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 (+)… Show more
“…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 .…”
mentioning
confidence: 94%
“…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).…”
mentioning
confidence: 98%
“…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.…”
The total synthesis of (3Z)- and (3E)-elatenynes have been achieved by a highly stereoselective and chelate-controlled intramolecular amide enolate alkylation.
“…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 .…”
mentioning
confidence: 94%
“…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).…”
mentioning
confidence: 98%
“…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.…”
The total synthesis of (3Z)- and (3E)-elatenynes have been achieved by a highly stereoselective and chelate-controlled intramolecular amide enolate alkylation.
The axially chiral allene framework has garnered significant attention from synthetic community, due to its wide applications in natural products, organic synthesis, pharmaceuticals, and materials science. Among the structurally diverse...
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