jo300722y_si_003.cif (21.39 kB)
Synthesis and Scalable Conversion of l‑Iduronamides to Heparin-Related Di- and Tetrasaccharides
dataset
posted on 2012-09-21, 00:00 authored by Steen
U. Hansen, Gavin J. Miller, Marek Baráth, Karl R. Broberg, Egle Avizienyte, Madeleine Helliwell, James Raftery, Gordon C. Jayson, John M. GardinerA 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 4C1 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.
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scalable synthesesparent iduronic acid functionalityamide hydrolysis method4 C 1 conformation1 C 4 conformationsmultigram accessTetrasaccharidesA diastereomericallyiduronate esterdonor disaccharidesNMR datalactone productsEfficient conversionsacceptorregioselective acylationiduronamide showScalable Conversionamyl nitritekilogram scale
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