Fluorinating antidepressants: where next?

In early 2019, our paper describing selective amide fluorination was published in Nature Chemistry. Here, I try to give some personal insight into what has happened since.

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In March 2019, our research on selective α-fluorination of amides with nucleophilic fluorine was published in Nature Chemistry, followed closely by my “Behind the Paper” blog post. In fact, it was rather a busy month for me as it also marked my arrival in Aachen, Germany to begin my independent research career after an unforgettable stay as a postdoc with the Maulide Group in Vienna. Now, a year and a half has passed since arriving to my first experience of Carnival, and these quieter times provide an opportunity to reflect and tell you a bit about what has happened in the meantime…

The Science

Let’s begin with the chemistry. The development of our fluorination methodology marked the start of our journey developing amide umpolung methodologies with heteroaromatic nucleophiles. Pauline, Daniel and myself had focussed on building up the fluorination substrate scope and looking for applications as we recognised the massive potential of what we were doing quite early on. But we had also seen glimpses of other intriguing reactivity with other systems. At this point, Carlos and Miran, two young and extremely talented scientists (both currently PhDs in the Maulide group – keep an eye on them!) took over and took off! They demonstrated that a vast range of different heteroatomic nucleophiles could be added selectively at the α-position of amides, providing a methodology that could really do something that no other could: selectively target amides over other carbonyl species; and use nucleophiles to functionalise what had itself traditionally been a nucleophilic position. It turned out that this mighty scope could be explained by another detail – that in a number of cases rather than the putative enolonium species which we had drawn, this actually collapsed into the very reactive α-triflated species. The work detailing all of this, together with some computational rationalisation by Boris, was published at the end of last year.

Our follow up study describing a wider range of nucleophiles and some mechanistic insight.

Meanwhile, another sub-team in the Maulide group were exploiting this discovery, demonstrating that this facile and selective route to α-triflated amides could be combined with asymmetric nickel catalysis to carry out enantioselective arylation of amides – you can check out the paper describing this here. Not long afterwards, we also began to contemplate whether we could actually expand all of this chemistry beyond amides, and the first steps into doing that were published just a few months ago.

Collaboration

Our fluorination paper had detailed some investigations into the activity of a fluorinated analogue of the blockbuster anti-depressant, citalopram. This was the first serious collaboration which I had been involved in and it really brought home to me the huge value that can be added to a project by teaming up with someone with completely different expertise to your own. The ability of synthetic chemistry to influence and make an impact in other areas should not be underestimated and gaining a different perspective on your project is really invaluable. That is something that I certainly hope to exploit as an independent research group leader in the future. In terms of other applications of our fluorination, as I mentioned at the end of the previous blog post, efforts to turn our method ‘hot’ are still continuing, currently in someone else’s very capable hands. I have since moved on but I’d like to try and explain now a bit about how this research helped to shape my journey.

The People

When I reflect on this project and, more generally, on my time as a postdoc, it is always the people that stand out. Vienna is a diverse and vibrant city and the Maulide group was built to match. For the fluorination project, I worked with two supremely talented co-workers – Daniel Kaiser who was just finishing his PhD and Pauline Adler, who was a postdoc who had started just a few months before me. I think that we excelled as a team because our skill sets, interests and perspectives on chemistry perfectly complemented each other. Beyond that small team and more generally, I couldn’t have wished for a better group of people to work with during my time in Vienna. We fed off each other’s strengths and were more productive and, importantly, had much more fun doing everything as a result. For anyone reading this and looking for a PhD or a postdoc position, don’t underestimate this aspect of picking which team to join. There has rightly been a lot of discussion recently about the value of diversity and I can only really say that in my experience, most of science that I have been involved in would not have succeeded without the diversity of thought that scientists with unique backgrounds bring to the table.

My Story

As I mentioned at the beginning of the post, I also had the exciting task of beginning to build my own research group in the Spring of 2019. I had known for a few months that I was making the move to Aachen (one of the best early Christmas presents I have received was the email telling me that my application for a Liebig Fellowship from the Fonds der Chemischen Industrie had been successful). I was hugely eager to get started, even if it was (and sometimes still is) a daunting prospect and a big change in role. But I was in luck, arriving at a fantastic institute with a hugely supportive mentor, and in a country which continues to invest heavily in fundamental scientific research.

We started with a completely blank slate and my book full of (generally pretty ambitious) ideas! I have always been quite ‘concept’ driven, liking papers that challenge preconceptions or that surprise the reader with the unexpected. However, one key aspect that our fluorination publication had showcased was the ability to ‘reverse’ classical reactivity and do something that no other method could do. As such, I knew that I wanted at least one of my group’s research areas to follow this theme of reversing expected reactivity or selectivity. But I also missed catalysis, which had been close to my heart since my PhD, and we saw some opportunities to discover something new in that field in combination with light.

Although it is still early days and our team is still small, we have had some success to date which you can read about here. My group now often find me reflecting or asking them what our latest discoveries might do that is unique and couldn’t be done before. Without doubt, that attitude comes from my experience with the fluorination project. But what I really take away from that time is that science should be fun. It is a chance to meet people from all over the world, take everyone’s experiences and strengths, and build a team stronger than the sum of its parts in exploring the unknown. That’s what I love most about what I do and what I want my group to continue to promote in the years to come.

The Teskey group at RWTH Aachen in January 2020.

Christopher Teskey

Junior Research Group Leader, RWTH Aachen University

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