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 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.