Synthesizing Inaoside A from Edible Mushroom

Although natural compounds from plants and animals have long played a key role in drug development, the chemical potential of mushrooms remains poorly understood. For the first time, Japanese researchers have successfully synthesized Inaoside A, a substance obtained from the edible mushroom Laetiporus cremeiporus.

For decades, natural compounds derived from plants and animals have inspired the creation of drugs and nutritional supplements. Plant-based compounds have led to the development of several well-known medicines, including morphine, aspirin, and paclitaxel. Despite their long history of use for health benefits, mushrooms and their rich chemical diversity have garnered far less attention from biochemists.

Against this backdrop, a team of researchers—led by Assistant Professor Atsushi Kawamura from Shinshu University’s Department of Biomolecular Innovation, along with Mr. Tomoya Takao and Dr. Hidefumi Makabe from the university’s Department of Agriculture—focused on Inaoside A, a compound of the α-D-ribofuranoside class that they had previously isolated from Laetiporus cremeiporus. The study was first published online on October 31, 2024, and later appeared in the Asian Journal of Organic Chemistry (Volume 13, Issue 12) on December 13, 2024.

Motivation for the Study

The research was driven by two key factors:

1. The α-D-ribofuranoside structure is frequently found in natural products, yet far fewer studies have reported the synthesis of α-D-ribofuranosides compared to their β-anomers. This has drawn significant attention from organic chemists.
2. Synthesizing Inaoside A was an essential step toward investigating its bioactivities and unlocking its full potential.

“The total synthesis of Inaoside A is a critical objective because its varied bioactivities need to be investigated,” explained Assistant Professor Kawamura.

The Path to Synthesis

The team used an α-selective Schmidt glycosylation reaction as the cornerstone of their approach. This reaction allows a glycoside to attach to another molecule in a specific orientation, known as the "α position."

Using retrosynthetic chemistry—a method where chemists work backward from the desired final product to determine the necessary starting materials and reactions—they identified two key compounds needed for the Schmidt glycosylation: an aglycone derived from vanillin and ribofuranosyl trichloroacetimidate.

However, conventional Schmidt glycosylation techniques typically favor the production of β-ribofuranosides over α-ribofuranosides. To overcome this challenge, the researchers developed a new substrate: a 2,3,5-tri-O-(tert-butyldimethylsilyl)-protected ribofuranoside. This substrate was not only straightforward to produce but also easy to deprotect after the glycosylation reaction. Using this method, the team achieved remarkable selectivity, producing α-ribofuranoside with an α/β ratio of 4:1 to 5:1.

Implications and Future Research

The ability to synthesize newly discovered natural compounds is vital for studying their characteristics and biological functions.

“By elucidating the chemical structures and biological activities of natural products derived from mushrooms, we aim to uncover their potential as functional foods and pharmaceutical leads,” said Kawamura.

With Inaoside A now readily synthesized, the researchers are optimistic about its future.

“Further studies on Inaoside A, including detailed investigations of its bioactivities, derivative synthesis, and structure–activity relationship analyses, are underway. Our goal is to develop this compound into something socially meaningful,” Kawamura added.

A Step Toward Unlocking Mushroom Potential

This achievement not only paves the way for deeper exploration into Inaoside A but also highlights the untapped potential of mushroom-derived compounds. As researchers continue to uncover the secrets of these natural products, they may lead to innovative medicinal and dietary applications that benefit human health.