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CC BY 4.0 · SynOpen 2025; 09(01): 1-9
DOI: 10.1055/s-0043-1773504
paper

Total Synthesis of the Prenylated Indole Alkaloid (±)-Notoamide N via an Electrochemically Mediated Vilsmeier–Haack Formylation of a Chlorinated Indole

Zhongnan Xu
a   Institute for Advanced and Applied Chemical Synthesis, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. of China
b   State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
c   Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
,
Xin-Ting Liang
a   Institute for Advanced and Applied Chemical Synthesis, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. of China
b   State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
c   Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
,
Jian-Guo Song
b   State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
,
Lorenzo V. White
a   Institute for Advanced and Applied Chemical Synthesis, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. of China
b   State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
c   Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
,
Martin G. Banwell  ∗
a   Institute for Advanced and Applied Chemical Synthesis, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. of China
b   State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
c   Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
,
Shen Tan∗
a   Institute for Advanced and Applied Chemical Synthesis, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. of China
b   State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
c   Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, Guangdong, P. R. of China
› Author AffiliationsThis work was funded by the National Natural Science Foundation of China (Grant Nos. 22250410259, 22250410258, and 22301104), the Guangdong Science and Technology Plan-International Cooperation Topic Program (Grant No. 2023A0505050093) and the Ministry of Science and Technology of the People’s Republic of China.
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Abstract

A total synthesis of the racemic modification of the prenylated indole alkaloid notoamide N has been realised. A crucial step involved the electrochemically mediated Vilsmeier–Haack formylation of a chlorinated 1,7-dihydropyrano[2,3-g]indole. The product aldehyde was engaged in biomimetic and tandem aldol condensation/intramolecular Diels–Alder reactions with a diketopiperazine derivative to give a diazabicyclo[2.2.2]octane-containing adduct. Epoxidation of this adduct led, via an in situ semi-pinacolic rearrangement of the initially formed oxirane, to the targeted spiro-oxindole notoamide N.

Keywords

aldol reaction - cycloaddition - electrochemistry - epoxidation - rearrangement - total synthesis

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0043-1773504. Included are an outline of the general synthetic protocols employed in this study, plots arising from the single-crystal X-ray analysis of compounds 11, 13, and 18; tabular comparison of the 13C{1H} NMR spectral data obtained on synthetically derived compound 6 with those reported in the literature for notoamide N; 1H and 13C{1H} NMR spectra of compounds 6 and 9–26.
  • Supporting Information


Publication History

Received: 07 October 2024

Accepted after revision: 21 October 2024

Article published online:
02 January 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

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