Okayama University chemists pioneer light-driven macrolactone synthesis

Macrolactones—large ring lactones—are core components of many natural products and pharmaceutical agents. Traditional synthetic routes rely on seco acids activated with condensing reagents, often requiring harsh conditions or multi-step procedures. An alternative approach using hydroxyaldehydes has remained limited, and radical-based macrolactonization of these substrates had never been reported.

Now, a research team led by Dr. Kenta Tanaka, Assistant Professor at the Research Institute for Interdisciplinary Science, Okayama University, and Dr. Isao Kadota at Okayama University, along with colleagues Sakura Kodaki, Haru Ando, and Hiroyoshi Takamura, has developed a groundbreaking photochemical strategy for macrolactonization. Their study, published in Precision Chemistry on November 13, 2025, introduces a radical, light-driven conversion of hydroxyaldehydes into macrolactones spanning 7- to 21-membered ring sizes.

By irradiating hydroxyaldehyde substrates with purple LED light in the presence of bromotrichloromethane (BrCCl₃), the authors generate an acyl-bromide intermediate in-situ via C–H bromination. This reactive intermediate undergoes intramolecular cyclization, yielding macrolactones in good overall yields. The process works across a wide range of ring sizes—from small to large macrocycles—and tolerates substrates bearing benzene rings, ether group, and even secondary alcohol.

“What this method delivers is a mild approach to build macrolactone rings directly from simple precursors under photochemical conditions,” says Dr. Tanaka.

The findings are particularly significant for chemical synthesis because macrolactones are fundamental to numerous high-value compounds. These include antifungal and antiparasitic agents, immunosuppressants, and several approved anticancer drugs—many of which rely on complex macrocyclic scaffolds. The ability to construct such frameworks more efficiently can accelerate both natural product synthesis and the development of new therapeutic molecules.

Compared with conventional methods, the photochemical radical macrolactonization avoids pre-activation steps, harsh reagents, or multiple purification stages. This makes it attractive for scaling up synthesis and improving cost-effectiveness in pharmaceutical manufacturing. The researchers suggest that the strategy can streamline the assembly of macrolide antibiotics and diverse macrocyclic drug candidates that were previously difficult to access.

Beyond macrolactones, the technique may also be extended to structurally related molecules or analogues—offering medicinal chemists a powerful new tool. By simplifying macrocycle assembly, the method could open exploration of modified macrocycles with enhanced biological performance.

Despite its promise, the authors note limitations and areas for future work: expanding ensuring scalability, substrate scope, and optimizing reaction conditions for industrial use. “We believe that combining photochemistry with radical macrolactonization can open many doors for next-generation natural product synthesis,” adds co-author Dr. Kadota.

In summary, this novel photochemical macrolactonization ushers in a new paradigm for macrocycle formation. By merging light, radical chemistry, and simple precursors, the team at Okayama University offers a potentially transformative route that could reshape how macrocyclic natural products and drugs are synthesized.

About Okayama University, Japan

As one of the leading universities in Japan, Okayama University aims to create and establish a new paradigm for the sustainable development of the world. Okayama University offers a wide range of academic fields, which become the basis of the integrated graduate schools. This not only allows us to conduct the most advanced and up-to-date research, but also provides an enriching educational experience.

Website: https://www.okayama-u.ac.jp/index_e.html

About Dr. Kenta Tanaka from Okayama University, Japan  

Dr. Kenta Tanaka is an Assistant Professor at the Research Institute for Interdisciplinary Science, Okayama University, Japan. His research focuses on developing light-driven radical methods for complex molecule construction. Dr. Tanaka’s work blends photochemistry, radical generation, and green synthetic design to enable novel routes to macrocycles and natural product frameworks. His innovation in photochemical macrolactonization promises to expand access to biologically important macrolactones and streamline drug discovery workflows globally.