molecular architectures that are difficult or impossible to reach through conventional routes. These goals are directly aligned with the needs of contemporary molecular innovation, especially in drug discovery, where faster access to diverse and three-dimensional analogues can shorten optimization cycles and improve decision-making in early development.
Work performed and main achievements
The work carried out in NAKED-C was organised into three scientific work packages. Together, they established a new strategy for late-stage diversification of drug molecules based on the controlled introduction and subsequent functionalization of a single carbon atom. The project delivered new reagents, new reactions, and new applications to medicinally relevant molecules.
Work Package 1 – Discovery Program.
The first stage of the project focused on the design and synthesis of a new class of “masked” atomic-carbon reagents. These compounds combined a diazo group, a hypervalent iodine unit and a redox-active ester in a single platform, enabling stepwise activation of one carbon atom. The project successfully prepared and characterized these reagents and showed, through mechanistic and electrochemical studies, that they could be activated under photoredox conditions. This led to the development of an efficient photocatalytic reaction for direct aryl C–H bond diazomethylation. The method was demonstrated on a representative range of arenes and heteroarenes, giving versatile intermediates for further transformations. This work established the conceptual and experimental foundation of the project.
Work Package 2 – Development Program.
The second stage translated this new chemistry to more complex and medicinally relevant molecules. A range of drug molecules was successfully functionalized in a late-stage manner, showing that the new reagents were effective beyond simple model substrates. The diazomethylated products were then diversified through a broad set of downstream reactions exploiting both the diazo group and the redox-active ester. These included bond-forming reactions with arenes, heterocycles, alcohols, water, carboxylic acids, thiols and hydrosilanes, as well as halogenation, azidation, cyclopropanation and radical-based transformations. In this way, the project demonstrated that a single installed carbon atom could serve as a modular assembly point for the construction of new chiral centres and structurally diverse analogues of drug-like molecules.
Work Package 3 – Med-Chem Program.
The medicinal-chemistry program was directed to the late-stage diversification of fenofibrate derivatives. This work included integration into an automated parallel synthesis workflow and led to a library of new analogues, highlighting the practical value of the NAKED-C concept for analogue generation in drug discovery.
Overall, the project achieved its main scientific goals. It delivered a new class of atomic-carbon reagents, established a photoredox-catalysed late-stage C–H diazomethylation, and developed a modular strategy to transform advanced molecules into structurally richer analogues. The core results were published in the Journal of the American Chemical Society.
The scientific vision of the project was to turn the idea of “naked” or atomic-carbon reactivity into a useful synthetic platform. Rather than relying on free atomic carbon, which is too reactive for practical use, the project sought to create tailored carbon-transfer reagents that could deliver one carbon atom selectively into complex organic frameworks. This strategy aimed to provide chemists with new ways to decorate existing molecules without rebuilding them from scratch. Such an approach is especially valuable in medicinal chemistry, where small structural changes can strongly affect biological activity, selectivity, or physicochemical properties. The original proposal was explicitly framed around the development of novel synthetic methodologies and their application to tailored compounds of potential relevance for drug design and development.
The pathway to impact was therefore clear: first, design new reagents and activation modes for single-carbon transfer; second, establish selective reactions on simple model substrates; third, demonstrate applicability in complex scaffolds, drug-like molecules, and late-stage diversification. The project was hosted at ICIQ, an institute whose research mission includes chemistry for health and advanced catalysis.
In this broader context, the project set out to deliver enabling chemistry rather than one single target molecule. Its objective was to expand the toolbox available for modern synthesis by providing methods that can reshape carbon skeletons, introduce complexity at a late stage, and access molecular architectures that are difficult or impossible to reach through conventional routes. These goals are directly aligned with the needs of contemporary molecular innovation, especially in drug discovery, where faster access to diverse and three-dimensional analogues can shorten optimization cycles and improve decision-making in early development.
Work performed and main achievements
The work carried out in NAKED-C was organised into three scientific work packages. Together, they established a new strategy for late-stage diversification of drug molecules based on the controlled introduction and subsequent functionalization of a single carbon atom. The project delivered new reagents, new reactions, and new applications to medicinally relevant molecules.
Work Package 1 – Discovery Program.
The first stage of the project focused on the design and synthesis of a new class of “masked” atomic-carbon reagents. These compounds combined a diazo group, a hypervalent iodine unit and a redox-active ester in a single platform, enabling stepwise activation of one carbon atom. The project successfully prepared and characterized these reagents and showed, through mechanistic and electrochemical studies, that they could be activated under photoredox conditions. This led to the development of an efficient photocatalytic reaction for direct aryl C–H bond diazomethylation. The method was demonstrated on a representative range of arenes and heteroarenes, giving versatile intermediates for further transformations. This work established the conceptual and experimental foundation of the project.
Work Package 2 – Development Program.
The second stage translated this new chemistry to more complex and medicinally relevant molecules. A range of drug molecules was successfully functionalized in a late-stage manner, showing that the new reagents were effective beyond simple model substrates. The diazomethylated products were then diversified through a broad set of downstream reactions exploiting both the diazo group and the redox-active ester. These included bond-forming reactions with arenes, heterocycles, alcohols, water, carboxylic acids, thiols and hydrosilanes, as well as halogenation, azidation, cyclopropanation and radical-based transformations. In this way, the project demonstrated that a single installed carbon atom could serve as a modular assembly point for the construction of new chiral centres and structurally diverse analogues of drug-like molecules.
Work Package 3 – Med-Chem Program.
The medicinal-chemistry program was directed to the late-stage diversification of fenofibrate derivatives. This work included integration into an automated parallel synthesis workflow and led to a library of new analogues, highlighting the practical value of the NAKED-C concept for analogue generation in drug discovery.
Overall, the project achieved its main scientific goals. It delivered a new class of atomic-carbon reagents, established a photoredox-catalysed late-stage C–H diazomethylation, and developed a modular strategy to transform advanced molecules into structurally richer analogues. The core results were published in the Journal of the American Chemical Society.
Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha
The project delivered two complementary methodological advances centered on single-carbon transfer chemistry. The first was the development of a novel class of atomic carbon reagents for late-stage photoredox-catalyzed aryl C–H bond diazomethylation. These reagents were designed to contain three orthogonal leaving groups, enabling sequential and modular downstream reactivity. Their photoredox activation generated electrophilic diazomethyl radicals that could react directly with aromatic C–H bonds, including in drug molecules, to give diazomethylated redox-active esters. This represented a substantial advance over earlier ester-based systems because the new reagent design greatly expanded the range of possible subsequent transformations.
This platform showed broad synthetic scope. The C–H diazomethylation worked on a range of simple arenes, heterocycles and selected drug molecules, with good chemo- and regioselectivity, especially on electron-rich aromatic sites. The resulting diazomethylated products were then diversified through both diazo chemistry and redox-active ester chemistry, enabling formation of C–C, C–O and C–S bonds, as well as transformations such as dichlorination, hydrofluorination, hydroazidation, click chemistry, cyclopropanation, and cyclopropenation. In parallel, the redox-active ester moiety enabled photocatalytic Giese-type alkylation, allylation and alkynylation, along with a borylation under nickel catalysis to access benzylic organoboron derivatives.
A particularly important outcome was the demonstration of the methodology in late-stage diversification of a fenofibrate derivative, where the platform was integrated into an automated parallel synthesis workflow. This produced a library of 24 new fenofibrate analogues, illustrating how the chemistry can support faster structure–activity relationship exploration in medicinal chemistry. The automated study also helped define current strengths and limitations of the method across sets of alcohol and alkynyl sulfone coupling partners. This work was performed in collaboration with Johnson & Johnson.
The second major achievement was the development of a single-carbon insertion into single C–C bonds using diazirines. In this strategy, diazirines served as precursors of arylchlorocarbenes that behaved as carbynoid species. Under photochemical conditions, these intermediates underwent site-selective insertion into tertiary C–H bonds, and the resulting intermediates were converted, through a silver-promoted Wagner–Meerwein rearrangement, into products corresponding to a formal one-carbon insertion into a single C–C bond. This provided a new skeletal editing platform based on selective C–H functionalization followed by bond reorganization.
This advance was demonstrated across a broad range of substrates. The methodology enabled six core-to-core conversions, including ring-expanded carbo- and heterocyclic systems, transformations of linear benzylic substrates, examples with simple alkanes, and late-stage modification of more complex molecules. The work showed that the process can be applied not only to model compounds but also to structures relevant to medicinal chemistry and natural-product-like cores. Importantly, the method was also adapted to a one-pot protocol and shown to be effective on gram scale in at least one representative case, supporting its practical potential.
Taken together, the work performed during the fellowship established a coherent toolkit for single-carbon transfer: one branch enabling late-stage construction of chiral centers from aryl C–H bonds through modular downstream functionalization, and another enabling skeletal editing through formal C–C bond insertion.
This platform showed broad synthetic scope. The C–H diazomethylation worked on a range of simple arenes, heterocycles and selected drug molecules, with good chemo- and regioselectivity, especially on electron-rich aromatic sites. The resulting diazomethylated products were then diversified through both diazo chemistry and redox-active ester chemistry, enabling formation of C–C, C–O and C–S bonds, as well as transformations such as dichlorination, hydrofluorination, hydroazidation, click chemistry, cyclopropanation, and cyclopropenation. In parallel, the redox-active ester moiety enabled photocatalytic Giese-type alkylation, allylation and alkynylation, along with a borylation under nickel catalysis to access benzylic organoboron derivatives.
A particularly important outcome was the demonstration of the methodology in late-stage diversification of a fenofibrate derivative, where the platform was integrated into an automated parallel synthesis workflow. This produced a library of 24 new fenofibrate analogues, illustrating how the chemistry can support faster structure–activity relationship exploration in medicinal chemistry. The automated study also helped define current strengths and limitations of the method across sets of alcohol and alkynyl sulfone coupling partners. This work was performed in collaboration with Johnson & Johnson.
The second major achievement was the development of a single-carbon insertion into single C–C bonds using diazirines. In this strategy, diazirines served as precursors of arylchlorocarbenes that behaved as carbynoid species. Under photochemical conditions, these intermediates underwent site-selective insertion into tertiary C–H bonds, and the resulting intermediates were converted, through a silver-promoted Wagner–Meerwein rearrangement, into products corresponding to a formal one-carbon insertion into a single C–C bond. This provided a new skeletal editing platform based on selective C–H functionalization followed by bond reorganization.
This advance was demonstrated across a broad range of substrates. The methodology enabled six core-to-core conversions, including ring-expanded carbo- and heterocyclic systems, transformations of linear benzylic substrates, examples with simple alkanes, and late-stage modification of more complex molecules. The work showed that the process can be applied not only to model compounds but also to structures relevant to medicinal chemistry and natural-product-like cores. Importantly, the method was also adapted to a one-pot protocol and shown to be effective on gram scale in at least one representative case, supporting its practical potential.
Taken together, the work performed during the fellowship established a coherent toolkit for single-carbon transfer: one branch enabling late-stage construction of chiral centers from aryl C–H bonds through modular downstream functionalization, and another enabling skeletal editing through formal C–C bond insertion.
Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)
The project moved beyond the state of the art in several ways. First, the project expanded the frontier of atomic-carbon-equivalent chemistry. The new reagents did not simply transfer a carbon atom; they were engineered to remain chemically programmable after installation while allowing the construction of chiral centers. This is a major conceptual advance because it turns a single C–H functionalization event into a gateway for multiple downstream bond-forming operations. In practice, this means that a simple aromatic feedstock or advanced drug molecule can be converted into a far richer family of analogues from a common intermediate.
Second, the project delivered value for late-stage functionalization, a field of growing importance in medicinal chemistry and molecular design. The methodology enabled direct editing of aromatic C–H bonds in complex molecules and translated these modifications into structurally diverse products, including new chiral centers and more three-dimensional architectures. This is significant because the ability to move efficiently from flat aromatic frameworks to more complex analogues can improve the exploration of biologically relevant chemical space.
Third, it provided a practical solution to the longstanding challenge of single-carbon insertion into single C–C bonds, an area far less developed than analogous transformations involving multiple bonds. By combining selective tertiary C–H insertion with a rearrangement step, the project introduced a new route to skeletal editing that accesses molecular frameworks difficult to obtain through conventional disconnections.
The project also demonstrated an encouraging level of practicality and transferability. The chemistry was shown on late-stage substrates, adapted in some cases to one-pot procedures, demonstrated at gram scale in representative examples, and integrated into an automated parallel synthesis platform for rapid analogue generation. These features increase the chances of uptake by other academic laboratories and by industrial medicinal chemistry teams.
Overall, the project generated an original body of knowledge at the interface of radical chemistry, carbene chemistry, skeletal editing, photoredox catalysis and late-stage functionalization. Its main contribution is not only a set of new reactions, but a new way of thinking about how one carbon atom can be inserted, revealed and exploited in complex-molecule synthesis.
Second, the project delivered value for late-stage functionalization, a field of growing importance in medicinal chemistry and molecular design. The methodology enabled direct editing of aromatic C–H bonds in complex molecules and translated these modifications into structurally diverse products, including new chiral centers and more three-dimensional architectures. This is significant because the ability to move efficiently from flat aromatic frameworks to more complex analogues can improve the exploration of biologically relevant chemical space.
Third, it provided a practical solution to the longstanding challenge of single-carbon insertion into single C–C bonds, an area far less developed than analogous transformations involving multiple bonds. By combining selective tertiary C–H insertion with a rearrangement step, the project introduced a new route to skeletal editing that accesses molecular frameworks difficult to obtain through conventional disconnections.
The project also demonstrated an encouraging level of practicality and transferability. The chemistry was shown on late-stage substrates, adapted in some cases to one-pot procedures, demonstrated at gram scale in representative examples, and integrated into an automated parallel synthesis platform for rapid analogue generation. These features increase the chances of uptake by other academic laboratories and by industrial medicinal chemistry teams.
Overall, the project generated an original body of knowledge at the interface of radical chemistry, carbene chemistry, skeletal editing, photoredox catalysis and late-stage functionalization. Its main contribution is not only a set of new reactions, but a new way of thinking about how one carbon atom can be inserted, revealed and exploited in complex-molecule synthesis.