Use of versatile intermediates enables free synthesis of "clovane-type terpenoids," a promising drug candidate

Among organic compounds produced by nature, a group of clovane-type terpenoids has long attracted attention as drug candidates due to their useful biological activities such as anti-inflammatory and neuroprotective effects. In particular, compounds discovered from corals in recent years, such as rumphellclovane E and sarinfacetamides A and B, have complex structures containing many oxygen and nitrogen atoms (highly oxidized skeletons) and have been considered difficult to synthesize using conventional methods.

A research group consisting of Graduate Student Daigo Ninomiya, Assistant Professor Shota Nagasawa, and Professor Yoshiharu Iwabuchi from the Graduate School of Pharmaceutical Sciences at Tohoku University successfully synthesized three natural products and synthetic derivatives (artificially modified analogues) in one fell swoop, starting from precisely designed versatile intermediates. This opened up a new strategy that enables efficient and free synthesis of highly functionalized clovane-type terpenoid groups. This research is expected to significantly advance small molecule drug discovery research based on clovane-type terpenoids as a starting point. The results were published online in Chemical Science.

The original versatile intermediate designed in this study is synthesized from an inexpensive commercially available compound called dihydrocarvone. The research group successfully assembled the molecular skeleton in one step while precisely controlling the three-dimensional shape of the molecule by performing a domino Michael-aldol reaction. This reaction required the use of acrolein, a substance that is difficult to handle safely, but the research group developed a safe surrogate and achieved a safe reaction using it.

This method made it possible to supply large quantities of versatile intermediates with only five reactions. Additionally, by changing the starting materials, it is also possible to create versatile intermediates called enantiomers, which have a mirror-image relationship like our right and left hands.

Subsequently, based on this versatile intermediate, the researchers successfully synthesized three types of naturally derived compounds and synthetic derivatives. The versatile intermediate is designed so that the structure can be easily converted by devising the arrangement of oxygen atoms on the skeleton. It is also designed to easily introduce the side chains (branching parts) that are characteristic features of sarinfacetamides A and B.

First, the group synthesized rumphellclovane E by performing structural conversion on the skeleton. Subsequently, they utilized the enone structure that is part of the compound to introduce side chain structures, achieving the synthesis of sarinfacetamides A and B and synthetic derivatives.

This research established a new strategy that enables efficient and flexible synthesis of highly oxidized clovane-type terpenoids. It is applicable not only to already known natural products and their derivatives, but also to new clovane-type terpenoids that may be discovered in the future. In fact, prior research by other groups has suggested that structurally diverse clovane-type terpenoids that have not yet been discovered in nature may exist. When such unknown natural products are discovered in the future, the strategy from this research will serve as a foundation for rapidly synthesizing and utilizing them for biological activity evaluation and drug discovery research.

Journal Information
Publication: Chemical Science
Title: A unified approach to highly functionalized clovane-type terpenoids: enantiocontrolled total synthesis of rumphellclovane E and sarinfacetamides A and B
DOI: 10.1039/D5SC04197J