Photochemical organocatalytic atropselective processes for the sustainable synthesis of biorelevant axially chiral molecules

Project Information

PHOTO-ATROP

Grant agreement ID: 101062360

DOI

10.3030/101062360

Project closed

EC signature date 8 June 2022

Start date 1 November 2022

End date 31 October 2024

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 186 720,08

Coordinated by

ALMA MATER STUDIORUM - UNIVERSITA DI BOLOGNA
Italy

Periodic Reporting for period 1 - PHOTO-ATROP (Photochemical organocatalytic atropselective processes for the sustainable synthesis of biorelevant axially chiral molecules)

Reporting period: 2022-11-01 to 2024-10-31

Summary of the context and overall objectives of the project

In recent years, enantioselective catalysis has become a critical tool in the synthesis of chiral molecules, particularly in drug development and the production of biologically significant compounds. While most enantioselective processes focus on sp3-hybridized stereocenters, many important natural products, drug molecules, and chiral ligands feature axial chirality, classifying them as atropisomers. Despite their significance, efficient methods for synthesizing atropisomers remain underdeveloped.
The Photo-Atrop project aims to address this gap by developing a sustainable and enantioselective organo-photocatalytic strategy for the synthesis of axially chiral molecules. Our approach leverages two complementary activation methods: photoredox catalysis and organocatalysis. These combined methods allow us to generate reactive radicals under mild conditions, enabling the selective functionalization of biaryl systems to produce atropisomers with high enantioselectivity.
What sets this project apart is its use of photochemical processes to introduce radical intermediates into atropselective reactions, an area that has remained largely unexplored. We believe that by harnessing visible light to generate reactive radicals from simple phenol substrates, we can create more sustainable and efficient pathways to synthesizing atropisomers.
This strategy also explores the potential for regio- and enantioselective perfluoroalkylation of biaryl phenols, a challenging transformation in traditional ground-state chemistry. The photochemical approach not only reduces the need for harsh reaction conditions but also opens up new possibilities for generating complex molecular structures that are difficult to achieve through conventional methods.
The Photo-Atrop project aims to provide insights that could transform how atropisomers are synthesized, offering a sustainable and scalable solution that aligns with the growing need for environmentally friendly chemical processes. By doing so, it addresses a significant challenge in synthetic chemistry, with potential implications for pharmaceuticals, materials science, and other industries that rely on chiral molecules.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The primary objective of our research was to develop a light-triggered enantioselective and atropselective process for synthesizing axially chiral phenols with high enantiopurity. The primary goal of our research was to develop a novel light-triggered enantioselective and atropselective process for synthesizing axially chiral phenols with high enantiopurity. To achieve this, we focused on meta-aryl substituted phenols, where a substituent on the ortho-position was strategically introduced to interact with a chiral organocatalyst. We began by exploring different wavelengths using Kessil LED lamps (390 nm, 427 nm, and 440 nm) to optimize the photochemical excitation of the phenolate intermediate. In parallel, we screened several organic and inorganic bases to promote phenolate formation under mild conditions, essential for ensuring the radical generation process.
A key challenge was the judicious selection of a chiral organocatalyst capable of inducing the desired axial chirality in the biaryl system. After testing a variety of chiral secondary amine catalysts, including the commercially available Jørgensen and MacMillan catalysts, we found that the Jørgensen catalyst in combination with tetramethylguanidine delivered the targeted ortho-perfluoroalkylated product. However, the reaction did not proceed without the external base, and further investigation revealed the formation of racemic products due to a significant base-catalyzed background reaction. Moreover, para-perfluoroalkylated by-products were also detected in smaller quantities.
We conducted temperature-dependent HPLC analysis to assess the rotational barrier of the aryl-aryl bond, which confirmed that rapid racemization was a primary obstacle to achieving high enantiopurity. Despite subsequent modifications of the aryl substituents and additional optimization efforts, we were unable to overcome the racemization issue, and this aspect of the project did not yield the desired atropselective results.

However, during these investigations, we uncovered a very promising side project centered on the photochemical perfluoroalkylation of 4-hydroxycoumarins, which led to the successful development of a new synthetic method. 4-Hydroxycoumarins are valuable scaffolds with significant therapeutic relevance, and their traditional functionalization methods rely on ground-state ionic reactivity. In contrast, we demonstrated that upon irradiation with purple light, 4-hydroxycoumarins could reach an excited state, enabling the generation of radicals from stable perfluoroalkyl reagents. This photochemical pathway allowed for the incorporation of perfluoroalkyl fragments, producing biologically relevant substituted chromanones through a dearomatization process.
The method proved robust, accommodating a broad range of electrophilic radicals and expanding the generality of the protocol. Detailed photophysical investigations revealed that deprotonated 4-hydroxycoumarins act as potent single-electron transfer (SET) reductants in their excited state, making them ideal candidates for activating perfluoroalkyl reagents toward radical formation. This successful approach not only broadens the scope of functionalizing 4-hydroxycoumarins but also opens up new possibilities for developing bioactive compounds and therapeutic agents. The versatility and mild conditions of this photochemical method make it a valuable contribution to sustainable synthetic methodologies in drug development and other relevant fields. The project is completed, and the resulting paper is being submitted to a scientific journal. Nevertheless, this strong reducing property of the 4-hydroxycoumarin develops a curiosity for us, that maybe this scaffold could be a promising photocatalyst or super reductant. Therefore, we modify the scaffold and try to explore its potential in diverse photocatalytic reactions as reductant. Interestingly, it showcases a versatile reactivity as a SET reductant and energy transfer catalyst. Therefore, we thoroughly characterized the photophysical properties in both the cases. This is project is also about to finish, manuscript preparation and supporting information is ongoing. It will be uploaded to a scientific journal soon.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our original objective was to develop a light-triggered, atropselective process for synthesizing axially chiral phenols with high enantiopurity. Atropselectivity is important because axially chiral molecules play a crucial role in drug design, catalysis, and natural products. If successful, this approach could have offered a novel, sustainable route to these biologically significant molecules. However, the project faced challenges, including racemization and insufficient rotational barriers, which prevented us from achieving the desired atropselective outcomes.
Despite this, we identified a promising alternative light-driven pathway, leading to the development of a successful photochemical strategy for the perfluoroalkylation of 4-hydroxycoumarins. This method allows for the single-step synthesis of chromanones, important scaffolds with significant bioactive potential. Unlike previous multi-step approaches, our method provides a more efficient and sustainable solution for generating these valuable compounds under mild conditions. The versatility of this approach, which enables the incorporation of various electrophilic radicals, broadens its applicability in drug development and other fields of bioactive molecule synthesis.
This result demonstrates a meaningful advancement in photochemical methodologies, and the prepared chromanones can serve as useful scaffolds in pharmaceutical applications where few methods previously existed to access them so efficiently. The ability to functionalize these scaffolds in a single step opens new opportunities for the rapid development of bioactive compounds and therapeutic agents. Given the increasing demand for sustainable and efficient synthetic methodologies in the pharmaceutical industry, our approach offers an environmentally friendly alternative to traditional methods, which often rely on harsher conditions and multi-step processes. Future work could explore further modifications to the functionalized chromanones to enhance their bioavailability or drug-like properties, as well as expanding the scope of substrates to include other biologically relevant scaffolds. This method’s efficiency and sustainability align with the European Union’s priorities for green chemistry, making it a valuable contribution to both academic and industrial research.

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