Desymmetrization of a centrosymmetric diepoxide: efficient synthesis of a key intermediate in a total synthesis of hemibrevetoxin B.
The preparation of an established intermediate in a total synthesis of hemibrevetoxin B is described. The acid-catalyzed cyclization of trans-4,5-epoxyoctane-2,7-dione exhibited a valuable mixture of kinetic and thermodynamic control: stereospecific epoxide opening was followed by equilibration of the products to provide the required trans-fused octahydropyrano[3,2-b]pyran ring system. Two-directional elaboration, by acetal substitution, ozonolysis, and sulfur ylide-mediated epoxidation, provided a centrosymmetric diepoxide. The key step of the synthesis was the first desymmetrization of a centrosymmetric molecule in natural product synthesis: Jacobsen asymmetric epoxide hydrolysis and acetonization provided the known synthetic intermediate in 97% yield and >95% ee over two steps. The exploitation of the center of symmetry of the AB ring system of the natural product contributed greatly to the efficiency (eight steps, 34% overall yield) of the synthesis.
Holland
Joanne M
JM
Department of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
Lewis
Mark
M
Nelson
Adam
A
D001685:Biological Factors / Q000032:analysis / Q000138:chemical synthesis; D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods*; D003500:Cyclization; D006576:Heterocyclic Compounds, 4 or More Rings / Q000032:analysis / Q000138:chemical synthesis*; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism
D001685:Biological Factors; D006576:Heterocyclic Compounds, 4 or More Rings; C409729:hemibrevetoxin B