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Synthesis and properties of macrolones characterized by two ether bonds in the linker

2010; Elsevier BV; Volume: 18; Issue: 17 Linguagem: Inglês

10.1016/j.bmc.2010.07.007

1464-3391

Ivana Palej Jakopović, Goran Kragol, Andrew K. Forrest, Catherine S.V. Frydrych, Vlado Štimac, Samra Kapić, Maja Matanović Škugor, Marina Ilijaš, Hana Čipčić Paljetak, Dubravko Jelić, David Holmes, Deirdre M. B. Hickey, Donatella Verbanac, Vesna Eraković, Sulejman Alihodžić,

Asymmetric Synthesis and Catalysis

In this paper synthesis of macrolones 1–18 starting from azithromycin is reported. Two key steps in the construction of the linker between macrolide and quinolone moiety, are formation of central ether bond by alkylation of unactivated OH group, and formation of terminal C–C bond at 6-position of the quinolone unit. Due to the difficulty in formation of these two bonds the study of alternative synthetic methodologies and optimization of the conditions for the selected routes was required. Formation of C-4″-O-ether bond was completed by modified Michael addition, whereas O-alkylation via diazonium cation proved to be the most effective in formation of the central allylic or propargylic ether bond. Comparison of Heck and Sonogashira reaction revealed the former as preferred route to the C–C bond formation at C(6) position of the quinolone unit. Most of the target compounds exhibited highly favorable antibacterial activity against common respiratory pathogens, without significant cytotoxicity profile when tested in vitro on eukaryotic cell lines.