
Chemistry
Radical strain-release photocatalysis for the synthesis of azetidines
R. I. Rodríguez, V. Corti, et al.
Discover a groundbreaking method developed by Ricardo I. Rodríguez and team that synthesizes densely functionalized azetidines using a novel photocatalytic radical strategy! This innovative approach showcases remarkable efficiency and versatility, opening doors to new azetidine derivatives, including celecoxib and naproxen.
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Introduction
Four-membered rings, particularly azetidines, are increasingly important in drug discovery due to their ability to mimic other heterocycles while offering improved three-dimensionality and metabolic stability. However, existing methods for azetidine synthesis suffer from limitations such as low functional group tolerance, the need for specialized precursors, or poor regio- and diastereoselectivity. Classical approaches like intramolecular displacement and lactam reduction are often hampered by these issues. While the aza-Paternò-Büchi reaction offers a milder approach using visible light and photocatalysts, its stereochemical control remains challenging. Another strategy utilizes strained 1-azabicyclo[1.1.0]butanes (ABBs), which can undergo double functionalization, but this process requires specific electrophilic partners and/or acidic conditions. The absence of a general, radical-based strategy for azetidine synthesis utilizing the strain-release properties of ABBs represents a significant gap in synthetic chemistry. This research aims to address this gap by developing a photocatalytic radical strain-release (RSR) method for accessing diversely functionalized azetidines from ABBs, leveraging the power of photocatalysis to achieve improved reactivity and selectivity.
Literature Review
The existing literature highlights the importance of azetidines in medicinal chemistry, with their prevalence in approved drugs despite the synthetic challenges. Existing methods, such as intramolecular displacement, lactam reduction, and the aza-Paternò-Büchi reaction, each possess drawbacks in terms of selectivity, functional group tolerance, or required reaction conditions. The use of ABBs as starting materials shows promise, but the scope of their application has been limited by requirements for specific reaction partners and conditions. This work builds upon existing research in photoredox catalysis and strain-release functionalization, aiming to combine these approaches for a more versatile and efficient synthesis of azetidines. The review further highlights the absence of general radical-based methods leveraging ABB strain release for azetidine construction, thus motivating the present study.
Methodology
The authors developed a photocatalytic radical strain-release (RSR) method for synthesizing azetidines. The core strategy involves the use of a photosensitizer (PS) to initiate the homolytic cleavage of sulfonyl imine precursors, generating two radical intermediates. These intermediates then react with an ABB substrate through a strain-release process, leading to the formation of a difunctionalized azetidine. The choice of PS is crucial. Initial experiments with thioxanthen-9-one (TXO) yielded low yields of the desired product and significant amounts of imine dimer. To address this, the authors explored different PSs, focusing on those with a small energy difference between their singlet and triplet excited states. This design choice, inspired by thermally activated delayed fluorescence emitters, aims to control the concentration of the triplet excited state and thereby regulate the rate of radical generation, thereby enhancing selectivity. A novel PS (PS 9) was identified as optimal, exhibiting high efficiency and selectivity. The reaction mechanism was investigated using time-correlated single-photon counting, laser flash photolysis (LFP), and electron paramagnetic resonance (EPR) spectroscopy, along with density functional theory (DFT) calculations. These studies confirmed an energy transfer (EnT) process between the excited PS and the sulfonyl imine, leading to homolytic cleavage of the N-S bond and subsequent radical addition to the ABB. DFT calculations supported the proposed mechanism, explaining the observed regioselectivity. The reaction was shown to be robust and versatile, accommodating various sulfonyl imines and ABB substrates, yielding densely functionalized azetidines in high yields. A three-component variation was also explored using aldimines and supersilanes, further expanding the scope of the method. Finally, post-synthetic manipulations demonstrate the utility of the generated azetidines, demonstrating their conversion to key intermediates for further chemical diversification.
Key Findings
The authors successfully developed a highly efficient and selective photocatalytic method for the synthesis of densely functionalized azetidines. The key to the success of the method lies in the careful selection and design of an organic photosensitizer (PS) with a small energy gap between its singlet and triplet excited states. This design choice enabled a fine control over the radical generation process, leading to high yields of the desired azetidine products and suppressing the formation of side products. The method tolerates various sulfonyl imine and ABB substrates, showcasing its versatility. The reaction mechanism was thoroughly investigated using a combination of experimental techniques (time-correlated single-photon counting, laser flash photolysis, EPR) and DFT calculations, which clearly demonstrated an energy transfer mechanism from the PS to the sulfonyl imine. The subsequent steps involve homolytic cleavage of the N-S bond, radical addition to the ABB, and final radical-radical combination to produce the azetidine. DFT calculations provided further support for the proposed mechanism and helped explain the observed regioselectivity. The generality of the method was demonstrated by the successful synthesis of a wide range of azetidine derivatives, including those bearing biologically relevant moieties such as celecoxib and naproxen, with excellent yields and high stereoselectivity where applicable. A three-component reaction variation using aldimines and supersilanes was also successfully implemented. Finally, the synthetic utility of the generated azetidines was showcased by the demonstration of various post-synthetic modifications, providing access to additional structurally diverse azetidine-based compounds. The method’s efficiency, selectivity, and versatility make it a valuable addition to the synthetic toolbox for accessing complex azetidine structures.
Discussion
The reported radical strain-release photocatalytic method provides a significant advancement in azetidine synthesis. The strategy addresses limitations of existing methods by offering a mild, efficient, and selective approach with broad substrate scope. The meticulous mechanistic studies provide a strong foundation for understanding the reaction's selectivity, paving the way for further optimization and expansion. The successful synthesis of biologically relevant azetidine derivatives highlights the method's potential in drug discovery. The three-component reaction variation further expands the method's synthetic utility, allowing access to a broader range of functionalized azetidines. The ability to selectively functionalize the C3 and N atoms provides synthetic flexibility for generating libraries of azetidine analogs for biological evaluation. This method could be particularly valuable in the development of new therapeutic agents featuring the azetidine core.
Conclusion
This research presents a highly efficient and versatile photocatalytic method for the synthesis of diversely functionalized azetidines using radical strain-release photocatalysis. The key innovations lie in the design of a photosensitizer for finely tuned radical generation and the application of this strategy to ABB substrates. The method's versatility and capacity to produce biologically relevant derivatives highlight its significant potential in drug discovery and organic synthesis. Future research might explore the application of this strategy to other strained heterocycles and expand the scope of functionalizable groups.
Limitations
While the method demonstrates high efficiency and selectivity for a wide range of substrates, some limitations exist. The specific photosensitizer employed might necessitate further investigation for broader applicability to different substrate classes. Although the method showcases excellent functional group tolerance, further studies might examine potential limitations with highly sensitive or reactive functionalities. The three-component reaction exhibits slightly lower yields than the two-component reaction. Further optimization might be needed to enhance efficiency in this variation.
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