生源启发下的喜树碱的简洁形式合成

doi:10.6023/cjoc202102034

摘要/Abstract

以色胺和方便易得的乙基戊烯二醛盐为起始物, 以简洁的步骤(最终实现喜树碱全合成共9步反应)完成了喜树碱的生源启发下的无保护基形式合成. 合成路线涉及关键的Pictet-Spengler反应, 分子内氧杂Diels-Alder反应高效构建单萜吲哚中间体, 以及Winterfeldt高效仿生氧化吲哚合成喹啉酮结构.

关键词: 喜树碱, Pictet-Spengler反应, 氧杂Diels-Alder反应, Winterfeldt氧化, 形式合成

A concise biogenetically inspired formal synthesis of camptothecin without use of protecting groups has been developed starting from tryptamine and easily prepared ethyl glutaconaldehyde salt. The synthesis features the key Pictet-Spengler reaction, efficient intramolecular oxa-Diels-Alder reaction to construct heptacyclic monoterpenoid indole alkaloid intermediate, as well as the following Winterfeldt biomimetic oxidation to form quinolinone moiety from indole skeleton.

Key words: Camptothecin, Pictet-Spengler reaction, oxa-Diels-Alder reaction, Winterfeldt oxidation, formal synthesis

引用此文

李远志, 朱孟倩, 徐亮. 生源启发下的喜树碱的简洁形式合成[J]. 有机化学, 2021, 41(7): 2885-2890.

Yuanzhi Li, Mengqian Zhu, Liang Xu. A Concise Biogenetically Inspired Formal Synthesis of Camptothecin[J]. Chinese Journal of Organic Chemistry, 2021, 41(7): 2885-2890.

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图/表 4

图1. 喜树碱及其衍生物

Figure 1. Camptothecin and its derivatives

图式1. 已报道的喜树碱的生源启发全合成路线和我们的合成设计

. Scheme1 (a) Previously reported biogenetically patterned total synthesis of camptothecin and (b) our synthetic plan

图式2. 2-乙基戊烯二醛盐(9)的制备

Scheme 2. Preparation of 2-ethylglutaraldehyde salt (9) Reagents and conditions: (a) acetone, reflux; (b) dimethylamine, EtOH/H2O, reflux; then KOH, THF/MeOH, reflux, 75% for two steps.

图式3. 合成关键中间体11和喜树碱(1)形式全合成

Scheme 3. Synthesis of key intermediate 11 and formal total synthesis of camptothecin (1) Reagents and conditions: (a)9, TFA, DCM, r.t. to –5 °C, then 15, NEt3, DCM, r.t., 80%; (b) ZnBr2, DCE, reflux, 72%; (c) O2, NaH, DMF, 75%; (d) Tf2NPh, DMAP, NEt3, DCM, r.t., 86%; (e) Pd(OAc)2, DPPF, HCOOH, NEt3, dioxane, 80oC, 90%; (f) DDQ, dioxane, r.t.; (g) Et3SiH, BF3•Et2O, DCM, r.t., 75% over two steps.

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