期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 17, 期 37, 页码 10462-10469出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201101389
关键词
antitumor agents; camptothecin derivatives; Diels-Alder reaction; structure-activity relationships; total synthesis
资金
- NSFC [21032002]
- Ministry of Health [2009ZX09501]
- 973 Program [2010CB833200]
- Fundamental Research Funds for the Central Universities [1082020502]
A new chemical synthesis of SN38, the active metabolite of the camptothecin prodrug irinotecan, has been achieved in 12 steps from simple, commercially available starting materials. A mild and efficient FeCl3-catalyzed Friedlander condensation was successfully applied to construct the AB ring system. Functionalization of the C ring was accomplished by a vinylogous Mukaiyama reaction of an in situ generated N-acyliminium intermediate with a silyl enol ether. An intramolecular oxa Diels-Alder reaction efficiently constructed the D and E rings in one step. Successive asymmetric dihydroxylation and I-2-based hemiacetal oxidation furnished the stereo-chemistry of SN38 with high enantiopurity. Utilizing the ABC-ring intermediate and a functionalized silyl enol ether permitted the synthesis of a number of new C18-functionalized SN38 derivatives. Several of the novel SN38 derivatives that bore a C10 methoxy group were found to exhibit comparable or more potent inhibitory activity against the proliferation of cancer cells relative to SN38.
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