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Simultaneous Analysis of 21 Chemical Reactions... AI to Transform New Drug Development
< Photo 1. (From left) Professor Hyunwoo Kim and students Donghun Kim and Gyeongseon Choi in the Integrated M.S./Ph.D. program of the Department of Chemistry >
Thalidomide, a drug once used to alleviate morning sickness in pregnant women, exhibits distinct properties due to its optical isomers* in the body: one isomer has a sedative effect, while the other causes severe side effects like birth defects. As this example illustrates, precise organic synthesis techniques, which selectively synthesize only the desired optical isomer, are crucial in new drug development. Overcoming the traditional methods that struggled with simultaneously analyzing multiple reactants, our research team has developed the world's first technology to precisely analyze 21 types of reactants simultaneously. This breakthrough is expected to make a significant contribution to new drug development utilizing AI and robots.
*Optical Isomers: A pair of molecules with the same chemical formula that are mirror images of each other and cannot be superimposed due to their asymmetric structure. This is analogous to a left and right hand, which are similar in form but cannot be perfectly overlaid.
KAIST's Professor Hyunwoo Kim's research team in the Department of Chemistry announced on the 16th that they have developed an innovative optical isomer analysis technology suitable for the era of AI-driven autonomous synthesis*. This research is the world's first technology to precisely analyze asymmetric catalytic reactions involving multiple reactants simultaneously using high-resolution fluorine nuclear magnetic resonance spectroscopy (19F NMR). It is expected to make groundbreaking contributions to various fields, including new drug development and catalyst optimization.
*AI-driven Autonomous Synthesis: An advanced technology that automates and optimizes chemical substance synthesis processes using artificial intelligence (AI). It is gaining attention as a core element for realizing automated and intelligent research environments in future laboratories. AI predicts and adjusts experimental conditions, interprets results, and designs subsequent experiments independently, minimizing human intervention in repetitive experiments and significantly increasing research efficiency and innovativeness.
Currently, while autonomous synthesis systems can automate everything from reaction design to execution, reaction analysis still relies on individual processing using traditional equipment. This leads to slower speeds and bottlenecks, making it unsuitable for high-speed repetitive experiments.
Furthermore, multi-substrate simultaneous screening techniques proposed in the 1990s garnered attention as a strategy to maximize reaction analysis efficiency. However, limitations of existing chromatography-based analysis methods restricted the number of applicable substrates. In asymmetric synthesis reactions, which selectively synthesize only the desired optical isomer, simultaneously analyzing more than 10 types of substrates was nearly impossible.
< Figure 1. Conventional organic reaction evaluation methods follow a process of deriving optimal reaction conditions using a single substrate, then expanding the substrate scope one by one under those conditions, leaving potential reaction areas unexplored. To overcome this, high-throughput screening is introduced to broadly explore catalyst reactivity for various substrates. When combined with multi-substrate screening, this approach allows for a much broader and more systematic understanding of reaction scope and trends. >
To overcome these limitations, the research team developed a 19F NMR-based multi-substrate simultaneous screening technology. This method involves performing asymmetric catalytic reactions with multiple reactants in a single reaction vessel, introducing a fluorine functional group into the products, and then applying their self-developed chiral cobalt reagent to clearly quantify all optical isomers using 19F NMR.
Utilizing the excellent resolution and sensitivity of 19F NMR, the research team successfully performed asymmetric synthesis reactions of 21 substrates simultaneously in a single reaction vessel and quantitatively measured the product yield and optical isomer ratio without any separate purification steps.
Professor Hyunwoo Kim stated, "While anyone can perform asymmetric synthesis reactions with multiple substrates in one reactor, accurately analyzing all the products has been a challenging problem to solve until now. We expect that achieving world-class multi-substrate screening analysis technology will greatly contribute to enhancing the analytical capabilities of AI-driven autonomous synthesis platforms."
< Figure 2. A method for analyzing multi-substrate asymmetric catalytic reactions, where different substrates react simultaneously in a single reactor, using fluorine nuclear magnetic resonance has been implemented. By utilizing the characteristics of fluorine nuclear magnetic resonance, which has a clean background signal and a wide chemical shift range, the reactivity of each substrate can be quantitatively analyzed. It is also shown that the optical activity of all reactants can be simultaneously measured using a cobalt metal complex. >
He further added, "This research provides a technology that can rapidly verify the efficiency and selectivity of asymmetric catalytic reactions essential for new drug development, and it is expected to be utilized as a core analytical tool for AI-driven autonomous research."
< Figure 3. It can be seen that in a multi-substrate reductive amination reaction using a total of 21 substrates, the yield and optical activity of the reactants according to the catalyst system were simultaneously measured using a fluorine nuclear magnetic resonance-based analysis platform. The yield of each reactant is indicated by color saturation, and the optical activity by numbers. >
Donghun Kim (first author, Integrated M.S./Ph.D. program) and Gyeongseon Choi (second author, Integrated M.S./Ph.D. program) from the KAIST Department of Chemistry participated in this research. The study was published online in the Journal of the American Chemical Society on May 27, 2025.※ Paper Title: One-pot Multisubstrate Screening for Asymmetric Catalysis Enabled by 19F NMR-based Simultaneous Chiral Analysis※ DOI: 10.1021/jacs.5c03446
This research was supported by the National Research Foundation of Korea's Mid-Career Researcher Program, the Asymmetric Catalytic Reaction Design Center, and the KAIST KC30 Project.
< Figure 4. Conceptual diagram of performing multi-substrate screening reactions and utilizing fluorine nuclear magnetic resonance spectroscopy. >
2025.06.16 View 5907 -
Every Moment of Ultrafast Chemical Bonding Now Captured on Film
- The emerging moment of bond formation, two separate bonding steps, and subsequent vibrational motions were visualized. -
< Emergence of molecular vibrations and the evolution to covalent bonds observed in the research. Video Credit: KEK IMSS >
A team of South Korean researchers led by Professor Hyotcherl Ihee from the Department of Chemistry at KAIST reported the direct observation of the birthing moment of chemical bonds by tracking real-time atomic positions in the molecule. Professor Ihee, who also serves as Associate Director of the Center for Nanomaterials and Chemical Reactions at the Institute for Basic Science (IBS), conducted this study in collaboration with scientists at the Institute of Materials Structure Science of High Energy Accelerator Research Organization (KEK IMSS, Japan), RIKEN (Japan), and Pohang Accelerator Laboratory (PAL, South Korea). This work was published in Nature on June 24.
Targeted cancer drugs work by striking a tight bond between cancer cell and specific molecular targets that are involved in the growth and spread of cancer. Detailed images of such chemical bonding sites or pathways can provide key information necessary for maximizing the efficacy of oncogene treatments. However, atomic movements in a molecule have never been captured in the middle of the action, not even for an extremely simple molecule such as a triatomic molecule, made of only three atoms.
Professor Ihee's group and their international collaborators finally succeeded in capturing the ongoing reaction process of the chemical bond formation in the gold trimer. "The femtosecond-resolution images revealed that such molecular events took place in two separate stages, not simultaneously as previously assumed," says Professor Ihee, the corresponding author of the study. "The atoms in the gold trimer complex atoms remain in motion even after the chemical bonding is complete. The distance between the atoms increased and decreased periodically, exhibiting the molecular vibration. These visualized molecular vibrations allowed us to name the characteristic motion of each observed vibrational mode." adds Professor Ihee.
Atoms move extremely fast at a scale of femtosecond (fs) ― quadrillionths (or millionths of a billionth) of a second. Its movement is minute in the level of angstrom equal to one ten-billionth of a meter. They are especially elusive during the transition state where reaction intermediates are transitioning from reactants to products in a flash. The KAIST-IBS research team made this experimentally challenging task possible by using femtosecond x-ray liquidography (solution scattering). This experimental technique combines laser photolysis and x-ray scattering techniques. When a laser pulse strikes the sample, X-rays scatter and initiate the chemical bond formation reaction in the gold trimer complex. Femtosecond x-ray pulses obtained from a special light source called an x-ray free-electron laser (XFEL) were used to interrogate the bond-forming process. The experiments were performed at two XFEL facilities (4th generation linear accelerator) that are PAL-XFEL in South Korea and SACLA in Japan, and this study was conducted in collaboration with researchers from KEK IMSS, PAL, RIKEN, and the Japan Synchrotron Radiation Research Institute (JASRI).
Scattered waves from each atom interfere with each other and thus their x-ray scattering images are characterized by specific travel directions. The KAIST-IBS research team traced real-time positions of the three gold atoms over time by analyzing x-ray scattering images, which are determined by a three-dimensional structure of a molecule. Structural changes in the molecule complex resulted in multiple characteristic scattering images over time. When a molecule is excited by a laser pulse, multiple vibrational quantum states are simultaneously excited. The superposition of several excited vibrational quantum states is called a wave packet. The researchers tracked the wave packet in three-dimensional nuclear coordinates and found that the first half round of chemical bonding was formed within 35 fs after photoexcitation. The second half of the reaction followed within 360 fs to complete the entire reaction dynamics.
They also accurately illustrated molecular vibration motions in both temporal- and spatial-wise. This is quite a remarkable feat considering that such an ultrafast speed and a minute length of motion are quite challenging conditions for acquiring precise experimental data.
In this study, the KAIST-IBS research team improved upon their 2015 study published by Nature. In the previous study in 2015, the speed of the x-ray camera (time resolution) was limited to 500 fs, and the molecular structure had already changed to be linear with two chemical bonds within 500 fs. In this study, the progress of the bond formation and bent-to-linear structural transformation could be observed in real time, thanks to the improvement time resolution down to 100 fs. Thereby, the asynchronous bond formation mechanism in which two chemical bonds are formed in 35 fs and 360 fs, respectively, and the bent-to-linear transformation completed in 335 fs were visualized. In short, in addition to observing the beginning and end of chemical reactions, they reported every moment of the intermediate, ongoing rearrangement of nuclear configurations with dramatically improved experimental and analytical methods.
They will push this method of 'real-time tracking of atomic positions in a molecule and molecular vibration using femtosecond x-ray scattering' to reveal the mechanisms of organic and inorganic catalytic reactions and reactions involving proteins in the human body. "By directly tracking the molecular vibrations and real-time positions of all atoms in a molecule in the middle of reaction, we will be able to uncover mechanisms of various unknown organic and inorganic catalytic reactions and biochemical reactions," notes Dr. Jong Goo Kim, the lead author of the study.
Publications:
Kim, J. G., et al. (2020) ‘Mapping the emergence of molecular vibrations mediating bond formation’. Nature. Volume 582. Page 520-524. Available online at https://doi.org/10.1038/s41586-020-2417-3
Profile: Hyotcherl Ihee, Ph.D.
Professor
hyotcherl.ihee@kaist.ac.kr
http://time.kaist.ac.kr/
Ihee Laboratory
Department of Chemistry
KAIST
https://www.kaist.ac.kr
Daejeon 34141, Korea
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2020.06.24 View 24507