Yu Jinquan: Activate the sleeping C-H key with endless enthusiasm

Yu Jinquan is one of the most active scientists in the field of C–H bond activation | Image source: Respondents

"Any major scientific problem in chemistry is not a 100-meter sprint, but a marathon. It is impossible for anyone to solve a major problem within three to five years. You really need endless enthusiasm to go through one failure after another, all the way to the final success. ”

This is the feeling of chemist Yu Jinquan after reviewing his personal research career. It is out of his endless passion for chemical research that he led the team to develop a number of new catalysts for C-H bond activation, many of which have been used in industrial production.

Today, Intellectual recommends an interview with National Science Review magazine with Professor Yu Jinquan of the Scripps Institute in the United States to share with readers.

Interview | Zhao Weijie (NSR News Editor)

Translate | Wang Zong'an

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Yu Jinquan, a professor at the Scripps Institute in the United States, is one of the most active scientists in the field of C–H bond activation. His team has developed many new catalysts for C-H bond activation (usually composed of metal catalytic centers and ligands), and is committed to breaking the C–H bonds in various organic compounds in the most concise, efficient and highly selective way, and connecting the activated C atoms with various other atoms or groups to synthesize various compounds "at will".

Recently, the National Science Review (NSR) conducted an exclusive interview with Yu Jinquan to discuss the fascinating research field of C–H bond activation, and listen to his review of his own research experience and advice to young researchers.

C–H key activation: progress and challenges

NSR: What are some important developments in C–H bond activation over the past 20 years?

Yu Jinquan: To evaluate the progress in this field, it is necessary to divide C–H bond activation into two sub-areas: the first is the initial functionalization of alkanes, mainly methane oxidation for fuel transportation, or the functionalization of alkanes for the production of bulk chemicals; and the second is the further functionalization of various organic synthesis reaction substrates to prepare complex molecules with new functions.

These two subfields are very different, with different evaluation criteria and different methods of solving problems. Confusing the two is a major obstacle hindering the development of the C–H bond activation field, especially in the subfield of further functionalization. In 2002, we conducted rational analysis and in-depth reflection on the challenges of "developing hydrocarbon activation reactions for organic synthesis", which was our first important step in entering this field.

For the oxidation of methane or alkanes, the challenge is not reactivity or selectivity, as we can solve these problems by adding excess substrates under high pressure or high temperature conditions. This type of reaction usually involves only one or two types of C–H bonds, so the main problem in terms of selectivity is to avoid excessive oxidation. In this case, it is enough to have only one good reaction. In fact, the most critical challenges are efficiency and cost, as such reactions are often used to produce relatively inexpensive bulk chemicals, as well as raw materials for fuel or chemical synthesis. Regrettably, progress in addressing this challenge has been very slow over the past 30 years. A reasonable suggestion is that this problem can be solved by heterogeneous catalysis or enzyme catalysis. We need catalysts that are as stable, efficient, and inexpensive as zeolites.

For the further C–H bond functionalization of fatty acids, ketones, amines, alcohols and other organic synthetic substrates, a huge challenge is the reactivity of the widely used substrates under mild conditions. Selectivity is also a huge challenge, because in these substrates, almost all C–H bonds are different due to the presence of functional groups, and the activation of each C–H bond will result in a different molecular structure. Moreover, complex molecular synthesis does not require only a certain transformation reaction, but requires a series of synthesis steps to form different bonds in turn to achieve efficient and perfect synthesis.

To systematically advance this subfield, we present four core challenges that need to be overcome, which I call 4Ys:

1 Reactivity: The use of a variety of natural substrates to form a variety of carbon-carbon and carbon-heteroatomic bonds;

2 EnantioselectivitY: desymmetry of the tetrahedral carbon center to control chirality during C–H metallization;

Site-selectivitY: Selectively activate multiple C–H bonds remotely without traditional electron or steric resistance effects;

4 SustainabilitY: Catalytic conversion is achieved using large-scale industrialized green oxidants, such as molecular oxygen or aqueous hydrogen peroxide solutions, as equivalent oxidants.

Over the past 10 years, we have made some significant progress in addressing these four challenges, largely thanks to six new ligand-based bifunctional catalysts invented in our lab.

NSR: Tell us about the new catalysts you designed in your lab. How do they help solve 4Y challenges?

Yu Jinquan: Our first breakthrough was the discovery of a bifunctional Pd(II) catalyst based on mono-protected amino acids (MPAA) in 2008. We observed that this MPAA ligand can greatly accelerate the activation of C–H bonds and facilitate the multiple subsequent bonding of carbon-carbon and carbon-heteroatomic bonds, and that's when we knew we had found a "game changer."

We have discovered through years of research that this ligand is actually bifunctional. Typically, in catalysis, ligands regulate the properties of metal centers by coordination. The MPAA ligand has another crucial role: the monoprotective amino group is directly involved in the transition state and cuts the C–H bond. Based on this basic understanding, we have developed five new ligands: MPAQ, MPAO, MPAAm, MPAThio, and, more recently, Pyri-Pyri ligand. These chiral ligands also enable us to achieve enantioselective C–H bond activation through asymmetric metallization for the first time after half a century of long-term exploration.

NSR: Is your reaction already industrially applicable?

Yu Jinquan: Yes, there are many. My chair professorship was donated by the renowned pharmaceutical company Squibb (my collaborator). For example, one of our C–H bond lactone reactions has been used by Pfizer to develop challenging positive-acting ectopic modulators. Novartis also applied one of our C–H bond activation reactions to process chemistry, cutting the steps in half. Our tetrahydropyrrole enantioselective C–H methylation reaction also spawned the drug candidate for Abide Therapeutials, founded by my colleague Benjamin Cravatt and recently acquired by Lundbeck for $400 million.

Our C-H arylation of alkylamines and C-H coupling of phenylacetic acid were used by Vividion Therapeutics (I myself am one of the co-founders) to synthesize a small molecular library designed specifically for drug discovery. Many potential drug candidates have been discovered through this molecular library, which was recently acquired by Bayer for $2 billion.

From the perspective of chemical synthesis, the most exciting applications will emerge in large-scale pharmaceutical industrial production. We are working with pharmaceutical companies including Bristol-Myers Squibb and Abbvie to optimize and amplify our responses. I believe that in the near future, one of our room-temperature C–H hydroxylation reactions will be used in the pharmaceutical industry.

NSR: Catalysts for C–H bond activation are typically based on metals such as palladium or copper. Which metal has the best catalytic effect? Why?

Yu Jinquan: From the 1960s to the 21st century, many other metals, such as iridium (Ir), rhodium (Rh), and ruthenium (Ru), were used in the study of C–H bond activation. We chose to study Pd(II) because our purpose is not just to develop a reaction or form a bond. Each step in the synthesis process requires the formation of a different carbon-carbon or carbon-heteroatomic bond. Initially, we wanted to develop a series of conversion reactions that could be used for synthesis and avoid unnecessary conversion reactions. To achieve this goal, Pd(II) has the greatest potential because in cross-coupling reactions, the Pd-C bond has a very diverse reactivity.

Cu(II) can also be applied to a variety of C–H bond activation reactions, and this discovery is one of the most unexpected surprises in the field of C–H bond activation. Using copper catalysts and molecular oxygen, we tried to mimic the C–H hydroxylation reaction of biological systems, and accidentally discovered the first C–O bond formation reaction in 2006 (this paper has been cited more than 1,000 times). Subsequent mechanistic studies have shown that this is not a bionic oxidation reaction, but rather that we may have stumbled upon an unexpected organometallic C–H bond activation reaction, similar to the Pd(II) catalytic reaction.

This discovery opened up systematic research into Cu(II) catalysts, as well as the development of many copper-catalyzed C–H bond activation reactions for carbon-carbon and carbon-heteroatomic bonds in our lab over the past 15 years. Other laboratories have also made many interesting contributions in the field of Cu(II) catalyst research.

However, compared to the Pd(II) catalyst, there is still a long way to go to announce a major breakthrough for the Cu(II) catalyst, mainly because we have not yet found an effective ligand.

NSR: What are the challenges in the field of C–H bond activation?

Yu Jinquan: From the perspective of practical application, the challenges are:

1 Expand the range of major natural substrates, including fatty acids, ketones, amines and alcohols; 2 Extend the activation site of aliphatic chains to one or two carbons farther away from the functional group; 3 Increase the catalytic cycle to 1000-10,000 levels to achieve large-scale production; 4 Use molecular oxygen, aqueous hydrogen peroxide solutions and other practical oxidants for a wider hydrocarbon bond activation reaction.

From an intellectual point of view, we need to invent more methods and new catalysts to improve site selectivity and enantioselectivity.

In short, the key to solving these challenges is the following three points: first, ligand discovery; second, ligand discovery; and third, ligand discovery.

NSR: How are Chinese scientists doing in the field of C–H bond activation?

Yu Jinquan: They are an important force in this field, and some of the results are very unique. For example, Xiaoguang Lei's team (Department of Chemical Biology, Peking University) synthesized (-)-Incarviatone A using multiple C–H bond activation reactions developed in our lab; Li Ang's team (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences) asymmetrically synthesized Delavatine A using one of our enantioselective C–H bond activation reactions; Bingfeng Shi's team (Department of Chemistry, Zhejiang University) used our proposed chiral transient guided group strategy to complete (+)- Steganone's total synthesis; Chen Gong's laboratory (School of Chemistry, Nankai University) uses C-H bond activation reactions to synthesize peptide-based natural products very elegantly; Mei Tiansheng's team (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences) has done pioneering work in establishing a redox catalytic cycle of palladium-catalyzed C–H bond activation reactions using electrochemical methods; Ye Mengchun's laboratory (School of Chemistry, Nankai University) recently reported a remote site-selective C-H bond activation reaction of nickel catalyzed Dai Huixiong's laboratory (Shanghai Institute of Materia Medica, Chinese Academy of Sciences) has made significant contributions to broadening the activation and transformation of C–H bonds catalyzed by Cu(II).

Prospects for the field of organic chemistry

NSR: Are there new approaches in synthetic chemistry?

Yu Jinquan: Organic chemists are always inventing new ways to meet various challenges. For example, the formation of complex thick rings, carbohydrate synthesis, nucleotide synthesis, synthesis of fluorine-containing compounds, electrochemical catalysis and photochemistry are still making important progress. I expect that the copper-catalyzed C–H bond activation reactions we initiated in 2006 will yield unexpected developments over the next 10 years.

NSR: Is there a universal catalyst or a universal catalyst design approach for a wide variety of substrates and reactions?

Yu Jinquan: In the field of catalyst design, "universal" may be a wrong word. Even in the traditional field of double-bond chemistry, it is naïve to expect the existence of a general-purpose catalyst. Enzymes are masterpieces of catalyst design, and nature has endowed enzymes with extraordinary selectivity, which inevitably limits the range of their substrates. In contrast, synthetic chemists have developed a number of catalysts that can adapt to a wider range of substrates, which we call broadly useful catalysts rather than general-purpose catalysts.

In principle, selectivity is achieved through precise molecular recognition, so it is not possible to achieve high selectivity on different kinds of substrates using the same catalyst. In addition, different carbon-carbon or carbon-heteroatotom bonding reactions often require different catalyst structures. Ideally, we could classify the substrate into several major categories and design different types of catalysts for them, which is how we study the C–H bond activation reaction. I think the gold standard for a broad catalyst is the ability to catalyze 10,000 substrates.

However, there are some principles that can be universally applied to the design of a variety of different catalysts. For example, we utilize weak coordination of substrates to achieve the concept of entropy requirements and bifunctional ligands to enhance enthalpy contribution, which has been widely successful in catalyst designs for different types of substrates, such as carboxylic acids and amines.

NSR: You describe your job as "molecular editing." What does this mean exactly?

Yu Jinquan: This means to change a molecule in any order and in any position by converting the C–H bond into other bonds that are useful in synthesis. In this sense, it is not enough to selectively activate a particular C–H bond. The biggest challenge is to be able to selectively activate multiple C–H keys in any order and in three directions to meet the needs of a given multi-step synthesis.

In my opinion, molecular editing is the ultimate tool for capturing the extreme diversity of chemical spaces and achieving ideal synthesis. Simply put, it was the Apollo 17 lunar mission in synthetic chemistry. Apollo 17 was the last mission of the Apollo program. ]

NSR: What is the method of "activating multiple C–H keys in any order"?

Yu Jinquan: The structure of the substrate molecules varies greatly, so different methods also need to be used. Classical methods of controlling site selectivity through electronic and spatial effects are still valuable, but very limited.

Most synthetically important C–H bonds are usually far from functional groups and have similar electronic properties, making it difficult to rely on existing textbook theories. If you delve into the catalytic process of enzymes, you will find that enzymes are able to form multiple weak interactions with substrates, thus achieving efficient site-selective catalysis. This selectivity is often attributed to the complex binding pocket of the enzyme, which guides (and may mislead) synthetic chemists to imitate this magical binding pocket without regard to the guiding effect, but the success achieved is very limited. However, if you delve into the selective remote oxidation of enzyme sites of fatty acids and distill their rationale, you will realize that enzymes are masters of remote orientation, and that site selectivity is controlled by the distance and topology of the large ring transition state.

Based on this understanding, we have established a new method called the "carpenter's approach", in which the catalytic guidance template is designed to be reversibly interact with the substrate and form a large ring transition state. Distance and geometry determine the energy barrier of the transition state, thus controlling site selectivity.

NSR: The 2021 Nobel Prize in Chemistry was awarded to Benjamin List and David MacMillan for their contributions to organic catalysis. Is this work relevant to your field of study?

Yu Jinquan: Organic catalysis is an important method for the preparation of chiral molecules in addition to metal catalysis, and its core is to obtain enantioselectivity of existing reactions. Typically, these reactions involve reactive functional groups, and stereoselectivity comes primarily from flat π bonds. Activation of inert C–H bonds focuses on inventing new reactions, providing new logic for synthesis. Enantioselectivity in C–H bond activation reactions involves a completely different stereoscopic model, i.e., breaking the symmetry of the tetrahedral carbon center. There is no doubt that enantioselective C–H bond activation reactions will also have a transformative effect on asymmetric catalysis, a major challenge my lab has been trying to solve.

Thinking and advising: Keep the passion and analyze with your heart

NSR: It's been five years since you won the 2016 MacArthur Genius Award. How did you use that bonus?

Yu Jinquan: It has helped me tremendously in many ways. In 2016, although we have made some promising discoveries, we are still exploring in the dark, and it is not clear how far we can push the field. Working on a challenging topic carries a high risk of losing money or even a job. This prize money allows me to explore truly high-stakes topics without having to pursue short-term results to gain the kinds of recognition that young scientists have always dreamed of (which is understandable).

NSR: How did you choose your research topic? Do you prefer basic work, or is it difficult, fun, or useful?

Yu Jinquan: Ideally, of course, you would want your subject to have all these characteristics. If chosen properly, these characteristics may overlap with each other. For example, our first project on the activation of the asymmetric C-H bond by using oxazoliline was very basic and important, because no one had yet established a model system to study the chiral transition state of C–H fracture. But obviously, if this topic stays at this level, it has no application value. Because the question is interesting and can provide critical missing knowledge to the field, I chose it in 2002.

The remote C–H key activation project we carried out in 2009 was very difficult. The system we originally built was far-fetched and equally unworkable. We chose it not only because it was fun, but also because we saw its potential.

Our latest research on oxidants using aqueous solutions of molecular oxygen and hydrogen peroxide is very important and valuable. These studies not only fill important scientific gaps, but also bring the C–H bond activation reaction closer to large-scale industrial production.

In chemical research, an important subject often requires many small steps to finally reach a stage where everyone can see its importance and application value. To this day, some of our topics and achievements are still criticized by many as out of touch with reality. For example, many people criticize our use of guided groups because most people are still unable to distinguish between the unguided activation reactions of methane or alkanes and the reactions of synthetic substrates, and are therefore misled. Therefore, it is crucial to have a long-term vision, to see the major challenges and solve them step by step.

NSR: Has COVID-19 affected your research?

Yu Jinquan: I travel less, have fewer meetings, and have more time to think. As it turns out, this is not a bad thing. This year (2021) our lab has produced several innovative ideas that have led to very exciting discoveries. For example, we established an important concept in catalyst design, that is, the acquisition of bifunctional ligands by tautomers, and for the first time achieved C–H hydroxylation based on molecular oxygen. The work has been published in the journal Science.

Of course, the pandemic has also reminded me that more attention should be paid to how we can use our new responses to develop drugs. Scripps researches all one project dedicated to developing small molecule drugs against COVID-19, and I'm also involved on the periphery, providing any possible help when needed.

NSR: You've had the iconic "exploding head" for years. When did you start with this hairstyle? Is there any reason for this?

Yu Jinquan: Mainly when I was studying at Cambridge University, it took a lot of money and time to get a haircut. After becoming a professor at Scripps, I started visiting the barbershop more, but I found that none of my colleagues liked my short hairstyles. Our head of department, Professor Nicolaou, even called me into his office and had a serious conversation about it. I remember him saying, "Kim Kwon, can you do me a favor and keep your hairstyle?" Because this iconic hairstyle goes well with your crazy chemistry. My close friend Phil S. Baran, another prominent synthetic chemist, once joked, "You have to keep your hairstyle, or your hair index won't grow as fast as it has in the last 10 years." ”

NSR: You're energetic and passionate, and many other successful scientists have similar personalities. Do you think it's necessary for scientists to be passionate?

Yu Jinquan: Yes, any major scientific problem in the field of chemistry is not a 100-meter sprint, but a marathon. It is impossible for anyone to solve a major problem within three to five years. You really need endless enthusiasm to go through one failure after another, all the way to the final success.

NSR: Have there been any people or things that have had a major impact on you during your scientific career?

Yu Jinquan: There are many. My master's supervisor Xiao Shude gave me great trust in experimental design and gave me strong self-confidence. My PhD supervisor, the late Dr. J.B. Spencer, was a very special friend who, like an older brother, greatly shortened the time I spent learning about Western scientific culture and living habits.

My postdoctoral supervisor, Professor E. J. Corey, is a great scientist in the field of organic chemistry and has a great charisma, and he advises me every step of my career like a father. When I proposed the first stand-alone topic on asymmetric hydrocarbon activation in 2002, he gave me a crucial influence. I distinctly remember showing him my draft proposal, which he drew a red exclamation point on the first page and said only one word to me: Stick to this idea! （Stick to this idea!）

NSR: What advice would you give to young chemistry researchers?

Yu Jinquan: Be focused, enthusiastic, self-critical, and most importantly, be completely honest and analytical.

We've all heard the phrase "think outside the box of the box" and "from 0 to 1", but you need to have excellent analytical skills to figure out what is "the old thinking", what is inside the box, what may be outside, what is meaningful from 0 to 1.

The article, originally titled "Activate C–H bonds with tons of enthusiasm: an interview with Jin-Quan Yu," was published online on December 28, 2021 in National Science Review, and Intellectuals was authorized to publish the article Chinese translation.

原文链接：Activate C–H bonds with tons of enthusiasm: an interview with Jin-Quan Yuhttps://doi.org/10.1093/nsr/nwab229

Plate editor| Lucas