Total Synthesis of Mannopeptimycins α and β

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• 作者：Bo Wang ; Yunpeng Liu ; Rui Jiao ; Yiqing Feng ; Qiong Li ; Chen Chen ; Long Liu ; Gang He ; Gong Chen
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：March 23, 2016
• 年：2016
• 卷：138
• 期：11
• 页码：3926-3932
• 全文大小：716K
• ISSN：1520-5126

文摘

The mannopeptimycins are a class of glycopeptide natural products with unusual structures and potent antibiotic activity against a range of Gram-positive multidrug-resistant bacteria. Their cyclic hexapeptide core features a pair of unprecedented β-hydroxyenduracididines (l- and d-βhEnd), an O-glycosylated d-Tyr carrying an α-linked dimannose, and a β-methylated Phe residue. The d-βhEnd unit also carries an α-linked mannopyranose at the most hindered N of its cyclic guanidine ring. Herein, we report the first total synthesis of mannopeptimycin α and β with fully elaborated N- and O-linked sugars. Critically, a gold-catalyzed N-glycosylation of a d-βhEnd substrate with a mannosyl ortho-alkynylbenzoate donor enabled the synthesis of the most challenging N-Man-d-βhEnd unit with excellent efficiency and stereoselectivity. The l-βMePhe unit was prepared using a Pd-catalyzed C–H arylation method. The l-βhEnd, d-Tyr(di-Man), and l-βMePhe units were prepared in gram quantities. A convergent assembly of the cyclic peptide scaffold and a single global hydrogenolysis deprotection operation provided mannopeptimycin α and β.