Periodic Reporting for period 1 - ChirAzaL (Unconventional Crafting of Chiral Aza-compounds using Visible Light Photocatalysis)
Reporting period: 2023-07-01 to 2025-06-30
The aim of ChirAzaL was to devise innovative and sustainable technologies in organic synthesis to access general, modular, and scalable crafting of two families of biologically relevant chiral nitrogen-containing molecules, namely: azetidines and multisubstituted linear amines. Such molecules are characterized by a complex three-dimensional arrangement and a high degree of saturation. Harnessing visible-light as sustainable and unexpensive source of energy, I will use a strain-release approach to access these synthetically complex scaffolds. Asymmetric phase transfer catalysis and chiral-metal templated catalysis will be the foundation of this proposal for securing stereocontrol. In order to accomplish the overarching goal of the research program, it will be divided into two main stages: an exploratory Stage I, followed by the consequently more applicative Stage II. The multidisciplinary skills acquired due to the interaction between the two phases, together with the transfer of knowledge between me and the hosting group will guarantee the successful realization of ChirAzaL.
Several photosensitisers were required to be tested. The first observations aided to conclude that the generation of dimer 4 was diminishing the yield of the desired compound 3. Reasoning to diminish the formation of 4, we decided to design a photosensitiser which beard a sufficiently high triplet energy to sensitise 2 but through an intentionally design poor manner. This idea targeted to become a poor triplet sensitirser and do not spend too much time in the triplet excited state. The latter was translated into a photosensitiser with a small gap of the excited states S and T. The WP 3 targeted the development of new photocatalysts (Figure 1) and testing the generality of the transformation. The generality of the developed method was explored by varying both the substitution pattern on the sulfonylimine and the ABBs. The reaction demonstrated broad applicability, tolerating a variety of functional groups, and consistently delivering the desired azetidines with high yield. Single-crystal X-ray analysis of diverse products revealed the relative configuration (Figure 2). Overall, WP1 successfully achieved its objectives by establishing a robust platform based on triplet-state sensitisation. This work not only lays the foundation for subsequent developments in WP2 but also represents a significant advance in the field of photochemistry. It demonstrates, for the first time, that strained ABBs can be directly functionalized following free radical chemistry -a long-standing mechanistic gap- and engaged selective bond-forming processes, offering a powerful new strategy for the construction of complex molecular architectures under sustainable conditions.
The ChirAzal project has made substantial progress toward achieving the scientific impact outlined in the original proposal. This breakthrough represents a fundamental advance in the field of synthesis and photochemistry, enabling new reactivity paradigms that were previously inaccessible. The methodology developed provides a sustainable, metal-free route to access complex, sp³-rich heterocycles with high levels of selectivity—molecular architectures that are of growing interest in pharmaceutical chemistry due to their potential to improve drug-likeness, conformational rigidity, and bioactivity.
In line with the original objectives, the scientific impact of the action lies primarily in the expansion of the synthetic toolbox available to chemists working at the interface of catalysis, photochemistry, and medicinal chemistry. The ability to control stereoselective bond formation via triplet-state reactivity without external sensitizers opens new frontiers for exploring new chemical space and complexity in drug development pipelines. The results have been consolidated into a full manuscript currently under submission to a top-tier journal, and additional follow-up studies are in progress.
While the societal and economic impacts of the project are necessarily indirect at this stage, the methodology's alignment with green chemistry principles (light as energy input, atom economy, catalyst efficiency, metal-free processes) supports the broader EU goals of sustainable innovation and environmental responsibility. Additionally, by reducing reliance on precious metal catalysts and enabling milder reaction conditions, ChirAzaL contributes to lowering both economic and ecological costs in synthetic methodology development.
Throughout the project, particular attention was paid to aligning with the principles of the MSCA Green Charter. The research activities were conducted using sustainable laboratory practices whenever possible, including the use of visible light as the primary energy input—an inherently green and energy-efficient strategy—and the avoidance of precious metal catalysts. Reactions were performed on small scale during the optimization phase to reduce material waste, and the project did not involve any travel beyond what was strictly necessary, in line with the Charter’s recommendations to reduce the environmental footprint of research.
Regarding supervision, the implementation was fully consistent with the highest standards promoted by the MSCA framework. The supervisor, Prof. Luca Dell’Amico, ensured continuous support and mentoring through regular in-person discussions, often on a daily basis, and always available when needed. In addition, structured feedback was provided at least once a month during group meetings, where I had the opportunity to present ongoing results to the entire research team. These sessions were instrumental in fostering critical discussion, refining research directions, and integrating the collective expertise of the group into the development of the project. This dynamic and responsive supervision environment played a key role in the scientific progress achieved during the action.
In line with the original objectives, the scientific impact of the action lies primarily in the expansion of the synthetic toolbox available to chemists working at the interface of catalysis, photochemistry, and medicinal chemistry. The ability to control stereoselective bond formation via triplet-state reactivity without external sensitizers opens new frontiers for exploring new chemical space and complexity in drug development pipelines. The results have been consolidated into a full manuscript currently under submission to a top-tier journal, and additional follow-up studies are in progress.
While the societal and economic impacts of the project are necessarily indirect at this stage, the methodology's alignment with green chemistry principles (light as energy input, atom economy, catalyst efficiency, metal-free processes) supports the broader EU goals of sustainable innovation and environmental responsibility. Additionally, by reducing reliance on precious metal catalysts and enabling milder reaction conditions, ChirAzaL contributes to lowering both economic and ecological costs in synthetic methodology development.
Throughout the project, particular attention was paid to aligning with the principles of the MSCA Green Charter. The research activities were conducted using sustainable laboratory practices whenever possible, including the use of visible light as the primary energy input—an inherently green and energy-efficient strategy—and the avoidance of precious metal catalysts. Reactions were performed on small scale during the optimization phase to reduce material waste, and the project did not involve any travel beyond what was strictly necessary, in line with the Charter’s recommendations to reduce the environmental footprint of research.
Regarding supervision, the implementation was fully consistent with the highest standards promoted by the MSCA framework. The supervisor, Prof. Luca Dell’Amico, ensured continuous support and mentoring through regular in-person discussions, often on a daily basis, and always available when needed. In addition, structured feedback was provided at least once a month during group meetings, where I had the opportunity to present ongoing results to the entire research team. These sessions were instrumental in fostering critical discussion, refining research directions, and integrating the collective expertise of the group into the development of the project. This dynamic and responsive supervision environment played a key role in the scientific progress achieved during the action.