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

详细信息    查看全文

• 作者：Steen U. Hansen ; Gavin J. Miller ; Marek Bar谩th ; Karl R. Broberg ; Egle Avizienyte ; Madeleine Helliwell ; James Raftery ; Gordon C. Jayson ; John M. Gardiner
• 刊名：The Journal of Organic Chemistry
• 出版年：2012
• 出版时间：September 21, 2012
• 年：2012
• 卷：77
• 期：18
• 页码：7823-7843
• 全文大小：712K
• 年卷期：v.77,no.18(September 21, 2012)
• ISSN：1520-6904

文摘

A diastereomerically pure cyanohydrin, preparable on kilogram scale, is efficiently converted in one step into a novel mallcaps">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 mallcaps">l-iduronate diacetate C-4 acceptor, and also mallcaps">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.