Direct Coupling of Catharanthine and Vindoline to Provide Vinblastine: Total Synthesis of (+)- and ent-(−)-Vinblastine

Abstract

A direct coupling of catharanthine with vindoline to provide vinblastine is detailed along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine amine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)−NaBH₄/air solution leads to oxidation of the C15‘−C21‘ double bond and reduction of the intermediate iminium ion directly providing vinblastine (43%) and leurosidine (23%), its naturally occurring C21‘ alcohol isomer. The yield of coupled products, which exclusively possess the natural C16‘ stereochemistry, approaches or exceeds 80%, and the combined yield of the isomeric C21‘ alcohols is 66%.