NAKED-C · New late-stage functionalization reagents for the construction of chiral centers to impact drug discoveryhis her

New late-stage functionalization reagents for the construction of chiral centers to impact drug discoveryhis her

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.

Data: CORDIS, © European Union