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.
