Total Synthesis of an Immunosuppressive C₂₅ Macrocyclic Terpenoid Produced by Terpene Synthase (<i>LcTPS</i>2)

Macrocyclic natural products, particularly those with no functionalities except unsaturation, are recognized for their therapeutic potential but are notoriously challenging to synthesize. In this study, we report the first total synthesis of an unconventional 18-membered, C₂₅ macrocyclic terpenoid, which has demonstrated substantial immunosuppressive activity. This synthesis was achieved through strategic modifications and innovative reaction engineering, utilizing α-terpineol and geraniol as starting materials, highlighting a novel approach in macrocyclic terpenoid synthesis.