In this insightful lecture, Barry Sharpe delves into his life and illustrious career in chemistry. Highlighting his humble beginnings from a fishing family, his journey to becoming a renowned chemist is filled with influential mentors and groundbreaking research in click chemistry. Sharpe shares anecdotes from pivotal moments in his career, shedding light on the underappreciated aspects of chemical research and the collaborative spirit that drives innovation.

The video provides an in-depth look into the development of click chemistry, illustrating how it revolutionized the field by offering a new approach to molecular synthesis. Despite facing challenges, such as skepticism from traditional funding bodies like the NIH, Sharpe's perseverance and innovative ideas, supported by influential colleagues and family, led to successful breakthroughs. He also shares his philosophy on chemistry and the creation of new properties, which have profound implications even beyond science, influencing fields like biotechnology and materials science.

Main takeaways from the video:

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Key Vocabularies and Common Phrases:

1. catalyst [ˈkætəlɪst] - (noun) - A substance that increases the rate of a chemical reaction without itself undergoing any permanent chemical change. - Synonyms: (accelerator, facilitator, promoter)

What happens is silicon, phosphorus, and sulfur love to change ligands with a suffix catalyst and they do it as fast as the QAC reaction, if you can believe it.

2. epoxidation [ɛˌpɒksɪˈdeɪʃən] - (noun) - A chemical reaction that transforms a compound containing a double bond into an epoxide, often used for introducing oxygen into organic molecules. - Synonyms: (oxidation, peroxidation, reaction)

And so the asymmetric epoxidation got me interested in.

3. polymer [ˈpɑːlɪmər] - (noun) - A large molecule composed of repeated subunits, often created through polymerization reactions. - Synonyms: (macromolecule, compound, substance)

But to get to 99% after 1000 steps, this is polymer chemistry, right? And here you have 99

4. asymmetric [ˌeɪsɪˈmɛtrɪk] - (adjective) - Not identical on both sides of a central line; lacking symmetry. - Synonyms: (lopsided, uneven, unbalanced)

And so the asymmetric epoxidation got me interested in.

5. synthesis [ˈsɪnˌθɪsɪs] - (noun) - The combination of components or elements to form a connected whole, particularly in the context of chemical substances. - Synonyms: (combination, integration, unification)

So even if you're planning your synthesis very carefully, there's only about a handful of reactions that good chemists would know.

6. substrate [ˈsʌbˌstreɪt] - (noun) - The substance on which an enzyme acts during a biochemical reaction. - Synonyms: (base, medium, surface)

So the molecule can act as a reaction vessel, and that's, well, chemical phases be.

7. cycloaddition [ˌsaɪkləʊəˈdɪʃən] - (noun) - A chemical reaction, typically involving unsaturated compounds, leading to a cyclic compound. - Synonyms: (addition reaction, ring formation, chemical process)

It was the idea of, why don't we let the enzyme take 50 pieces on each side and do the cycloaddition, the azide, Carolyn's thing, where you get this very weak

8. fidelity [fɪˈdɛlɪti] - (noun) - The degree of exactness with which something is copied or reproduced. - Synonyms: (accuracy, precision, loyalty)

It's a beautiful polymer. Very, very good fidelity.

9. precedent [ˈprɛsɪdənt] - (noun) - An earlier event or action that is regarded as an example or guide to be considered in similar circumstances. - Synonyms: (example, model, standard)

It didn't have any precedent for working, so people didn't know what we were trying to sell.

10. helices [ˈhiːlɪsiːz] - (noun) - Spiral structures occurring in biological molecules, like DNA. - Synonyms: (spirals, coils, whorls)

Here's what the thing looks like. Hans Zulath is our collaborator in the Netherlands and his students got these pictures of these helices.

Nobel Prize lecture - Barry Sharpless, Nobel Prize in Chemistry 2022

Barry Sharpez was born in 1941 in Philadelphia, Pennsylvania, USA. He was awarded a PhD from Stanford University, California in 1968 and is now active as professor at Scripps Research, La Jolla, California, USA. So please join me in, please join me in welcoming doctor sharpest up on stage introduction and ladies and gentlemen and friends and former students and colleagues out there too. It's a unique feeling. It's all inspiring to have two lectures that I, of course I understood every word of but also that I couldn't have given myself because they are so beautifully organized and that's my failing in life. I can't plan things. So some things need to be fixed up in the final written version of this.

But I have some observations to share. What I really like to share is how three of us were wisely chosen by this committee because we have the same spirit that we've evolved from our experiences over, in my case a longer lifetime. But it's a profound thing to realize what you can do if you don't try to just do any old way of making molecules. And that's the main message I can give you. So, I don't know, is this a forward and reverse thing too? Okay, so yeah, this is the launching of click chemistry. And it started before there was any really motivation for knowing that it would work. But I did know that some reactions were better than others. And anybody who's been a chemist for years, like Morton and I have, know that you don't really have much faith in a reaction that's never given you more than 1020 percent yield. Why would you consider using it in a plan? So even if you're planning your synthesis very carefully, there's only about a handful of reactions that good chemists would know.

Okay, I can go to the bank with this one, I think. Here's the way it started in. Let's see, how do I push the laser pointer? Oh, it's right there. Okay, so this is where cook chemistry started, in this old building which had pigeons in it and stuff. And we cleared it out and built some labs in there with Alfred Bader's funding. Alfred and Isabel Bader to, well, Alfred, he was coming around to Dartmouth College even, and the Stanford with his patched elbow suit and his handy out coffee cups. Our generation knows who Alfred Bader is. Younger people like. I'm sure Keller never ran into him in that role but he was the man who said, what can I do for you? Here's a man making chemicals for sale. And how many would go around door to door like that? But that's the way he was.

And he started his lab in a garage, I forget which city in the midwest. And he is an important man who decided he liked. Oh, and Victor snikis at Queen's College in Canada. He's indebted to Alfred, too, because he endowed a big chair for Victor, who was another wonderful chemist who I've admired for years. And Hartmuth Kolb is here in the audience. Hartmuth was the first click chemist because he came back from Seabagi when it merged. He had been a postdoc in the lab. He came back from Seabagi when it merged with Novartis, with whatever the other guy was, Sando, and became Novartis. And when something like that happens, the quality is going down. And Hartmuth got out of there wisely, and he started organizing a chemical group, and he made hundreds of blocks, building blocks for chemists to have versatility in discovery chemistry.

They thought these blocks were actually supposed to be small drugs or something in Japan. It just was ahead of its time. It didn't have any precedent for working, so people didn't know what we were trying to sell. And somebody bought the company to make it into a drug supply line for their own new startup, pharma company. So Hartmuth left again, and. Okay, now, this is the man who made it possible for click chemistry. It may not be known to many people, but I couldn't get funded very well because I don't write grants very well, and I could never get funded for doing cook chemistry. They hated it at the NIH and the study sections. They wanted total synthesis or complex problem, very complex hammer and tongues ways of making big molecules in those days. So Richard rescued me, saw my potential, and he funded click chemistry. 90% of all the funding for click chemistry came from.

From Richard's rich friends and that he could constantly get this aboard his institute. My wife, on our fifth anniversary, well, she's the genius in the family. I won a Nobel prize, but everybody knows she's the genius. And she names things like click chemistry and Sleeping Beauty. But her. Her click chemistry has always stuck, and it stuck in the crawl of a lot of people for years because it wasn't popular. It just didn't appeal to people. It seemed Mickey Mouse. And anyway, I can't say that I would be here today, or I would have been here the last time, either, if it weren't for Jen. And I don't know where anybody's sitting. I get nervous. So I'll just say, oh, oh, good, good. Over there. Okay. Yeah. She keeps me connected to the real world. And besides also having really incredibly, she's a writer and she's trained english major writer.

Now is this. I guess I don't know how to change this. Let's see. How do you make this? I can't get the normal thing to. What is it? Maybe I should start it again. Just go back and try to do it without the comments. Okay. Then I go, let's just go this way and see. No, it's going to go that. Okay. There. Oh, wait, what happened? So I was born to be a process chemist. I was a fisherman from norwegian, swedish fishing family. My grandparents and I worked on fishing boats until I was ready to go to college. And actually, even while that time before I went to at Stanford for graduate school.

And so I like catching things and interesting things. And also quantity was important when you're fishing for commercial reasons. So a process chemist, I'm not interested in little tiny scale reactions. I mean, I can do them and understand the meaning of them for analysis, but I want to make a handful of something and so that I can do something, whatever I want with it and just put it on the shelf as a reagent. So that's what a process chemist does. And so simplicity. My lifelong mission was to make things faster. I'm very impatient in the lab, and my son will, who works here, worked in the lab a year and a half. He's like me. We make things quickly and they crash out and we go on to, and so the asymmetric epoxidation got me interested in.

Well, this is not quite written the way I would. The main thing about I learned was, came from George Hammett, a nonlinear thinker who was a professor and came back to work at exon for years. It's not making compounds that we're interested in. There's no sense to making compounds. There's too many of them. But it's the making of properties. You got to find properties. That's the magic of chemistry. We have properties all around us we haven't made yet. Things that are easy to make. And that's what click chemistry has helped. Yeah.

Now, this is why I'm disorganized, probably because I. But the periodic table was very helpful to me. I dove into it as a kid in high school or even before in grammar school, and I read it all about every element and its properties. And does it react with water or. I just needed to know about everybody. And of course, a lot of these things you can't find anything out about you go and look for things here you won't find, well, Syria, these are okay, these are important today and countries fighting over them. But the transition metals really set us off during my lifetime. But, you know, I'm not so enamored of them right now. Copper, of course, is never never land here between the main group. And copper is really, really special. It's very slippery. You can't stop it.

It's everywhere in our body at atomolar concentration. And so there's plenty of copper if we can learn to house it better to do the chemistry that Carolyn and Morton like to do, even when the heart is beating. Elements in the table that I particularly have a relationship with is selenium. That came for interesting reason. MIT. I thought I needed to write an NIH grant because I didn't think NIH grant would support chemistry. That's how naive I was. So I went out to Wisconsin for two months, learned from the experts on selenium biochemistry, came back, wrote an NIH grant, and then Selena proceeded to discover that selenium was fascinating, simple chemistry, making olefins. So, in two years of doing that on the side, it got me tenured at MIT. Okay, so, Derek Barton was a friend and advisor to me. I liked his way of looking for new reactivity. And I was actually told by him I couldn't stop doing asymmetric chemistry if I wanted to win a Nobel prize, which I thought was.

That was Derek's point of view, and I was looking to get out of it, because I can't stay on something very long. But went on for a while, did these. Dartmouth came, and we really did a job on the asymmetric epoxidation, dihydroxylation. That was probably the best reaction I've ever seen for catalytic oxidation. I put this in for those who. I'll leave it in the written version, and it just enumerates the events. epoxidation was fine, and it sidetracked me with chirality. But chirality wasn't what I was interested in. I was interested in making efficient bonds. And I found out more and more the only bonds that matter are the bonds between things that are separate. Like people. The first, they get in the same room, maybe they hold hands. That's like velcro.

But then eventually, if you're wearing the right bracelets, there's a click, and then you're together forever. But when you put two things together, molecules, modules, that's where the properties come from. That's what nature teaches us. But we don't have the right to build things the way nature does. Top down, she's making big molecules whose sole reverential involvement is to control themselves and the other guys to make the right connections. So, no, but we can start at the bottom. That's our privilege. We start at the bottom with a few things. Maybe we need a few thousand because we don't have all this massive territory we can cover, but we can come up from the bottom and make function. And that function can be affordable for, hopefully, much more people than biotechnology could possibly imagine being.

Anyway, I made some enemies in this world. Enemies came heavily from saying the grail of carbon. Carbon bond formation was perhaps a false grail, and I would defend that to this day, but let's not get involved in that. That probably set back chemistry's acceptance for years. And MG came. He was a great student doing the asymmetric epoxidation and was the man who did the mechanism at MIT, but he was in Virginia. And then Richard Lerner loved MG when he was out on sabbatical, and he hired him as a professor at Scripps and MG. I got together and we had, let's see now. I'm just going to jump to the end whenever I get in trouble, so don't worry overnight. So Richard, he just.

Richard loved this project, too. It was the idea of, why don't we let the enzyme take 50 pieces on each side and do the cycloaddition, the azide, Carolyn's thing, where you get this very weak. We skin our hero, all of us, because of his great physical. Organic chemists are much more important than people realize, and we didn't do them much good in the last 50 years. So I suggest we worry about them again in the future to help us so the enzyme can hold this thing together and this cycle addition could increase its likelihood. But it seems very pathetic because the concentrations we had of the pieces, and you'll see them in the next slide. This is what MG and I decided to do.

That's our first article on clique, that's the manifesto that was written for click chemistry when we didn't even have a perfect reaction. So we were kind of making it up as we went along here, what might be, but we didn't have those reactions at that time. And where's my. Okay. This inspired MG. And I. Reza Guderi, a beloved colleague at MIT, bought a copy of Kevin Kelly's book out of control. If you haven't read Kevin Kelly's book, you've got to read it. Even though it's written in 96 or 94, it's still relevant today to what life is that a lot of us don't think of about life. And life is out of control. Of course, naturally, if it were in control, who'd be controlling it? And it would fail if it had some human controlling it. So Kevin Kelly says, nothing is more addicting than God games. He's got a chapter on God games.

And don't get me wrong, these God games are not irreverent. Sim Earth, Sim City, whatever. But your first rule about God games that you learn is to be a God, you have to relinquish control. You set down your system and you watch it. Well, I mean, those games sound really hard to imagine succeeding. And so we were out walking on the beach at Scripps a few days later, after reading the copies of the book Reza gave us. And we both said, well, what did you make of this book? What did you like? And we both loved the God game part, because we realized there was a question where you could really see a problem, because everybody takes x rays of big molecules and they're sitting still, frozen to death with their mates at minus hundreds kelvin. And then we make predictions about how we're going to stick something in this hole and other things we take. But it's like the ugly stepsisters trying to get into the Cinderella slipper, breaking everything. And so humans are trying to design the finished product.

Oh, you're stable on water. You could be a drug that's really arrogant when you think about it. So what about if you let the molecule take a couple parts and somehow it can make a connection that's permanent? So the molecule can act as a reaction vessel, and that's, well, chemical phases be. This is something everybody knows about today. I give Derek some credit here. I should mention Regina Bohacek, Colin McMartin, and Wayne Guida, who also had an elegant story on this, how the mass of the universe that we can see, the visible universe, could be occupied by one molecule of every possible drug that was less than 500 molecular weight, and it wouldn't be any matter left over to work with. So it's absurd how much stuff there could be. So my guess is about 99.99% of space close to us, two or three steps away, four steps away from things we could execute, that have good, perfect reactions, that could make. That could make a useful molecule strike into a real functional molecule. But most, the screen is the problem.

This is where I would say we should. That's my insight from the last few days, I thought the biggest problem we have is screens. I mean, how are you going to discover. I have to stop, right? I have ten minutes. Okay. We got some extra time from the failure. Okay, thank you. So how are we going to screen for something? I don't know what you want out of the chemical. Everybody might have their own magic chemical interest for function from a human being or an animal, but how do you screen for that? You don't allow the screen directly in humans legally. So that's a problem. But there are other things too, like how to make a building just overall have something that makes it last 100 years longer than wood for falling down corrosion and concrete or you'll see what happened to me. Most of chemists, we think about life, especially since, well, Bersalius put us into thinking about life as organic chemistry, which was a very misleading thing and absolutely absurd, of course, but that's okay.

He did some great things for chemistry. But his own student, Wohler, proved him wrong, of course, from Germany, a postdoc. So here's the in situ with fancy Mike Peak at Scripps. Could make anything look great. Richard Lerner loved him. And this is the enzyme acetylcholinesterh. And here it is making in its guts this thing that MG and I worked on together, making a triazole, clicking it together in its heart. And the inhibitor that came out was, I'm going to have to jump over this one because what was the inhibitor? White. Okay, maybe that'll come later. But the inhibitor was femtomolar and it went down as low as two femtomolar. And this was the most potent inhibitor ever made from almost any enzyme, but let alone for acetylcholinesterase.

So that was a real, the first inhibitor we ever made in my lab. And it was made by MG and Warren Lewis and Luke Green. That was femtomolar. And that's pretty remarkable from 50 pieces on each side. So there were a lot of combinations, certainty of molecular chance. Well, when we started doing this assembly of modules, we found out, right, we ran headline into a problem. The best reactions that were out there were far from good enough. And here, I'll just show this slowly, quickly, the quickest way. We found MG and Harmuth and I working in Jan in the last few days to figure out, because we had other ways to explain this. But here, if I have perfect reaction, what does it look like? Well, it actually looks like this. After 1000, you can do this in the computer, you find this thing you put in and it takes it to the power from one up to 1000 or higher, whatever you want to do.

So here it is. If you do 1000 steps in a row with a 99% yield, most organic chemists are going to go to the bank with this kind of a reaction. And in solid phase synthesis, Morton could tell me they don't need that even. They just use excess reagent. Right. So 99% yield, this is what it buys you. After 1000 serial steps, you're down to 0.004. And then I come to 99.9. I get up to here, 99.99. I'm here. But to get to 99% after 1000 steps, this is polymer chemistry, right? And here you have 99.99. Usually helps to have another nine, and the thing almost never fades. And that's what this new reaction is like. And it's a polymer reaction.

So, okay, let me. Let me just get through to that. This is the reaction that's magic and came into our lap with jia ja dong. It's a suffix reaction. What happens is silicon, phosphorus, and sulfur love to change ligands with a suffix catalyst and they do it as fast as the QAC reaction, if you can believe it. Room temperature, 130 degrees, it doesn't matter. The reaction doesn't even get explode when it's done neat. It's a polymer reaction. And here is the early team that published that. And polymer has been working for a long time with me now at Scripps. He came back. He was a student who came back as a professor at Scripps, and we work on the polymer together. Here's MG, who's been involving suffix chemistry, and click chemistry from the beginning. Almost. Heartmuth, of course, was really at the very beginning. Here's Jiazha dong and Larissa ket Krasnova on this suffix chemistry.

Now, what I want to show you is just how the polymer, you melt the polymer together, the two monomers, crystalline, melt them together, and then you put the catalyst in, it makes the polymer. You put some more dmf. You put dmf in, and then you pump it into a stirred solution. Ja, ja, hereda. It's shown. You get a. It crashes out in methanol. You wind it up. He called it bird net soup. Bird net polymer. It's a beautiful polymer. Very, very good fidelity. Okay, I know I'm running out of time here, but here you can see I have no time, right? Oh, okay. So 500. Here's another type we make from another gas, from sulfur, the tetraphorite. And this polymer is very, very easy to make, and it forms perfectly. And it has this extra spot where we can put. We put Azt out there with a connection through a qaC.

And so we had this huge molecule of 500 thymidines on it. Every spot had a thymidine sticking out and it was a helical structure. And if we didn't have this yield up here at 99.998 we wouldn't have gotten this yield. I'm sure this yield's too high, but even if it was 98 you can see the massive amount of yield you get out of this reaction. And here's the nmRs. The NMRs are ridiculous. This is a molecule with 500 units connecting and this is the proton NMR and this is the reference for fluorine. That's the fluorine at 500 MHz or wherever the resonance frequency is. But it's just like one fluorine and these guys chiral centers in them and there are helocets. Here's what the thing looks like. Hans Zulath is our collaborator in the Netherlands and his students got these pictures of these helices.

The pitch of some of, they know the pitch of them. Each of these will have like a nucleotide sticking out every turn. Every pitch is about twelve degrees. But the main point is that this is DNA, of course, and that's another nice polymer with sulfate phosphate affinities. But when you look at this from outer space and you come in and you're smart, you're looking at somebody shows you that, you'd say, well, those are phosphates or sulfates. You can't tell by looking at them because they're either neutral or they have a minus one charge. Just to remind you that this chemistry that's helical is also related to life's chemistry. And finally, this is what I wanted to say.

We ran head on into an amazing thing we've been trying to do biochemistry, but I never did polymer chemistry before and I found it very hard to do. I didn't understand the arguments. And we got tremendous help from molecular foundry at Berkeley that Carolyn used to run that molecular foundry. Can you imagine? She does every jack of all trades, I guess. But Ye Lu is a former student with MG and I. He has been there for ten years or so and we Pong knew him and we got going. They would measure our polymers, our polysulfate polymers and the main thing about these polysulfates is they are immortal, much as you might say. A sulfate looks like a weak wimp link. This thing is not coming apart in vivo. It's just stable. So it's just a connector.

And here's what it does. If you make this polymer, and then you use it to make these films, you just dissolve it and dissolve it and make films. And you put those films as capacitors. This was ye and his student Henry's idea, because they had experience with capacitors under duress, under high heat and high temperature. And we don't have good ones right now. So what you make is sort of wrapped up coils of these films, and wrapped them around the zone where the horrible things are happening. In a Tesla or a power station. If you have a capacitor, it has to load its charge and then, wham. Drop. And if it leaks and you get heat, and you get so much heat that you can't function anymore.

And the high field doesn't help either. You. So what we found was something amazing. I thought, this is one of the polymers we made, and we made it to have a high tg so we could have a high temperature. And these are gold electrodes, and the film that's laid down on those is our polysulfate film. It's clear. And then you wrap it around, and so a Way that you can run the field through it. And at 150 degrees, 750 volts, the polysulfate is way up there ahead of all the ones used in electric cars now or for any purpose where you need survival of this electric sort of. It's an insulator, but it holds a charge, and that drops. It loads dropped. So we ran it 50,000 times over 3 hours, and it just runs straight. There's no decay.

And if we want, we can show that if you wound it, then it has to, it makes a short. And then you do a few square wave cycles, and it comes back on a reproducible cycle and. And it loses maybe one or 2% because it healed itself, it just burned up the part that wasn't any good. And now it's back to being a healthy capacitor material. So this was a complete intrusion into my life of physics. And I thought that was really a cool thing, because how physics, especially physics with fields, right? Electromagnetic fields. This is magic, its action at the distance. How the hell is this poem? Well, we know. We think we know and how it's working, and we're after that now.

And a man in Germany, Dietmar Stahlke, who's one of the few people I think understands main group chemistry, bonding silica, aluminum, silicon, sulfur, and phosphorus and sulfur. That's really messed up, that bonding, as it stands now in our life as chemists. So his way of looking at it, he can explain why this thing is not conducting this phosphorus sulfur linkages will resist conduction. There are no PI bonds. Most people, we all draw them as PI bonds. O PI bonds. There are no PI bonds there. So that's the end. But I just had to get that last message out that the certainty of chance. This is the certainty of chance that Jan wanted me to introduce, because I just.

I can't get over how much chance when you can make things quickly and you can test them against something reasonable. The certainty of chance is huge, right? I mean, do you intuit that? That's what. That's why I think it's important that certainly a chance, and that's from a guy who is a jazz musician and the first person to say that he believed in the certainty of chance. He was, oh, I can't remember the Dados type movement and the fact that life is one of the chances that we see here in front of us is one of the chances this universe offered. And it's occupied.

Sorry for all the lack of order, but I just thought. Oh, and I humble thanks to all my wonderful students and postdocs and visiting professors and collaborators. And I'm going to get the names out there, of course, in a long list in the paper, but I couldn't get them together for today, so I apologize. But the ending was the main part of this story. It's certainly a chance again. Thank you.

Chemistry, Innovation, Science, Click Chemistry, Nobel Prize, Research Collaboration, Nobel Prize