Substrate-Controlled Asymmetric Total Synthesis and Structure Revision of (−)-Bisezakyne A

The first asymmetric total synthesis and subsequent structure revision of (−)-bisezakyne A, a Laurencia C₁₅ acetogenin from Alpysia oculifera, has been accomplished. Our substrate-controlled synthesis of this oxolane natural product features a highly stereoselective “protecting-group-dependent” intramolecular amide enolate alkylation strategy for the synthesis of the key 9,10-<i>trans</i>-9,12-<i>cis</i>-10-hydroxytetrahydrofuran intermediate through “nonchelate” control. In addition, our synthesis determined the absolute configuration of the halogenated marine natural product

Highly Stereodivergent Construction of a C₂‑Symmetric <i>cis</i>,<i>cis</i>- and <i>trans</i>,<i>trans</i>-2,6-Dioxabicyclo[3.3.0]octane Framework by Double Intramolecular Amide Enolate Alkylation: Total Synthesis of (+)-Laurenidificin and (+)-Aplysiallene

The highly stereoselective construction of C2-symmetric cis,cis- and trans,trans-2,6-dioxabicyclo[3.3.0]octane (fused bis-tetrahydrofuran) skeletons 4a and 4b has been accomplished via a novel stereodivergent double intramolecular amide enolate alkylation of common cyclization substrate 5 through the judicious choice of “chelate” versus crown ether-promoted “nonchelate” control. Application of this methodology has provided access to substrate-controlled concise total syntheses of (+)-laurenidificin (3) and (+)-aplysiallene (ent-2), which possess cis/cis- and trans/trans-fused bis-tetrahydrofuran cores, respectively