of heparin-like oligosaccharides on ..
Synthesis of Heparin Oligosaccharides | Request PDF
Besides being compatible with the trichloroacetimidate donors, the silyl protecting group is robust and has also been applied with thioglycosides under various activating systems.,, The Boons group used this strategy to prepare disaccharide building blocks for their heparin/HS oligosaccharide synthesis (). Glycosylation of 1-thioglycoside donor 120 with the TDS-protected acceptor 121 formed the latent disaccharide 122. After oxidation and protecting group manipulation, the TDS group in 122 was removed and the resulting hemiacetal was converted into the trichloroacetimidate disaccharide donor 123. Eight disaccharide building blocks were prepared in this manner and were used to construct a panel of 11 heparin/HS tetrasaccharides and 1 hexasaccharide having different backbone structures and sulfation patterns. These tetrasaccharides were used to probe the important structural features of HS for inhibiting β-secretase, a protease considered to be involved in the development of Alzheimer’s disease.
Chemoenzymatic Synthesis of Heparin Oligosaccharides …
The Bonnaffé group developed an impressive synthesis of a heparin dodecamer by the active–latent strategy, using the allyl glycoside and glycosyl trichloroacetimidate combination. To improve the overall synthetic efficiencies, a PMB group was employed to protect the 4-position at the nonreducing end of the oligosaccharide intermediate. This substituent could be removed selectively to expose a free hydroxyl group for further elongation of the chain. In this synthesis, the PMB-derivatized latent allyl disaccharide 103 was first transformed into a trichloroacetimidate donor, 105, and the allyl disaccharide acceptor 104 (). Glycosylation of acceptor 104 by imidate 105 generated the latent allyl tetrasaccharide, which was then modified to an active trichloroacetimidate donor 106 (). The reaction of 106 with tetrasaccharide 107, followed by removal of the PMB group at the nonreducing end, and another round of glycosylation, furnished the dodecasaccharide 108 in 45% overall yield from the acceptor 107. After completion of the backbone, deprotection and sulfation were performed. O-Deacetylation by potassium carbonate, and reduction with 1,3-propanedithiol, followed by simultaneous O- and N-sulfation with the sulfur trioxide–pyridine complex gave the sulfated dodecamer. The simultaneous sulfation with pyridine–SO3 of the hydroxyl and amino groups did not proceed to completion. A second round of sulfation with pyridine–SO3 in basified water was necessary to complete the sulfation., Hydrolysis of the methyl esters, followed by hydrogenolysis, gave the fully deprotected dodecamer 109, which is the longest heparin oligosaccharide yet prepared by chemical synthesis.