Synthesis and scalable conversion of L-iduronamides to heparin-related Di- and tetrasaccharides

Steen U. Hansen, Gavin J. Miller, Marek Baráth, Karl R. Broberg, Egle Avizienyte, Madeleine Helliwell, James Raftery, Gordon C. Jayson, John M. Gardiner, Egle Mcdonald

    Research output: Contribution to journalArticlepeer-review


    A diastereomerically pure cyanohydrin, preparable on kilogram scale, is efficiently converted in one step into a novel L-iduronamide. A new regioselective acylation of this iduronamide and a new mild amide hydrolysis method mediated by amyl nitrite enables short, scalable syntheses of an L-iduronate diacetate C-4 acceptor, and also L-iduronate C-4 acceptor thioglycosides. Efficient conversions of these to a range of heparin-related gluco-ido disaccharide building blocks (various C-4 protection options) including efficient multigram access to key heparin-building block ido-thioglycoside donors are described. A 1-OAc disaccharide is converted into a heparin-related tetrasaccharide, via divergence to both acceptor and donor disaccharides. X-ray and NMR data of the 1,2-diacetyl iduronate methyl ester and the analogous iduronamide show that while both adopt 1C4 conformations in solution, the iduronate ester adopts the 4C 1 conformation in solid state. An X-ray structure is also reported for the novel, 4C1-conformationally locked bicyclic 1,6-anhydro iduronate lactone along with an X-ray structures of a novel distorted 4C1 iduronate 4,6-lactone. Deuterium labeling also provides mechanistic insight into the formation of lactone products during the novel amyl nitrite-mediated hydrolysis of iduronamide into the parent iduronic acid functionality. © 2012 American Chemical Society.
    Original languageEnglish
    Pages (from-to)7823-7843
    Number of pages20
    JournalJournal of Organic Chemistry
    Issue number18
    Publication statusPublished - 21 Sept 2012


    Dive into the research topics of 'Synthesis and scalable conversion of L-iduronamides to heparin-related Di- and tetrasaccharides'. Together they form a unique fingerprint.

    Cite this