Total Synthesis of (±)‐Cristaxenicin A: Construction of Nine‐Membered Ring by Eschenmoser–Claisen/Cope Rearrangement Cascade

Abstract

Abstract Cristaxenicin A, a natural marine product with a skeleton consisting of a nine‐membered carbocycle fused with a dihydropyran ring, displays strong antiprotozoal activity against Leishmania amazonensis and Trypanosoma congolense . The synthesis of cristaxenicin A is challenging because of its unique oxidation pattern at C11 and C20, the cis ‐cyclononane with a C5─C6 double bond, and the C1─C19 alkene moiety functionalized as an enol acetate. Herein, we report the first total synthesis of (±)‐cristaxenicin A. The nine‐membered ring was constructed from 2,2‐divinylcyclopentanecarbonitrile through an addition reaction with 4‐( tert ‐butyldimethylsilyl)oxy‐2‐butenal followed by a one‐pot sequence of the Eschenmoser–Claisen and Cope rearrangement reactions. After the formation of a trans ‐fused bicyclo[7.3.0]dodecane skeleton through an intramolecular Stetter reaction, the cyclopentane ring was transformed into a dihydropyran ring by oxidative cleavage, followed by intramolecular acetalization. Two reactions described herein, namely, the formation of a cyclononadiene ring via the Cope rearrangement without using an oxy‐Cope substrate and a new protocol for the construction of a dihydropyran ring from a cyclopentene derivative, provide a powerful tool for the total synthesis of natural products with highly functionalized complex structures.