Synthesis of Diverse 6-Oxa-allocolchicinoids by a Suzuki-Miyaura Coupling, Acid-Catalyzed Intramolecular Transacetalization Strategy

The synthesis of allocolchicine analogues is of importance as these compounds have been found to possess promising anticancer activity by affecting tubulin polymerization. In this paper, the synthesis of 28 novel substituted 6-oxa-allocolchicinoids is reported. The key steps involved in the synthesi...

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Published inEuropean journal of organic chemistry Vol. 2015; no. 23; pp. 5167 - 5182
Main Authors Yadav, Dharmendra B., Taleli, Lebusetsa, van der Westhuyzen, Alet E., Fernandes, Manuel A., Dragoun, Maxim, Prokop, Aram, Schmalz, Hans-Guenther, de Koning, Charles B., van Otterlo, Willem A. L.
Format Journal Article
LanguageEnglish
Published WEINHEIM Wiley 01.08.2015
Subjects
Chemistry
Chemistry, Organic
Physical Sciences
Science & Technology
Heterocycles
ASYMMETRIC-SYNTHESIS
Intramolecular transacetalization
Colchinoids
ALLOCOLCHICINE ANALOGS
Antitumor agents
Cross-coupling
INHIBITION
RING
TUBULIN
DERIVATIVES
BINDING
CYCLIZATION
COLCHICINOIDS
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Summary:The synthesis of allocolchicine analogues is of importance as these compounds have been found to possess promising anticancer activity by affecting tubulin polymerization. In this paper, the synthesis of 28 novel substituted 6-oxa-allocolchicinoids is reported. The key steps involved in the synthesis were a Suzuki-Miyaura coupling reaction, followed by an acid-catalyzed intramolecular transacetalization to afford the desired 5-alkoxy-5,7-dihydrodibenzo[c,e]oxepines. In addition, when thiophenol and phenol were used in the transacetalization step, the 5-(phenylsulfanyl)-5,7-dihydrodibenzo[c,e]oxepine and 4-(5,7-dihydrodibenzo[c,e]oxepin-5-yl)phenol skeletons were obtained, respectively. The cytotoxicity of the synthetic compounds was unfortunately not impressive; however, one of the compounds was shown to sensitize vincristine-resistant leukemia and lymphoma cells to vincristine, a result vindicating further synthetic studies.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.201500573