Cross-Coupling (C-X): Pioneering Mild Aqueous Cross-Coupling Methodologies to Enable Selective Functionalisation and Diversification of Halogenated Natural Products

Informations projet

C-Xaq

N° de convention de subvention: 659399

DOI

10.3030/659399

Projet clôturé

Date de signature de la CE 25 Mars 2015

Date de début 1 Mai 2015

Date de fin 30 Avril 2017

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 183 454,80

Contribution de l’UE

€ 183 454,80

Coordonné par

THE UNIVERSITY COURT OF THE UNIVERSITY OF ST ANDREWS
United Kingdom

Periodic Reporting for period 1 - C-Xaq (Cross-Coupling (C-X): Pioneering Mild Aqueous Cross-Coupling Methodologies to Enable Selective Functionalisation and Diversification of Halogenated Natural Products)

Période du rapport: 2015-05-01 au 2017-04-30

Résumé du contexte et des objectifs généraux du projet

Natural Products (NPs) have historically played an important role in medicine. During the past three decades, >60% of anticancer agents entering clinical trials are based on NPs. Analogues of bioactive NPs are required to determine the biological target, establish the molecular mechanism of action, improve bioactivity and bioavailability. NPs are key to medicine, yet the generation of analogues of these important compounds can often be challenging. I proposed to investigate an exciting new approach to NP analogues pioneered by the Goss lab. By developing new, mild, aqueous and selective cross-coupling chemistries I aimed to enable the selective diversification of organic molecules, and in particular NPs, containing carbon-halogen bonds. With my expertise in organometallic chemistry and computational chemistry and in collaboration with the Goss lab, we are poised to bring significant advance to this new field of research. Over 5000 halogenated NPs have been isolated and identified to date, presenting a series of attractive test-bed’s for this proposed research. Additionally, with the advent of synthetic biology, it has recently been possible for the Goss group and others to engineer new to nature NPs containing halogen handles. The Goss group demonstrated selective functionalisation of these NPs developing and using mild and aqueous Suzuki Miyaura cross-coupling conditions. Building upon this success, I was eager to develop methodology to enable, under mild aqueous conditions, a greater diversity of cross-coupling reactions of aryl halide containing small molecules and then NPs to be employed.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We can divide the results obtained during this C-Xaq project in two main parts:

1) Development of mild aqueous conditions for the selective cross-coupling of small (low risk) then NP embedded (medium risk), aromatic halides.

2) Development of mild aqueous Suzuki-Miyaura cross-coupling conditions compatible with living cells in a bioorthogonal manner

This interdisciplinary research has resulted in two major manuscripts that we submitted to leading journals (one to Chemical Science (online) and one to Nature Communications (accepted)). These manuscripts are a credit to the quality and novelty of the research that we have been driving forward. Importantly, we have contributed to develop the medicinal chemistry research area significantly beyond state-of-the-art as our methods can be successfully applied for the synthesis of relevant new to nature natural products analogues which are important to the health and well-being of society.
Furthermore, I had the opportunity to disseminate such important results in very prestigious events:
• 253rd ACS National Meeting & Exposition – Advanced Materials, Technologies, Systems & Processes,
2nd- 6th April 2017, San Francisco, USA
• “67th Lindau Nobel Laureate Meeting, dedicated to Chemistry”
25th-30th June 2017, Lindau, Germany (selected candidate)

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

NPs represent an unprecedented source of drug leads, yet the necessary analogue generation to explore and optimize their bioactivity and bioavailability can be challenging. This proposed research develops this new field significantly beyond state-of-the-art expanding the simple chemistry developed by the Goss lab that allowed aqueous cross-coupling of aromatic moieties, to enable the diverse functionalization of haloaromatics embedded within natural and new to nature “natural” products. Success opens up a large range of chemical space that could be easily accessed with this novel mild-aqueous methodology. It is hoped that developments in this research would be taken up rapidly by industry and other scientists. Indeed, environmentally-friendly chemistry is emerging as one of the most important challenges for the new century. As this work seeks to broaden the scope of cross-coupling methodologies, it has many potential applications in science from materials to medicine to chemical biology. As such, the nature of the proposed research is expected to have an impact on scientists of different fields, promoting the share of knowledge and interdisciplinary collaborations.

Mild and aqueous cross-couplings to enable selective diversification of halogenated NP