期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 141, 期 13, 页码 5381-5391出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b00040
关键词
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资金
- Fonds der Chemischen Industrie
- Max Planck Society
- Alexander von Humboldt Foundation
Halogen bonding (XB) has recently emerged as a promising noncovalent activation mode that can be employed in catalysis. However, methodologies utilizing XB remain rare, and the hydrogen-bonding (HB) catalysis congeners are more widespread in comparison. Herein, we demonstrate a remarkable case whereby employment of XB catalysis in strain-release glycosylation generates O,N-glycosides in excellent anomeric selectivity exceeding HB activation. Deeper investigation unraveled XB catalyst dependencies on multiple stages of the mechanism and a hitherto unknown XB-glycosyl acceptor activation. We present a proof of concept to interrogate sp(3)-rich glycosidic chemical space for novel biological activity, by integrating XB-catalyzed construction of a glycosidic compound collection, and evaluating these analogues via cell-based phenotypic screens. We show that XB-catalyzed strain-release glycosylation defines a new class of glycosides that inhibit the hedgehog signaling pathway through a nonsmoothened mode of action, opening new opportunities to combat acquired cancer resistance.
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