Improved Total Synthesis of Millepachine through a Negishi Acylative Cross-Coupling Protocol

The chalcone Millepachine exhibits interesting biological properties, such as cytotoxic and antitumor activity against various cancer cells. Despite these characteristics, the only published synthesis gives the product in modest yield. Herein, a study on the acylative Negishi cross-coupling for obtaining Millepachine in higher yield is presented. Both iodo- and bromo-2H-chromene derivatives, as precursors of the organozinc halides, are synthesized and different routes for obtaining the organometallic species are explored. The transmetalation from the aryllithium proves to be the most efficient method to obtain a reactive organozinc species for the Negishi cross-coupling with 4-methoxycynnamoyl chloride. Up to 75% yield of pure product is obtained corresponding to 43% overall yield from commercially available 3-methoxyphenol.