Asymmetric Catalysis at a Distance: Catalytic, Site-Selective Phosphorylation of Teicoplanin

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We report three distinct, peptide-based catalysts that enable site-selective phosphorylation of three distinct hydroxyl groups within the complex glycopeptide antibiotic teicoplanin A(2)-2. Two of the catalysts are based on a design that capitalizes on a catalyst substrate interaction that mimics the biological mechanism of action for teicoplanin. These catalysts are based on a DXaa-DXaa peptide motif that is known to target the teicoplanin structure in a specific manner. The third was identified through evaluation of a set of catalysts that had been developed for historically distinct projects. Each catalyst contains additional functionality designed to dispose a catalytic moiety (a nudeophilic alkylimidazole) at a different region of the glycopeptide structure. A combination of mass spectrometry and 2D-NMR spectroscopy allowed structural assignment of the distinct phosphorylated teicoplanin derivatives. Mechanistic studies are also reported that support the hypotheses that led to the discovery of the catalysts. In this manner, small molecule catalysts have been achieved that allow rational, catalytic control over reactions at sites that are separated by 11.6, 16.5, and nearly 17.7 angstrom, based on the X-ray crystal structure of teicoplanin A(2)-2. Finally, we report the biological activity of the new phosphorylated teicoplanin analogs and compare the results to the natural product itself.
Publisher
AMER CHEMICAL SOC
Issue Date
2013-08
Language
English
Article Type
Article
Keywords

GLYCOPEPTIDE ANTIBIOTICS; STAPHYLOCOCCUS-AUREUS; SEMISYNTHETIC DERIVATIVES; CYCLIZATION STEPS; CRYSTAL-STRUCTURE; HAIRPIN FORMATION; CHIRAL CATALYSTS; NATURAL-PRODUCTS; MYO-INOSITOL; VANCOMYCIN

Citation

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.135, no.33, pp.12414 - 12421

ISSN
0002-7863
DOI
10.1021/ja406067v
URI
http://hdl.handle.net/10203/201332
Appears in Collection
CH-Journal Papers(저널논문)
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