Total synthesis of the microtubule stabilizing antitumor agent laulimalide and some nonnatural analogues: the power of Sharpless' asymmetric epoxidation.
Three different routes are described for the synthesis of deoxylaulimalide (3), which is the immediate precursor of the marine sponge metabolite laulimalide (1). These routes mainly differ with respect to their ring closing step. Thus, route 1 uses a Still-Gennari olefination, route 2 a Yamaguchi lactonization, and route 3 an intramolecular allylsilane-aldehyde addition for establishing the macrocyclic structure. The unprotected deoxy derivative 3 was subjected to Sharpless' asymmetric epoxidation (SAE). With (R,R)-tartrate the 16,17-epoxide laulimalide (1) is formed selectively, whereas (S,S)-tartrate generates the 21,22-epoxide 142. This demonstrates the high reagent control involved in the SAE process, which in this case is used to achieve high stereo- and regioselectivity. Laulimalide and some derivatives thereof have been tested with respect to antitumor activity and compared to standard compounds paclitaxel and epothilone B.
Ahmed
Anjum
A
Institute of Organic Chemistry, University of Vienna, Währinger Strasse 38, A-1090 Vienna, Austria.
Hoegenauer
E Kate
EK
Enev
Valentin S
VS
Hanbauer
Martin
M
Kaehlig
Hanspeter
H
Ohler
Elisabeth
E
Mulzer
Johann
J
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001943:Breast Neoplasms; D002625:Chemistry, Organic / Q000379:methods; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D034261:Epothilones / Q000494:pharmacology; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D018942:Macrolides; D015394:Molecular Structure; D017239:Paclitaxel / Q000494:pharmacology; D011161:Porifera / Q000737:chemistry; D008941:Spindle Apparatus / Q000187:drug effects; D013237:Stereoisomerism; D043823:Taxoids / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D034261:Epothilones; D007202:Indicators and Reagents; D018942:Macrolides; D043823:Taxoids; C117306:isolaulimalide; C117305:laulimalide; D017239:Paclitaxel; C093788:epothilone B