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

Miller

Abstract

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 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.

Citation

Miller. (2012). Synthesis and Scalable Conversion of l-Iduronamides to Heparin-Related Di- and Tetrasaccharides. Journal of Organic Chemistry, 7823 -7843. https://doi.org/10.1021/jo300722y

• Acceptance Date: Aug 17, 2012
• Publication Date: Aug 17, 2012
• Journal: Journal Of Organic Chemistry
• Print ISSN: 0022-3263
• Publisher: American Chemical Society
• Pages: 7823 -7843
• DOI: https://doi.org/10.1021/jo300722y
• Publisher URL: http://dx.doi.org/10.1021/jo300722y