BIORELEVANT TOTAL SYNTHESIS OF THE ELEUTHEROBIN CORE

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This total synthesis of the eleutherobin core proposes, as its main objective, to construct this extremely potent antitumor marine product by an efficient and biologically relevant route. The fact that eleutherobin and taxol share a common mechanism of action and tubulin binding domain with discodermolide and the epothilones suggests the possibility that, although structurally quite different, these anticancer agents each achieve similar forms at the binding site. Structural (bond) reorganization may furnish the active form. Whether such rearrangement occurs in vivo or can be shown to be synthetically useful are important questions to ask and comprise a key feature of the proposed synthesis. Reorganizations envisioned in this idea include a novel fragmentation. Ready construction of substrates appropriate to test the fragmentation will also flow from this plan. Other interesting chemical questions asked explore pertinent intraannular functional romp interactions, including redox pathways and stereoselective isomerization of enones, as well as exerting such stereocontrol in an intermolecular interaction (for example, using a "Bayliss-Hillman" reaction) related to a proposed role of the active site in the aforementioned biomimetic rearrangement. The overall approach, which projects completion in a competitive 15-20 steps, should also supply important SAR information by way of its intermediates and easily derived analogues (especially thio- and aza-ethers), afford rapid access to the briarellins and asbestinins (related, bioactive diterpenes), and provide a novel fragmentation methodology to afford medium rings.