Synthesis 2023; 55(11): 1700-1705
DOI: 10.1055/a-1948-3335
paper
Special Issue dedicated to Prof. Cristina Nevado, recipient of the 2021 Dr. Margaret Faul Women in Chemistry Award

A Seven-Step Total Synthesis of (–)-Thebaine

Shen Tan
a   Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
,
Yu-Tao He
a   Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
,
Ping Lan
a   Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
,
Martin G. Banwell  ∗
a   Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
b   Guangdong Key Laboratory for Research and the Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, P. R. of China
,
Lorenzo V. White∗
a   Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, Guangdong 510632, P. R. of China
› Author AffiliationsWe thank the National Natural Science Foundation of China (Grant No. 22250410258) and the Ministry of Science and Technology of the People's Republic of China for financial support.
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This paper is dedicated to Professor Cristina Nevado, University of Zürich, in recognition of her receipt of the 2021 Dr. Margaret Faul Women in Chemistry Award

Abstract

The morphinan alkaloid (–)-thebaine is an industrially important chemical intermediate deployed in the semi-synthesis of various opioid medicines. Here, a seven-step total synthesis of this natural product is reported from simple, commercially available starting materials. The pivotal aryl allyl ether substrate, which is obtained through successive Suzuki-Miyaura cross-coupling and Mitsunobu substitution reactions, was engaged in a double-Heck cyclization sequence. The tetracyclic product of these processes was subjected to a photochemical hydroamination reaction that generated a N-Boc piperidine derivative embodying the full pentacyclic morphinan framework. Over a further three simple steps, this last compound was converted into (–)-thebaine.

Key Words

Heck reaction - hydroamination - Mitsunobu reaction - morphinan alkaloids - thebaine

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1948-3335.
  • Supporting Information


Publication History

Received: 05 August 2022

Accepted: 21 September 2022

Accepted Manuscript online:
21 September 2022

Article published online:
08 November 2022

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