Skeletal Isomerization of Ergosterol-5,8-peroxide Leading to the Discovery of Unprecedented Ergostanes and Collective Syntheses of 5,6-Epoxysterols and (+)-Sarocladione

Mushrooms are representative health foods, and their health-promoting activities are thought to be derived partially from the low molecular weight components contained.

We have succeeded in the collective syntheses of sterols, representative mushroom components, in short steps from ergosterol according to biosynthetic hypothesis. Moreover, we have demonstrated that some of the synthetic compounds have an inhibitory activity against amyloid β aggregation, which would be useful for prevention of dementia.

First, we achieved skeletal isomerization of ergosterol-5,8-peroxide, which was thought to be a primary oxidation product of ergosterol, under extremely mild conditions comparable to biological environments.

The newly discovered conditions have made it possible to practically supply 5,6-epoxysterols, which were difficult to supply using conventional methods. In the course of the research, we also discovered an unprecedented 7/9/5-tricyclic ergostane whose structure was unambiguously determined by NMR and X-ray analyses.

Based on the own deduced biosynthetic pathways, we have succeeded in synthesizing a total of 13 mushroom-derived natural products. This synthesis allowed us to correct the wrong structure of one natural product.

Moreover, we also succeeded in synthesizing a unique tricyclic natural product isolated from a deep-sea-derived fungus.
Although the synthesis of this unique natural product had already been reported, the previous method required high temperatures and an expensive catalyst.

It is noteworthy that we achieved the synthesis only in three steps all at ambient temperature using a series of inexpensive reagents.

Aggregation and deposition of amyloid beta protein has been pointed out as a cause of Alzheimer's disease.
Some of the synthesized compounds in this study were found to inhibit amyloid beta aggregation and rescue the survival of neuronal cell death .

This research will help elucidate the biosynthetic pathways and biological roles of sterols contained in mushrooms, and will also contribute to the practical supply and structural determination of rare sterols that can only be obtained in small amounts from natural sources.