Stereoselective Construction of C ₂ -Symmetric Adjacent Bis-α,α′- cis -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 ( 1b ) bearing a C15–C24 adjacent bis-tetrahydrofuran (THF) backbone with threo/cis/threo/cis / threo stereochemistry. This approach features construction of C 2 -symmetric adjacent cis/threo/cis bis-THF core 5 via a novel double intramolecular amide enolate alkylation (IAEA) protocol, reductive desymmetrization of C 2 -symmetric bis-THF 5, and chelation-controlled nucleophilic addition (CCNA) as the key steps. In addition, (+)-membranacin ( 1a ), the C24 epimer of 1b, was synthesized via Mitsunobu inversion.