Stereoselective Construction of <i>C</i> ₂ -Symmetric Adjacent Bis-α,α′- <i>cis</i> -Disubstituted THF Skeleton via Double Intramolecular Amide Enolate Alkylation: Total Syntheses of (+)-Membranacin and (+)-Squamocin-N

Described herein is the highly stereoselective and concise first asymmetric total synthesis of (+)-squamocin-N (<b>1b</b>) bearing a C15-C24 adjacent bis-tetrahydrofuran (THF) backbone with <i>threo/cis/threo/cis</i>/<i>threo</i> stereochemistry. This approach features construction of <i>C</i>₂-symmetric adjacent <i>cis/threo/cis</i> bis-THF core <b>5</b> via a novel double intramolecular amide enolate alkylation (IAEA) protocol, reductive desymmetrization of <i>C</i>₂-symmetric bis-THF <b>5</b>, and chelation-controlled nucleophilic addition (CCNA) as the key steps. In addition, (+)-membranacin (<b>1a</b>), the C24 epimer of <b>1b</b>, was synthesized via Mitsunobu inversion.