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| - Total Synthesis of Microtubule-Stabilizing Agent (−)-Laulimalide1
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| - An enantioselective first total synthesis of laulimalide (1) is described. Laulimalide, a remarkablypotent antitumor macrolide, has been isolated from the Indonesian sponge Hyattella sp. and theOkinawan sponge Fasciospongia rimosa. Laulimalide represents a new class of antitumor agentswith significant clinical potential. The synthesis is convergent and involved the assembly ofC3−C16 segment 4 and C17−C28 segment 5 by Julia olefination. The sensitive C2−C3cis-olefinfunctionality was installed by Yamaguchi macrolactonization of a hydroxy alkynic acid followedby hydrogenation of the resulting alkynoic lactone over Lindlar's catalyst. Initial attempts ofintramolecular Still's variant of Horner−Emmons olefination between the C19-phosphonocetate andC3-aldehyde provided a 1:2 mixture of cis- and trans-macrolactones. The trans-isomer was photoisomerized to a mixture of cis- and trans-isomers. The other key steps involved ring-closing olefinmetathesis to construct both dihydropyran units, stereoselective anomeric alkylation to functionalizethe dihydropyran ring, stereoselective reduction of the resulting alkynyl ketone to set the C20-hydroxyl stereochemistry, and a novel Julia olefination protocol for the installation of the C13-exo-methylene unit. The sensitive epoxide at C16−C17 was introduced in a highly stereoselective mannerby Sharpless epoxidation at the final stage of the synthesis.
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