Synthesis and Scalable Conversion of l‑Iduronamides to Heparin-Related Di- and Tetrasaccharides

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 <sup>1</sup><i>C</i><sub>4</sub> conformations in solution, the iduronate ester adopts the <sup>4</sup><i>C</i><sub>1</sub> conformation in solid state. An X-ray structure is also reported for the novel, <sup>4</sup><i>C</i><sub>1</sub>-conformationally locked bicyclic 1,6-anhydro iduronate lactone along with an X-ray structures of a novel distorted <sup>4</sup><i>C</i><sub>1</sub> 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.