(Press-News.org) Organic chemistry features a wide array of reactions for creating complex molecules, among which the Diels–Alder reaction stands out for its versatility and precision. This reaction enables the construction of intricate polycyclic compounds—structures often found in natural products and pharmaceuticals—by joining dienes and dienophiles with high regio- and stereoselectivity.
One particularly valuable diene for this purpose is ortho-quinodimethane (oQDM), known for its ability to form fused-ring systems. However, synthesizing this reactive intermediate has traditionally required harsh conditions and the elaborate precursor preparation, limiting its practical use. This challenge has persisted for over 70 years in the field of organic synthesis.
Addressing this longstanding issue, a research team led by Professor Junichiro Yamaguchi at Waseda University, in collaboration with Dr. Kei Muto at the Institute of Transformative Bio-Molecules, Nagoya University, Japan, has developed a novel palladium (Pd)-catalyzed, multicomponent reaction. Their method uses readily available chemicals—2-vinylbromoarenes, diazo species, and carbon nucleophiles, containing a dienophile group—to generate oQDM and ultimately form a range of polycyclic compounds efficiently. Their findings were published in the journal Chem on June 2, 2025.
“The molecule oQDM has fascinated chemists for decades because of its potential to build complex structures, yet its instability has made it elusive,” says Yamaguchi. “We were motivated by the idea of transforming this fleeting intermediate into a practical synthetic tool. Inspired by how nature constructs complex molecules from simple components, we sought to replicate that elegance in the lab using catalytic control and accessible materials.”
In this study, the researchers developed a method that enables carbon–carbon bond formation via a highly reactive benzyl–Pd intermediate. This reactivity allows for the efficient construction of polycyclic structures with a vinyl group. The team demonstrated the broad applicability of the reaction by synthesizing a variety of complex compounds, including equilenin, a naturally occurring hormone-related molecule.
Their method significantly reduces the number of steps and harsh conditions typically required to access such compounds. As a result, this approach could make complex molecular structures more accessible for drug discovery and other applications. The researchers suggest that their reaction platform could be useful for building chemical libraries for drug screening and for developing new materials with functional properties.
“Our method enables access to molecular skeletons found in bioactive compounds, including hormone-based drugs and lead structures for anticancer and antiviral agents,” explains Yamaguchi. “It also allows for the rapid construction of compound libraries, which can support both pharmaceutical and materials research.”
This strategy offers a practical solution for synthesizing challenging polycyclic compounds while expanding the tools available to synthetic chemists working on applications in health and materials science.
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Reference
Authors: Kazuya Inagaki1, Yuna Onozawa1, Yuki Fukuhara1, Daisuke Yokogawa2, Kei Muto3, and Junichiro Yamaguchi1
DOI: 10.1016/j.chempr.2025.102615
Affiliations:
1Department of Applied Chemistry, Waseda University
2Graduate School of Arts and Sciences, The University of Tokyo
3Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University
About Waseda University
Located in the heart of Tokyo, Waseda University is a leading private research university that has long been dedicated to academic excellence, innovative research, and civic engagement at both the local and global levels since 1882. The University has produced many changemakers in its history, including eight prime ministers and many leaders in business, science and technology, literature, sports, and film. Waseda has strong collaborations with overseas research institutions and is committed to advancing cutting-edge research and developing leaders who can contribute to the resolution of complex, global social issues. The University has set a target of achieving a zero-carbon campus by 2032, in line with the Sustainable Development Goals (SDGs) adopted by the United Nations in 2015.
To learn more about Waseda University, visit https://www.waseda.jp/top/en
About Professor Junichiro Yamaguchi from Waseda University
Professor Junichiro Yamaguchi is an organic chemist at the Faculty of Science and Engineering, Waseda University. His research focuses on creating efficient methods to construct complex molecules, especially polycyclic and aromatic compounds. He earned his Ph.D. from the Tokyo University of Science in 2007 and completed postdoctoral research at The Scripps Research Institute. He began his academic career at Nagoya University before joining Waseda in 2016 and becoming a professor in 2018. In addition to his research, Professor Yamaguchi is committed to science communication and leads Chem-Station, a popular chemistry portal that shares advanced science in engaging ways.
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