Different recipe, same sauce

Kyoto University designs a hat trick of reactions to access shagene A
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Just north of Antarctica and a little east of the southern tip of South America is the Scotia Sea. Besides the glimpse of the occasional iceberg, these waters offer little to tourists. 

To biologists, however, the Scotia Sea possesses a diverse ecosystem that is a source of drugs and other therapeutic agents. Such was the case in 2014, when the discovery of shagene A, a compound effective against the parasitic disease leishmaniasis, was reported. A new study in Agnewandte Chemie by Kyoto University removes the need to visit this remote region by describing the total synthesis of the tricyclic terpenoid.

In contrast to orphan diseases, which receive little attention because patients are few, leishmaniasis is one of many neglected tropical diseases afflicting a billion people, typically the poor in developing countries. Leishmaniasis alone affects more than 10 million people worldwide, with another million infected every year.

Drugs for the disease are available, but they are sometimes injected and have several side effects. Shagene A, on the other hand, kills the responsible parasite without side effects. The problem, according to research team leader Chihiro Tsukano, is its availability.

“This natural compound can only be obtained in very small quantities, and since the sample has been used up no further research is possible,” he notes. 

Its same therapeutic properties make shagene A an attractive seed for drug discovery, but along with its rarity is its unstable, distorted structure, which makes it a challenge to synthesize in the lab. 

The instability of shagenes comes from their congested 3/6/5 tricyclic ring system. To synthesize the structure of shagene A, Tsukano and his colleagues designed a total synthesis of 21 steps that depends on three key reactions, each using a different transition metal catalyst. Among them, one was especially significant, remarks Yoshiji Takemoto, another author of the study.

“We envisaged a catalyzed double-bond isomerization of alkylidene cyclopropane to relieve the strain.” This reaction depended on using ketones as a directing group, an approach that Takemoto adds, “has no precedent.”

This strategy allowed the researchers to produce multiple tricyclic rings systems with different substitution patterns, including ones causing the instability seen with shagene A. 

“Based on the established synthetic route, we were not only able to supply shagene A, but also congeners. Now, we are also investigating more bioactive compounds for further development of leads for leishmaniasis,” states Tsukano. 

Tsukano, Chihiro
Publication information


【KURENAI ACCESS URL】http://hdl.handle.net/2433/265391

Chihiro Tsukano, Ryotaro Yagita, Takayoshi Heike, Tagwa A. Mohammed, Kazuya Nishibayashi, Kazuhiro Irie, Yoshiji Takemoto (2021). Asymmetric Total Synthesis of Shagenes A and B. Angewandte Chemie International Edition, 60(43), 23106-23111.