The total synthesis and structure confirmation of the potent cytotoxic agent (−)-asimitrin (1a), a C37 annonaceous acetogenin having a hydroxylated adjacent bis-tetrahydrofuran (THF) core, are described. The present synthesis features a highly stereoselective, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 17-hydroxy-16,17-erythro-16,19-trans-THF 6, our direct ketone synthesis/L-Selectride reduction protocol for stereoselective introduction of the C(21)−C(34) unit, Sharpless asymmetric dihydroxylation (SAD), and internal Williamson etherification for construction of the 20,23-trans-THF ring. This approach can be applied to three additional derivatives of the THF backbone, which exhibit trans/cis (1b), cis/cis (1c) and cis/trans (1d) conformations. Application of our modular strategy to the synthesis of other annonaceous acetogenins as well as analogues for medicinal chemistry studies provides access to a new area of natural products with potential for new drug development._x000D_
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<br>Keywords_x000D_
<br>intramolecular amide enolate alkylation · cyclization · bis-THF · natural products · total synthesis
