Tokyo University of Science succeeds in the total synthesis of the plant-derived natural product "merrillianin" — Expectations for the development of anti-rheumatic drugs

A research group led by Professor Isamu Shiina and Assistant Professor Takatsugu Murata of the Department of Applied Chemistry, Faculty of Science, Tokyo University of Science announced that they are the first group to successfully achieve artificial synthesis of merrillianin, a natural product indicated to have anti-rheumatic activity found in the pericarp of Illicium merrillianum, a plant of the genus Illicium. This accomplishment is expected to facilitate development of therapeutic drugs for nervous system diseases and rheumatic conditions. The study results were published in the international academic journal Organic Letters.

Merrillianin is a natural organic compound (sesquiterpene lactone) isolated in 2002 from the pericarp of I. merrillianum that is expected to have antirheumatic activity. Plants of the genus Illicium have been used in Chinese herbal medicines since ancient times. Some sesquiterpenes contained in these plants are known to be effective for nervous system diseases. Prior to this work, merrillianin had never been chemically synthesized due to its very complex molecular structure.

The research group achieved merrillianin total synthesis via an intramolecular cyclization reaction using the asymmetric Mukaiyama aldol reaction and samarium (II) iodide (SmI₂). The Mukaiyama aldol reaction is a type of aldol reaction which produces β-hydroxy carbonyl compounds under Lewis acid conditions via a reaction between a ketone or aldehyde and a silyl enol ether. SmI₂ is a metal compound composed of samarium and iodide that is used as a single-electron reducing agent in organic syntheses.

The total yield was 1.6%, and the absolute configuration of merrillianin was successfully determined. Tricyclic dilactone was also produced as a key intermediate. Applications are expected in the synthesis of other Illicium sesquiterpenes.

Journal Information
Publication: Organic Letters
Title: Total Synthesis of the Sesquiterpene (−)-Merrillianin
DOI: 10.1021/acs.orglett.3c03877