What’s the future of medicinal chemistry?

INTRODUCTION

Dear Community,

I’m keeping my introduction intentionally short this month to quickly draw your attention to THE LEAD REACTION, which features Dr. Song Lin, Tisch University Professor in chemistry and chemical biology at Cornell University.

Professor Lin was recently awarded the 2025 Snapdragon Prize for Innovation in Chemistry Technology, so we decided to sit down for a chat. How did he find himself immersed in groundbreaking electrosynthetic chemistry research? How will medicinal chemistry evolve? And what do kids’ cartoon characters have to do with it all? Find the answers below.

And if you know of other innovators combining interesting chemistry with emerging and/or tangential technologies, please let us know. We’d love to feature them in a future issue of Synthesis.

Until next time,
Matt Bio

THE LEAD REACTION

Organic Chemistry: Electrified!

Synthesis chats with Cornell Professor Song Lin – natural-born chemist and recipient of the 2025 Snapdragon Prize for Innovation in Chemistry Technology.

What initially drew you to chemistry?

Like many kids, I grew up watching cartoons and I particularly enjoyed eccentric scientist characters who mixed liquids of different colors and – “BOOM!” – there would be a liquid of a completely different color. My love of these fun chemical changes grew into a fascination for chemistry and science experiments in general.

In high school, I leaped at the chance to participate in chemistry olympiads, which gave me hands-on experience and the freedom to experiment.

I joined an organic chemistry lab as soon as I could during college and immediately knew I’d made the right choice. I loved it.

The Lin Lab tagline is “Electrifying Organic Chemistry.” How did you find your niche?

After graduate school, I aspired to become a professor and was advised to learn something different as a postdoc. By enriching my knowledge and broadening my scientific horizons, I knew I would have a better chance of being truly innovative. I decided to explore the world of inorganic chemistry, joining Chris Chang’s lab (at UC Berkeley back then), which had several fascinating research programs. I was focused on catalysis and energy, which introduced me to the field of electrochemistry.

While thinking about potential routes towards setting up my own lab, I had something of an epiphany: “Why can’t we also use electrochemistry to make organic molecules?” I found myself really excited about marrying my two areas of expertise to do something different.

What are the broad aims of The Lin Lab?

On a high level, the twin objectives of The Lin Lab reflect my personal ambitions. First, to develop (electro)chemical tools that change the way people do things – whether that’s creating new pharmaceuticals or materials to benefit society. Second, to generate timeless knowledge to fill the textbooks of the future. For us, that means understanding how molecules interact and come together, especially in electrochemical settings.

Could you share any specific examples of how your research feeds into drug development?

Sure. Over the years, we’ve been fortunate to initiate interesting collaborations that highlight the impact of our work in a more applied setting.

With Genentech, we developed an electrochemistry-based reaction that allows synthesis of a drug candidate in two steps rather than nine or ten – a significant efficiency gain. Now, we are looking into using a similar approach to help medicinal chemists synthesize new molecules that are not easily accessed.

In another ongoing collaboration, we iterated on earlier work to develop a chemical reaction together with AbbVie that I believe is now being used by scientists at the tens-of-kilograms scale for a pipeline project. I can’t say more about the details, but I can say we just submitted a paper for publication…

How do you think medicinal chemistry will evolve in the coming years?

One important recurring theme will be the increasing incorporation of new or emerging technologies, with electrochemistry, photochemistry, flow chemistry, and biocatalysis being good examples. Any tool that provides new and/or faster pathways to molecules will be increasingly valuable – especially, if those molecules weren’t previously or easily accessible.

Another important trend is that chemists are now focusing on not only how to make molecules but also how to generate useful data from reactions. Though high-throughput experimentation has been around for a while, there are still bottlenecks that need to be solved in terms of reliably generating high-quality data at scale. We know that such data can be extremely powerful, helping us discover or make molecules faster and allowing us to integrate machine learning to dramatically increase our ability to access new drugs.

Why do you think you were awarded the Snapdragon Prize for Innovation in Chemistry Technology?

Well, many people out there are deserving of such an award, so that’s a tough question.

I do know that Snapdragon cares deeply about technology. By innovating, the company has been really successful in the space of flow chemistry as well as reactor development and engineering. It’s a leader in this field.

Our focus on electrochemistry transformed into a gateway to adopt and gain expertise in other emerging technologies that help us reach our end goals.

My lab’s deep appreciation of new technology somewhat mirrors Snapdragon’s approach, so that could be one reason we were recognized.

How important is external recognition for The Lin Lab and your team?

Any validation of what we do is important to us all, of course. It’s recognition that we’re reasonably good at what we do and that we’re making a positive contribution to society.

I’ve never been the most confident person; I still feel really fortunate that I have a job! Moreover, I work in a field that I’ve loved since being a little kid. Everything else on top of that is a wonderful bonus.

Looking 10 years into the future, what will The Lin Lab have achieved?

Honestly, I don’t know. In July 2026, we will celebrate the 10th anniversary of the Lab; if you’d asked me the same question 10 years ago, I couldn’t have predicted some of the projects we’re working on today. And that’s the beauty of being an academic – you can work on whatever you want. Through many collaborations with both industry and other academic groups, The Lin Lab has developed the aforementioned deep interest in technology, which evidently takes us in surprising directions. We are organic chemists, and yet we’re making nanofabricated devices and circuitry in a clean room. I could have never imagined such a future.

What I can say is that the next 10 years will see us continuing to pursue the two goals I mentioned earlier: inventing technology that will benefit society and generating knowledge that will change how people think and learn.

THE METHOD

Going with the flow to tackle complex chemistry

Matt Bio recently described two projects that showcase flow chemistry’s role in scaling up complex synthetic methods from pilot scale to commercial production. The first case study focused on a cryogenic organometallic reaction that was made possible at commercial scale using platform reactor technology. The second tackled photochemistry-based synthesis of an asymmetric atropisomer.

Interestingly, one question from the audience prompted Matt to offer insight that beautifully links THE METHOD and THE LEAD REACTION in this newsletter:

“Electrochemistry is where photochemistry was about 10 years ago; we’re starting to see more and more applications. Electrochemistry is more complex than photochemistry because you have the third phase of the electrode. But it also benefits from continuous flow, which keeps the anode and cathode close together to avoid ohmic heating. The chemical transformations of interest are much less well developed at the moment, but I think we’ll see the field evolve over time.”

Watch the webinar to explore the case studies in detail.

THE CATALYST

What we are reading

In drug substance manufacture, much of the focus is typically on getting the reaction step right. However, the workup and isolations of the reaction products can occupy 70% or more of the total manufacturing cycle time for an API and generate significant waste. The workup and isolation processes also have significant impact on product quality and form the basis of the quality control strategy.

I was recently reviewing the literature in this area and came across a paper by a former colleague of mine, Jacob Janey, wherein he and co-authors report on the development of a high-throughput workflow for the systematic optimization of a liquid-liquid extraction (LLE) process to control a genotoxic impurity.¹

Following this study, a group from GSK, reported on the use of a highly automated of a high-throughput LLE platform. With the aid of the platform, the team was able to generate a rich data set which was then used to develop a predictive model for a complex separation. The model was used to optimize the workup in silico. The model was validated at kilo-scale and was able to deliver an improved product recovery.²

A research team at Merck created an even more efficient workflow, increasing throughput to 96 conditions per run. The platform was used to rapidly assess LLE process variables such as solvent, co-solvent, salts, pH, additives and additive concentration. The HPLC data processing was also automated to generate heat-maps of results for rapid visual assessment. The platform was successfully applied to the case of a molnupiravir intermediate where the workup was optimized to identify a partition between 44% 2-MeTHF/IPA and 60 wt% ammonium sulfate that gave efficient enzyme settling with >90 product recovery.³

These papers highlight the opportunities for process improvement when workup conditions are the focus of optimization. The evolution of the tools from 2016 to 2023 is impressive. Given the rapid pace of change in automation and data connectivity, I anticipate that we will soon realize the ability to apply algorithm-guided end-to-end optimization of reaction, workup and isolation as a connected workflow.

¹ Org. Process Res. Dev. 2016, 20, 10, 1728–1737
² Org. Process Res. Dev. 2021, 25, 12, 2738–2746
³ Org. Process Res. Dev. 2023, 27, 11, 1954–1964

THE SIDEBAR

Data-driven decision making

In pharmaceutical process development, we generate a tremendous amount of data. Exciting AI-powered tools help us find the right information at the right time, putting us in the best possible place to make the right decisions.