Skeletal editing and the future of cut-and-paste chemistry

 

In this episode of C&EN Uncovered, host Craig Bettenhausen speaks with Chemical & Engineering News associate editor Brianna Barbu about her article diving into the new and exciting frontier of the skeletal editing of molecules. Check out Brianna’s story on skeletal editing and how it may affect the future of the chemical industry.

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The following is a transcript of the episode. Interviews have been edited for length and clarity.

Craig Bettenhausen: Welcome to C&EN Uncovered. I’m Craig Bettenhausen. C&EN Uncovered is a podcast series from Stereo Chemistry. In each episode, we’ll take another look at a recent cover story in Chemical & Engineering News and hear from C&EN reporters about striking moments from their reporting, their biggest takeaways, and what got left on the cutting-room floor.

With Halloween around the corner, it’s only fitting to talk about skeletal editing. While not exactly swapping out your osteoarthritic humerus, Bionic Woman style, it’s still a very future-forward innovation that could fundamentally change the chemical industry. In this episode, we aim to dive deep into the world of skeletal editing and how these reactions affect future innovations. We’ll put a link to the story in today’s show notes. I’m here with C&EN associate editor Brianna Barbu, who wrote the article. Hello, Bri.

Brianna Barbu: Hey, Craig.

Craig: So, for anyone that hasn’t had a chance yet to read your article, can you give a brief recap of what’s in the story? 

Brianna: Sure. It’s about sort of the current state of this fast-growing subfield of organic chemistry known as skeletal editing, which in short is sort of the art of developing reactions to alter organic molecules by one core, heavy atom at a time. We’re not talking about, like, changing a hydrogen for something else; that is C-H activation.

Craig: That’s a whole other podcast.

Brianna: Yeah, it’s gotten really popular over the past 5 or so years thanks to the efforts of a small but plucky group of dudes who are really passionate about adding, deleting, and swapping atoms from, specifically, mostly drug molecules—

Craig: OK.

Brianna: —but can also be, maybe, agrochemicals. I haven’t actually heard about anyone doing it for agrochemicals, but that’s because I don’t talk to enough agrochemists.

Craig: There’s often a lot of crossover in those two areas. 

Brianna: Polymers also, but we’re not going to talk about polymers.

Craig: I mean, what makes it skeletal editing? As opposed to just, you know, you’re always changing something about a molecule when you’re doing synthesis. That’s the whole idea. Why is it skeletal?

Brianna: Yeah, that is a really good question, and that is, like, the fundamental question: defining skeletal editing, which Mark Levin talked about at length with me, because apparently molecular editing has a whole history associated with it that he was kind of unaware of when he coined the term skeletal editing. Which is very hard to say. I’m going to have to say this so many times in this episode.

OK, let’s break it down. There’s two words, skeletal and editing, and you have to define what skeletal means, and you have to define what editing means. Skeletal is, of the two terms, probably the easier one, or the more intuitive one, in a way, because, you know, you look at a molecule’s structure and you can sort of see, like, there’s the atoms that are sort of in the core of the molecule, the middle ones, and, like, the overall shape of the molecule—that’s the skeleton of the molecule. It’s like the carbon atoms and the heavy hetero atoms, the oxygens and the nitrogens and the sulfurs.

Craig: That kind of central shape, kind of like how caffeine and theobromine and certain parts of the DNA structure all kind of look the same in the middle. 

Brianna: If you were to make this molecule into earrings, the structure of the earring would be the skeleton of the molecule.

Craig: For people not in the chemistry world: chemical structure earrings and necklaces are a real thing—and popular.

Brianna: Yes, there’s a lot of very nerdy chemistry merch.

Craig: True.

Brianna: So that’s the skeleton. Editing is where things get a little bit dicey, almost, because, like you said, Craig, almost any change that you make to a molecule could be considered editing it because you’re making an alteration. But we’re journalists; we think about different levels of edits to our stories. There’s some kinds of edits that completely change the overall structure and flow of your story. That is not what a skeletal edit is. A skeletal edit would be like moving a single sentence or changing a word. Like it’s something that’s small and precise yet has the power to completely change the behavior of a molecule, because sort of any small change to a molecule can have a really big impact on a drug molecule’s pharmacological properties. If a nitrogen is in one position on a ring versus another position on a ring, it might bind to the target protein very differently. And skeletal editing is about easy ways to take molecules to its creators. The ideal that they’re shooting for is you have a molecule, and you’re wondering, Oh, would it have better properties as a drug or agrochemical—or like, whatever you’re designing this organic molecule for—if you simply scooted one atom to a different place? Or deleted one atom?

Craig: Yeah, I noticed that a lot of the reactions in your article were in a chemical ring. You’re taking a nitrogen out or putting one in, or swapping out something in one of these rings.

Brianna: Yeah. Nitrogen is a very important atom in a lot of organic molecules, drug molecules, so controlling the position of that is really important.

Craig: What attracted you to this as a topic for a long-form article?

Brianna: Oh, that’s a—yeah—I had been keeping an eye on skeletal editing as a topic almost since I started this job a little over 2 years ago. I think when I first realized it was like a really big deal, was in fall, winter 2023, early 2024, when Mark Levin published a couple of papers back to back about atom swapping.

Craig: OK.

Brianna: So this is a paper that I cite in the story, where you take a benzene and you stick in a nitrogen and turn it into pyridine. So take an all-six-carbon ring, remove one carbon, stick in a nitrogen. And there were two papers that came out, like, within weeks of each other. And I covered neither paper. Beth Halford covered the first one. Mark Peplow covered the second one. There were all of these, like grad students and med chemists in the chem Twitter community that were talking about these papers about atom swapping, and they had this hashtag, #pyridineabuse.

Craig: Pyridine abuse. I like that.

Brianna: Yeah, they, like, would tag a chemistry paper where, like, chemists were doing something really weird to pyridines specifically. This hashtag blew up. And I was sort of like, yeah, like a lot of organic chemists are talking about these atom swaps, this skeletal editing, stuff like this could be something to keep an eye on as a feature. I just kept seeing more and more papers and more and more people in the chemistry community using the term skeletal editing, and a lot more discussions on social media of skeletal editing and what it meant and whether it was good for anything or if it was just a flashy buzzword that people were sticking into their papers.

Craig: So there’s a real watershed moment where it sort of went from being something people were playing with to something people were like, Oh, wait a second, there’s something here.

Brianna: Organic chemistry is, sort of, it’s very trend driven in a lot of ways. Like, people will, like, hop on to certain classes of reactions. And like, you know, for good reason. There’s classes of reactions that are very famous because a lot of people use them, and they’re very useful. Click chemistry, cross-coupling reactions, C-H activation. 

Craig: C-H activation and CO2 activation—really hot right now.

Brianna: These are classic reactions, like the staples of pharmaceutical synthesis, Nobel Prize winning. I’m not, I’m not saying that skeletal editing will be among these things. I want to stress it is far too early to tell what the long-term impact of skeletal editing is going to be on synthesis or chemistry. Organic chemists can be a little bit sky-eyed in a way of, like, how they think about changing the world with the reactions that they’re developing, or, like, making their mark on the chemistry community by coming up with something completely new and completely novel. And the folks that I talked to for this article sort of ran the gamut. I talked to many people for this story. Mark Levin’s just a particularly good spokesman for skeletal editing. He and Richmond Sarpong kind of coined the term.

Craig: Where are they based?

Brianna: So, Mark Levin’s at the University of Chicago, and Richmond Sarpong is at [the University of California] Berkeley. And they had a Nature Synthesis review in 2021 where they sort of laid out the philosophy of skeletal editing.

Craig: I also noticed that there was a, seemed like a geographic concentration in the US. There were a couple of researchers who were from Korea and other places. But it also seems to be US centric. Is there any—

Brianna: Oh, there’s plenty of folks in Europe doing it. OK, like Bill Morandi at, I think he’s in Zurich, is another sort of big name that I couldn’t get a hold of. Like him and his postdoc, Julia Reisenbauer; Yoonsu Park’s in Korea. Mark and Richmond told me about some folks in, like, France and the UK who were doing skeletal editing stuff.

Craig: So it’s a growing sub-subfield.

Brianna: Yes.

Craig: I think you mentioned at one point, like, it’s enough that you could have a really meaty small conference, right? I think that was one of the lines in your story.

Brianna: Yeah, instead of just a few random guys in a room, they’re actually having two symposium sessions, I think, at Pacifichem in December, focused on molecular editing, which is slightly broader than skeletal editing: it also includes stereochemical editing, which doesn’t add or subtract or swap.

Craig: So we talked some about putting in and subtracting nitrogens and carbons. But what about some of the other elements that sometimes make their way into the skeletons of organic molecules, things like boron, oxygen, silicon? Is anybody editing those in and out of things?

Brianna: I don’t know about boron. I mean, Yoonsu Park talked about expanding his furan to pyrrole, so oxygen-to-nitrogen swap in the other direction, so putting oxygen in. He talked about, like, wanting to work with sulfur as well, which, you know, is one row down from oxygen on the periodic table. These are things that people are thinking about. I’m not sure if there’s like additional difficulties with certain atoms over other atoms.

The interesting thing about skeletal editing is that, unlike other like classes of reactions like cross-coupling, there’s not one mechanism that really unites it. It’s kind of, like, whatever chemistry gets you from point A with a carbon in that spot to point B with a nitrogen in that spot. It could be a metal-catalyzed photochemistry. It could be radical chemistry. As Richmond Sarpong said, it’s up to your imagination to get there.

Craig: Yeah, I was going to ask about that, because it seemed like the conditions were really, really diverse between the different types of reactions.

Brianna: Yeah. 

Craig: Whereas your cross-coupling reactions are all kind of similar. Not exactly, but there’s a lot of variation on the same theme. But this is just the Wild West.

Brianna: Kind of, yeah, at this point.

Craig: Interesting.

Brianna: Because, I mean, you have to remember this: although, like, reactions that have the ability to change one atom in a molecule have existed for, like, over 100 years, the concentrated push to think about developing methodology to do this specifically is only 5 years old, really. It really is still, like you said, kind of the Wild West, where people are still really trying out a bunch of things and seeing, first of all, what works, like what even makes this transformation possible. And the next challenge is standardizing it, making it practical.

Craig: Yeah.

Brianna: that’s the real test for these reactions, I think, or I have been told by my sources: is it going to be practical enough to use in industry? That’s really sort of the next hurdle that these reactions have to cross.

Craig: And I guess sometimes you need some chemist to get obsessed, like, I know a chemist who is really obsessed with getting boron into things.

Brianna: Yeah.

Craig: And they’ve developed several reactions around boron, and that’s great. And boron is further along because that specific person got obsessed, which is an important part of how chemistry works. 

Brianna: I mean, Mark Levin would literally admit to—part of the anecdote is in the story. But he has this giant ChemDraw of, like, all of the nitrogen-containing heterocycles, because, like, his obsession is nitrogen, mostly. He made a big ChemDraw all of the nitrogen-containing heterocycles just to see what was possible for all of the different kind of atom-swapping reactions that he wanted to do. So his, yeah, his whole thing is swapping nitrogen.

Craig: One of my graduate school advisors was, copper was his thing, and they actually made him a T-shirt at one point that said, “What about copper?” Because he would ask that so frequently.

Brianna: I mean, would we have all of the phosphine ligands that we have if someone didn’t really, really love phosphines?

Craig: Yeah, I have no strong feelings about phosphines, but I’m glad other people do.

Brianna: You should have strong feelings about phosphines. They’re awesome.

Craig: Fair enough. So why now? Why is this kind of chemistry catching so much momentum right now in particular?

Brianna: That’s another really good question. You know, I think it’s sort of maybe a combination of, like, a few really passionate individuals have been working on this for long enough that their efforts are starting to yield a lot more fruit. And then, as those efforts start to yield fruit, people start jumping in and developing things, and then those efforts are now starting to yield fruit. And now we’re seeing a big increase in the number of papers that are published in this area.

Craig: And it’s kind of a different way to think about synthesis, you know, not having to necessarily build it from the center out in the same way.

Brianna: Yeah. The interesting thing about skeletal editing, in some ways, is—although I’m sure that eventually one of these reactions will get optimized for process—really, the target audience is medicinal chemists.

Craig: OK.

Brianna: Who are looking to quickly diversify and screen a lot of quite similar molecules, yeah. So you don’t want to go all the way back to, you know, step one of a very complicated synthesis, right? Yeah. You want to take something in the middle and make a little tweak, and then now you have a whole other branch of your chemical family tree to explore and see whether it’s going to treat the disease that you’re trying to treat.

Craig: So you’ve been watching this story for a while. It got the big cover story. But I assume you’re not putting this down. What are you watching for next on this topic?

Brianna: Oh, I mean, like I said, I think it’ll be interesting to see what other atoms get involved and whether this, you know, actually makes it out of academic labs into industry, because I think that’s going to be the real test for whether this is going to live up to these very lofty goals that some of the inventors have set, and whether it helps discover something.

Craig: It seems like there’s going to be a lot to keep following on this, so we’ll look forward to continued coverage from you. Unless it all fizzles, and then you can tell us that. Bri, thanks for diving deep on this with us. You can find me on social media as @Craigofwaffles. Bri, how can listeners get in touch with you?

Brianna: I primarily use Bluesky and LinkedIn. So I’m BriBarbu on Bluesky and Brianna Barbu on LinkedIn.

Craig: So you can find Brianna’s story about skeletal editing on C&EN’s website, or in the July 10 print issue of C&EN. We put a link in the show notes along with the episode credits. We’d love to know what you think of C&EN Uncovered. You can share your feedback with us by emailing CENfeedback@acs.org. This has been C&EN Uncovered, a series from C&EN’s Stereo Chemistry. Stereo Chemistry is the official podcast of Chemical & Engineering News. And Chemical & Engineering News is an independent news outlet published by the American Chemical Society. Thanks for listening.