Photoinduced Decarboxylative Phosphorylations

Projektinformationen

PhotoPhos

ID Finanzhilfevereinbarung: 101027513

DOI

10.3030/101027513

Projekt abgeschlossen

EK-Unterschriftsdatum 3 März 2021

Startdatum 1 September 2021

Enddatum 31 August 2023

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 224 933,76

EU-Beitrag

€ 224 933,76

Koordiniert durch

UNIVERSITY OF BRISTOL
United Kingdom

Periodic Reporting for period 1 - PhotoPhos (Photoinduced Decarboxylative Phosphorylations)

Berichtszeitraum: 2021-09-01 bis 2023-08-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Periodic Reporting for period 1: Reporting period: 2021-09-01 to 2023-08-31

Summary of the context and overall objectives of the project: Alkyl phosphonates play a ubiquitous role across diverse domains such as pharmaceuticals, agrochemicals, and materials science. Streamlining their synthesis could be significantly enhanced by harnessing readily available C(sp3) alkyl radicals—a versatile class of synthetic intermediates derived from carboxylic acid precursors under photocatalytic conditions. Presently, challenges persist in effecting alkyl radical addition to phosphite reagents due to their inherent low reactivity with phosphites and reversible addition through a-scission.

This work proposes the introduction of a novel phosphite reagent termed 'BecaP,' characterized by a radical-stabilizing catechol group and an efficient leaving moiety, specifically designed for trapping alkyl radicals. Utilizing visible light as a sustainable energy source, this reagent facilitates the synthesis of alkyl phosphonates in an irreversible manner. Leveraging recent advancements in decarboxylative borylation pathways, this initiative aims to significantly broaden photochemical methodologies, pioneering novel techniques for synthesizing organophosphorus compounds.

The envisioned project, situated at the University of Bristol, represents a pioneering endeavor seeking to expand the frontiers of synthetic chemistry. Its success hinges upon the generation, transfer, and dissemination of knowledge, fostering an environment conducive to innovation. Moreover, this endeavor aligns with a comprehensive training plan, fostering professional development while contributing to the advancement of synthetic methodologies in this domain.

• What is the problem/issue being addressed?
This project aims to address two key questions:
1. Development of novel visible-light-mediated photocatalytic decarboxylative phosphonylation methods for the broad range of C(sp 3 ) alkyl radicals, which was unprecedented by visible light photocatalysis before.
2. Applications of the developed method in the late-stage phosphonylations of drugs and synthesis of biologically active molecules e.g. Phaclofen
• Why is it important for society?
Organic chemistry is integral to the well-being of our society. It is through inventing and developing new reactions that we can identify the next generation of drugs, agrochemicals, and pharmaceuticals. From this perspective, the use of visible light to promote phosphonylation reactions might offer great opportunities in terms of sustainability.
• What are the overall objectives?
1 To develop novel approaches for the preparation of alkyl phosphonates.
2 To develop a robust phosphite reagent for less reactive alkyl radicals.
3 To apply the developed method in drug synthesis and late-stage drug modifications.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

I. In accordance with the MSCA proposal, the initiation of the decarboxylative phosphonylation project in our laboratory took place. Our preliminary investigations involved the examination of alkyl radicals, derived from both corresponding carboxylic acids and boronic acid derivatives, with a variety of commercially available (trimethyl/triethyl phosphite reagents) and easily obtainable phosphite reagents.
II. Following a series of meticulous optimization experiments, we successfully identified the most suitable phosphite reagent, aptly named "BecaP," which yielded the desired alkyl phosphonate products as outlined in the MSCA proposal (refer to our publication for comprehensive details). Subsequently, we broadened the scope of both deboronative and decarboxylative phosphonylation reactions, resulting in the synthesis of a diverse library comprising over 50 distinct examples.
III. Our commitment to elucidating the reaction mechanism was demonstrated through a series of rigorous experiments. Furthermore, we applied our developed methodology to the gram-scale synthesis of the drug molecule phaclofen, originating from another drug molecule, baclofen, underscoring the robustness of our innovative protocol.
IV. The culmination of our endeavors found expression in the acceptance of this high-quality work by a prestigious High Impact Journal of the American Chemical Society (JACS). Notably, the submission received commendable reviews and was accepted directly, affirming the significance and excellence of our research contributions.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Career development work and main results achieved so far:
1. The awardee has been involved in the supervision of one master thesis student and one Postdoctoral fellow. The awardee has also acquired considerable expertise in how to manage, motivate and assist students and this will be beneficial for his future career.
2. The awardee has helped the host prepare the publications resulting from this project and this has greatly enhanced his writing skills.
3. Towards the end of the fellowship, the awardee has been able to propose a novel research project that he has now handovered to the new postdoc in the Host laboratory. An excellent publication is expected to come out from the extended project.
4. Conferences attended: The awardee has attended three international conferences (PSRC-10, Japan), (LIT-23, Germany), and (ICOC-23, India).
5. Sub-group and Friday group meetings: The awardee has been given regular biweekly and Friday group (once in 6 months) meetings.
6. Lecture on previous work on Monday group meeting: The awardee has given a talk on his previous work and was actively involved in literature-based Monday group meetings.


Impact-related work and main results achieved so far:
Academic impact: The results of this fellowship have been published in a high-impact JACS journal, that has increased the visibility of both the Awardee and the Host supervisor.
Industrial impact: The beneficiary and the host supervisor had the privilege of presenting their research findings through talks in Japan, India, Germany, and Switzerland, drawing significant attendance from various industrial participants. These engagements served as platforms for disseminating valuable insights into our work, providing attendees with a comprehensive understanding of our research endeavors.
Societal impact: The Host supervisor as well as the awardee has initiated an outreach activity at the international conferences: 1. Summer School Conference, Switzerland (by Host), Light-induced transformations, Germany and ICOC-23, India (by awardee).
Overall, social (Twitter/LinkedIn) and direct feedback from people across the globe certainly confirmed that this project has sparked significant interest in the synthetic community.
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)
This work provided new ways to construct chemical C-P bonds using visible light as a clean source of energy. The methodology that we have developed enables the design and assembly of high-value organophosphorus compounds efficiently.

Work Summary