Total Synthesis of (±)-Cristaxenicin A: Construction of Nine-Membered Ring by Eschenmoser-Claisen/Cope Rearrangement...

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.