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.