A Concise Biogenetically Inspired Formal Synthesis of Camptothecin

doi:10.6023/cjoc202102034

Abstract

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

Cite this article

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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Fig. & Tab. 4

Figure 1. Camptothecin and its derivatives

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

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.

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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