Asymmetric Total Synthesis of Cytotrienin A: Late‐Stage Installation of C11 Side Chain onto the Macrolactam Scaffold

Cytotrienin A, an ansamycin‐class antibiotic, exhibits potent apoptosis‐inducing activity and has attracted much attention as a lead compound for anticancer drugs. Herein, we report a new asymmetric synthetic route to cytotrienin A, employing an unexplored approach involving the late‐stage installat...

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Bibliographic Details
Published in:Angewandte Chemie 2023-07, Vol.135 (29), p.n/a
Main Authors: Tateishi, Yuki, Sato, Ryo, Komatsu, Shingo, Noguchi, Masatsugu, Nagasawa, Shota, Sasano, Yusuke, Kanoh, Naoki, Iwabuchi, Yoshiharu
Format: Article
Language:English
Subjects:
Acylation
Antibiotics
Antineoplastic drugs
Antitumor agents
Apoptosis
Asymmetry
Boron
Chemistry
Cross coupling
Hydroquinone
Installation
Lead compounds
Macrocycles
Redox Chemistry
Redox properties
Total Synthesis
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Summary:Cytotrienin A, an ansamycin‐class antibiotic, exhibits potent apoptosis‐inducing activity and has attracted much attention as a lead compound for anticancer drugs. Herein, we report a new asymmetric synthetic route to cytotrienin A, employing an unexplored approach involving the late‐stage installation of a C11 side chain onto the macrolactam core. In this strategy, we utilized the redox properties of hydroquinone and installed a side chain on the sterically hindered C11 hydroxy group by the traceless Staudinger reaction. This study also demonstrated that the boron‐Wittig/iterative Suzuki–Miyaura cross‐coupling sequence was effective for the concise and selective construction of the (E,E,E)‐conjugated triene moiety. The developed route opens new opportunities for the structure–activity relationship studies of the side chains of these ansamycin antibiotics and the preparation of other synthetic analogs and chemical probes for further biological studies. Asymmetric total synthesis of cytotrienin A, an ansamycin antibiotic with apoptosis‐inducing activity, is described. The strategic use of the redox properties of hydroquinone and the traceless Staudinger reaction enabled the late‐stage installation of the C11 side chain, which plays a critical role in its biological activity, onto the macrolactam and opens new opportunities for the structure–activity relationship studies of ansamycin antibiotics.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202303140