Synthesis of N-(hydroxy)amide- and N-(hydroxy)thioamide-containing peptides

    Authors

    L. Wang;O. Phanstiel

    Abbreviated Journal Title

    J. Org. Chem.

    Keywords

    MATRIX METALLOPROTEINASES; INHIBITORS; ANALOGS; CHEMISTRY; LIGAND; DESIGN; ACIDS; Chemistry, Organic

    Abstract

    Methods developed with N-(benzoyloxy)amines and hydroxamic acids were used in the synthesis of N-(hydroxy)amide-containing pseudopeptides. Acylation of N-(benzoyloxy)phenethylamine with the acid chloride of N-alpha-Fmoc-L-leucine provided a N-alpha-Fmoc-N-(benzoyloxy)-L-leucinamide in 90% yield. Deprotection of the benzoyl group (using 10 vol % NH4OH/MeOH) provided the N-alpha-Fmoc- N-(hydroxy)-L-leucinamide in 87% yield. In general, the appended Fmoc group allowed for further elaboration of the N-hydroxy-N-(alkyl)amides using classic peptide-coupling methods, A practical synthetic strategy was developed, and racemization issues were addressed using diastereomeric Val-Leu derivatives. In addition, N-(hydroxy)thioamides were generated from the corresponding N-(benzoyloxy)thioamides. N-(Benzoyloxy)thioamides were obtained in moderate yields (53-76%) from the reaction of the corresponding N-(benzoyloxy)amides with Lawesson's reagent (i.e., 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. In summary, this new technology allows for the introduction of either N-hydroxyamide or N-(hydroxy)thioamide linkages into pseudopeptide chains without racemization.

    Journal Title

    Journal of Organic Chemistry

    Volume

    65

    Issue/Number

    5

    Publication Date

    1-1-2000

    Document Type

    Article

    Language

    English

    First Page

    1442

    Last Page

    1447

    WOS Identifier

    WOS:000085913800025

    ISSN

    0022-3263

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