Total Synthesis of Mannopeptimycins α and β

Bo Wang, Yunpeng Liu, Rui Jiao, Yiqing Feng, Qiong Li, Chen Chen, Long Liu, Gang He, Gong Chen

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3926-3932
Number of pages7
JournalJournal of the American Chemical Society
Volume138
Issue number11
DOIs
StatePublished - Mar 23 2016

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All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Wang, B., Liu, Y., Jiao, R., Feng, Y., Li, Q., Chen, C., Liu, L., He, G., & Chen, G. (2016). Total Synthesis of Mannopeptimycins α and β. Journal of the American Chemical Society, 138(11), 3926-3932. https://doi.org/10.1021/jacs.6b01384