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Synthesis of l‑Iduronic Acid Derivatives via [3.2.1] and [2.2.2] l‑Iduronic Lactones from Bulk Glucose-Derived Cyanohydrin Hydrolysis: A Reversible Conformationally Switched Superdisarmed/Rearmed Lactone Route to Heparin Disaccharides

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posted on 17.04.2015, 00:00 by Steen U. Hansen, Charlotte E. Dalton, Marek Baráth, Glenn Kwan, James Raftery, Gordon C. Jayson, Gavin J. Miller, John M. Gardiner
l-Idofuranoside cyanohydrin 1 is converted on large scale into a mixture of l-IdoA methyl pyranosides and furanosides, which is converged to provide short 2-step routes to bicyclic [3.2.1] or [2.2.2] l-iduronate lactones. The former is obtained via a 100 g scale synthesis of 3-OBn l-IdoA. A two-step conversion of this mixture provides either pure anomer of the novel [2.2.2] l-iduronate thioglycoside lactones. Both [3.2.1] and [2.2.2] lactones are converted into GlcN-IdoA heparin precursor disaccharides. The [2.2.2] lactone enables a scalable 3-step route from 1 to a new type of highly disarmed O-4 iduronate thioglycoside, which is an effective acceptor with glucoazide thioglycoside donors. The resulting new iduronic [2.2.2] lactone disaccharides are readily rearmed by mild methanolysis to provide GlcN-IdoA thiophenyl disaccharide donors, intercepting their established utility for the assembly of both heparin- and heparan sulfate-like oligosaccharides. The [2.2.2] lactonization acts as a conformational switch to superdisarm iduronate components, reversible by lactone ring opening. In addition, the separated 2,4-diacetates also provide short access to all four anomeric and ring size isomers of l-iduronic acid methyl glycosides, including the first syntheses of the parent idofuranosides. X-ray structures are reported for a [2.2.2] iduronate lactone and examples of both methyl l-idopyranoside and novel methyl-l-idofuranoside systems.