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 (1)C(4) conformations in solution, the iduronate ester adopts the (4)C(1) conformation in solid state. An X-ray structure is also reported for the novel, (4)C(1)-conformationally locked bicyclic 1,6-anhydro iduronate lactone along with an X-ray structures of a novel distorted (4)C(1) 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.
School of Chemistry and Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
Steen U
SU
Hansen
Gavin J
GJ
Miller
Marek
M
Baráth
Karl R
KR
Broberg
Egle
E
Avizienyte
Madeleine
M
Helliwell
James
J
Raftery
Gordon C
GC
Jayson
John M
JM
Gardiner
D000577:Amides / Q000737:chemistry*; D004187:Disaccharides / Q000138:chemical synthesis / Q000737:chemistry*; D006493:Heparin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry*; D007067:Iduronic Acid / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009844:Oligosaccharides / Q000737:chemistry*; D013237:Stereoisomerism
D000577:Amides; D004187:Disaccharides; D009844:Oligosaccharides; C464536:heparin disaccharide; D007067:Iduronic Acid; D006493:Heparin