Total synthesis of microtubule-stabilizing agent (-)-laulimalide.
An enantioselective first total synthesis of laulimalide (1) is described. Laulimalide, a remarkably potent antitumor macrolide, has been isolated from the Indonesian sponge Hyattella sp. and the Okinawan sponge Fasciospongia rimosa. Laulimalide represents a new class of antitumor agents with significant clinical potential. The synthesis is convergent and involved the assembly of C(3)-C(16) segment 4 and C(17)-C(28) segment 5 by Julia olefination. The sensitive C(2)-C(3) cis-olefin functionality was installed by Yamaguchi macrolactonization of a hydroxy alkynic acid followed by hydrogenation of the resulting alkynoic lactone over Lindlar's catalyst. Initial attempts of intramolecular Still's variant of Horner-Emmons olefination between the C(19)-phosphonocetate and C(3)-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 olefin metathesis to construct both dihydropyran units, stereoselective anomeric alkylation to functionalize the dihydropyran ring, stereoselective reduction of the resulting alkynyl ketone to set the C(20)-hydroxyl stereochemistry, and a novel Julia olefination protocol for the installation of the C(13)-exo-methylene unit. The sensitive epoxide at C(16)-C(17) was introduced in a highly stereoselective manner by Sharpless epoxidation at the final stage of the synthesis.
Ghosh
A K
AK
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA. arunghos@uic.edu
Wang
Y
Y
Kim
J T
JT
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000302:isolation & purification; D003500:Cyclization; D007202:Indicators and Reagents; D018942:Macrolides; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000302:isolation & purification; D011161:Porifera / Q000737:chemistry*; D013237:Stereoisomerism; D043823:Taxoids
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D018942:Macrolides; D043823:Taxoids; C117305:laulimalide; D017239:Paclitaxel