The Synergistic Merging of Iridium-Catalysed Hydrogen Borrowing and Asymmetric Catalysis in the Pursuit of Enantioenriched Small Molecules

Periodic Reporting for period 1 - IRIDOX (The Synergistic Merging of Iridium-Catalysed Hydrogen Borrowing and Asymmetric Catalysis in the Pursuit of Enantioenriched Small Molecules)

Reporting period: 2018-08-14 to 2020-08-13

"The action ""IRIDOX"" looked at the development of new synthetic organic methodologies using iridium catalysis, in conjunction with other techniques, to develop the synthesis of small biologically relevant heterocycles.

Heterocycles, small organic molecules that feature both carbon and other atoms (normally nitrogen or oxygen) in a ring, are incredibly important structural motifs for the development of pharmaceuticals and agrochemicals. These types of structures can be found in almost all commercially available drugs and herbicides. Therefore, it is of considerable importance for chemists to develop methods to construct and prepare such target molecules, allowing the more rapid synthesis of such targets.

This project aims to assist this goal by developing new methods to prepare piperidines (an important class of heterocycle) from cheap and commercially available precursors using a metal-catalyst (nominally iridium, but later it was found that related metals such as rhodium and ruthenium were also competent for such transformations, and in some cases, found to be superior. The development of chemical methodologies to prepare such synthetic targets is of great importance for society as it will enable the faster and more efficient synthesis of pharmaceuticals and allow the development of new medicines to treat diseases and medical issues.

The project completed its goal by developing 5 new methodologies (work packages) that enable the synthesis of a number of different desirable heterocycles, each of these methods use either iridium/rhodium/ruthenium catalysts or catalyst free. Each of the 5 methodologies developed represents an important step towards more efficient drug synthesis. Additionally, each work package relies a one carbon equivalent and hydrogen and uses either methanol, formaldehyde, or formic acid as the key sources. Each of these three chemicals are cheap and abundant feedstock chemicals, thus increasing the environmentally friendly nature of each of these transformations."

During the project a number of new synthetic methods have be developed in order to access new heterocyclic motifs. Each of these methods involved a considerable amount of time optimising the reactions and then applying the methodology to a number of different examples to prepare a library of related compounds. In addition to this aspect of the project, the novel methods have been used to prepare pharmaceuticals and their analogues such as the SSRI antidepressent Paroxetine and the antibiotic Rosoxacin, highlighting the real-life application of these strategies.

The science developed during the project has been disseminated in a number of ways including:

(a) 3 peer-reviewed publications (with two more publication due to be published in the future).
(b) The fellow has disseminated the results at a number of academic institutes in Europe, including the UK, Spain, and Italy.
(c) The research and each peer-reviewed publication was publicised widely on both personal and institutional social media accounts.

Unfortunately this aspect of the project was most adversely affected the worldwide COVID-19 pandemic as a number of conferences and outreach activities in Spring 2020 were cancelled on public health grounds, limiting the ability to further disseminate the results. Equally further events to disseminate the results and participate in outreach activities where forbidden on public health grounds.

This MSCA has pushed the frontiers of synthesis organic chemistry in the field of metal-catalysed heterocycle synthesis Each piece of science developed during this project is novel and all 5 projects can be described as progress beyond the state of the art.

The science investigated during this MSCA is purely fundamental science so it does not have any immediate wider impacts that can be realised. However, interested parties such as pharmaceutical companies are aware of the science and this has the potential to have wider socio-economic and health impact through the development of new medicines and treatments.

Training and Impact on the Fellows career
During the fellowship the fellow undertook a number of training activities:

(1) Departmental training for the use of the analytical services available in the Department of Chemistry (NMR, mass spectrometry)

(2) Appropriate Health and Safety and Fire training to enable safe working practises during the fellowship

(3) Training from the Department of Earth Sciences on the preparation of samples and use of trace metal analysis

(4) A “Developing Teaching and Learning” course delivered by the Oxford Institute of Learning

(5) On the job training activities from colleagues and mentors in a whole range of fields including practical and theoretical chemistry, I.T. data management, interviewing and line management.

These training activities further improved the fellow’s skills and careers prospects. Of particular note is the Developing Teaching and Learning course, this course was a nationally SEDA accredited qualification at the UKSPF Descriptor 1 which involved a number of hours of in person lectures followed by the writing and submission of a portfolio providing critical analysis of the fellows teaching styles and abilities.

Scientific Aspect of Project

Periodic Reporting for period 1 - IRIDOX (The Synergistic Merging of Iridium-Catalysed Hydrogen Borrowing and Asymmetric Catalysis in the Pursuit of Enantioenriched Small Molecules)

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