A Total Synthesis of the Antimitotic FR182877

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

FR182877 is a novel anti-mitotic agent recently isolated from a strain of Sptreptomyces by a team at Fujisawa Pharmaceutical Company. The compound exhibits potent in vitro activities against leukemia, mammary, lung, colon, T cell, melanoma and bone cancer cells. The mechanism of action is closely related to taxol, epothilone and discodermolide, promoting microtubule assembly. FR182877 has an unprecedented hexacyclic structure highlighting a strained tetra-substituted olefin. Our proposed synthesis of this natural product features a stereocontrolled transannular Diels-Alder reaction giving a 5,6,12-tricycle. Next, a key tandem radical-mediated Michael addition-anionic Dieckmann sequence complete the carbon skeleton. Our 16-step sequence will provide access to analogs that may have improved biological selectivity and water- solubility.