Orthogonally protected disaccharide building blocks for synthesis of heparin oligosaccharides

A method for synthesizing a heparin oligosaccharide of formula:

• wherein n is an integer ranging from 1 to 100 and the wavy line represents an α- or β-linkage,
• comprising the steps of:
• a) contacting a starting unit of formula (II) with an orthogonally protected disaccharide building block of formula (I) in the presence of a catalyst to produce a trisaccharide of formula (V):
• wherein L is the leaving group O-trichloroacetimidyl, P1,P2, P3 and P4 are hydroxyl protecting groups, and of them P1 is an ester-type protecting group selected from the group consisting of acyl and benzoyl (Bz), P2 is levulinyl (Lev), P3 is benzyl (Bn) or substituted benzyl, and P4 is selected from the group consisting of naphthylmethyl (NAP), substituted naphthylmethyl, p-methoxybenzyl and substituted p-methoxybenzyl, and wherein the wavy line represents an α-or β-linkage,
• wherein n=1, R=Lev;
• b) optionally performing m cycles of chain elongation reaction on the product from the prior step (a) or cycle, with each cycle comprising the steps of:
• (i) selectively oxidizing the product from the prior step (a) or cycle with an oxidizing agent to produce a product of formula (V), wherein P4=H,n=m;
• and
• (ii) glycosylating the product from step (b)(i) by adding a disaccharide building block of formula (I) to produce a product of formula (V), wherein n=m+1 and m is an integer ranging from 1 to 99;
• c) cleaving the Lev group by contacting the product from step (b)(ii) with a hydrolysis reagent to produce a primary alcohol of formula (VI):
• d) selectively reacting the primary hydroxyls of the product of formula (VI) from step (c) by contacting it with an oxidizing agent to obtain an acid of formula:
• e) reacting the product from step (d) with an alkoxide to remove the P1 and benzoyl protecting groups to produce a product of formula:
• f) performing O-sulfonation by reacting the product from step (e) with a sulfonating agent to produce a sulfonated product of formula:
• g) performing hydrogenolysis and azide reduction by reacting the product from step (f) with H2 in the presence of a hydrogenolysis/hydrogenation catalytic agent to produce a D-glucopyranoside product of formula:
• h) performing N-sulfonation by reacting the product of step (g) with a sulfonating agent to produce the heparin oligosaccharide of formula (VI).