Dienedioic acid as a useful diene building block via directed Heck-decarboxylate coupling

Dienes are useful reagents for cross-couplings in the synthesis of unsaturated natural products, but decarboxylative Heck reactions of dienes are limited by facile E/Z isomerism. Here configurationally stable divinyldicarboxylic acid is used as a coupling reagent in which the carboxylates direct the Heck reaction prior to decarboxylation. The concise construction of diene scaffolds is quite useful in the synthesis of polyenes. Many diene building blocks have been developed based on Suzuki, Still and Hiyama couplings. Herein, the commercially available and environmentally friendly compound dienedioic acid is used as a diene building block. Broad substrate scope, good functional group tolerance, and late-stage derivatization of complex drug molecules are achieved. Different moieties can be conveniently introduced to both sides. Piperine and the methyl ester of azoxymycin C are each prepared in three steps. Additionally, one product shows promising anticancer activities in leukemia K562 and MV-4-11 cells. Mechanistic studies indicate that the reaction proceeds through a Heck-decarboxylate coupling procedure, and the carboxylic group acts as a directing group to promote the reaction and control regioselectivity. Our research suggests that dienedioic acid can serve as a good alternative for diene preparation via a directed Heck-decarboxylate coupling.