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 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.