Total Synthesis of 7-Ethyl-10-hydroxycamptothecin (SN38) and its Application to the Development of C18-Functionalized Camptothecin Derivatives

被引：15

作者：

Yao, Yuan-Shan ^{[2
,3
]}

Liu, Jia-Li ^{[1
]}

Xi, Jie ^{[2
]}

Miu, Bukeyan ^{[2
]}

Liu, Guai-Sai ^{[2
]}

Wang, Shaozhong ^{[2
]}

Meng, Linghua ^{[1
]}

Yao, Zhu-Jun ^{[2
]}

机构：

[1] Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[2] Nanjing Univ, State Key Lab Coordinat Chem, Nanjing Natl Lab Microstruct, Inst Chem Biol & Drug Innovat,Sch Chem & Chem Eng, Nanjing 210093, Jiangsu, Peoples R China

[3] Univ Sci & Technol China, Joint Lab Green Chem, Dept Chem, Hefei 230026, Anhui, Peoples R China

来源：

CHEMISTRY-A EUROPEAN JOURNAL | 2011年 / 17卷 / 37期

关键词：

antitumor agents; camptothecin derivatives; Diels-Alder reaction; structure-activity relationships; total synthesis; PLANT ANTITUMOR AGENTS; IN-VITRO CYTOTOXICITY; ASYMMETRIC-SYNTHESIS; EFFICIENT; RING; (+)-CAMPTOTHECIN; CYCLIZATION; IRINOTECAN; INHIBITOR; CANCER;

D O I：

10.1002/chem.201101389

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：10462 / 10469

页数：8