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

Abstract

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.

Stereoselective total synthesis of (3Z)- and (3E)-elatenynes

“…By this route, (10 S )-9,10- syn homoallylic alcohol 9 could be stereoselectively prepared through application of ate complex ( n -BuLi/DIBAL-H) reduction/Keck allylation protocols to yield α-alkoxy amide 10 ( vide infra ). Based on our previous work, 7 we were confident that key 6,7- cis -6,9-cis-THF intermediate 10 could be accessed by subjecting 6,7- syn -ω-bromo-α-alkoxy amide 11 to our stereoselective chelate-controlled IAEA reaction. Finally, we imagined that IAEA substrate 11 could be prepared in a straightforward manner from the known 6,7- syn epoxy alcohol 12 .…”

“…This requires the stereoselective synthesis of 9,10- syn homoallylic alcohol 9 from α-alkoxy amide 10 through application of our direct ketone synthesis/L-Selectride protocol. 7 Thus, the Grignard reaction of 10 with CH 2 CHCH 2 MgBr, and the subsequent L-Selectride reduction of the resulting ketone 18 , afforded the desired 9,10- syn -homoallylic alcohol 9 in moderate yield (59% for two steps) and good selectivity (dr = 8 : 1 by 1 H NMR analysis). In an alternative approach, 10 was reduced using the ate complex derived from n -BuLi and DIBAL-H 12 and subjected to Keck allylation 13 to afford homoallylic alcohol 9 in improved yield (75% for two steps) and improved selectivity (dr = 46 : 1 by 1 H NMR analysis) 14 CM reaction of the alcohol 9 with cis -3-hexene in the presence of Grubbs second-generation catalyst [G-II, (H 2 IMes)(Cy 3 P)Cl 2 RuCHPh] 15 afforded alkene 20 as an inseparable mixture of stereoisomers (95% total yield, E / Z = 6 : 1 by 1 H NMR analysis).…”

“…1) via intramolecular amide enolate alkylation (IAEA). 7 In addition, our strategy utilizes Marshall's protocol [cross metathesis (CM)/SAD/Williamson cyclization] 8 for the efficient construction of 2nd THF skeleton in the adjacent bis-THF unit.…”