Synthesis of a Systematic 64-Membered Heparan Sulfate Tetrasaccharide Library.

Heparan sulfate (HS) has multifaceted biological activities. To date, no libraries of HS oligosaccharides bearing systematically varied sulfation structures are available owing to the challenges in synthesizing a large number of HS oligosaccharides. To overcome the obstacles and expedite the synthesis, a divergent approach was designed, where 64 HS tetrasaccharides covering all possible structures of 2-O-, 6-O- and N-sulfation with the glucosamine-glucuronic acid-glucosamine-iduronic acid backbone were successfully produced from a single strategically protected tetrasaccharide intermediate. This extensive library helped identify the structural requirements for HS sequences to have strong fibroblast growth factor-2 binding but a weak affinity for platelet factor-4. Such a strategy to separate out these two interactions could lead to new HS-based potential therapeutics without the dangerous adverse effect of heparin-induced thrombocytopenia.

Direct synthesis of 2-deoxy-ß-glycosides via anomeric O-alkylation with secondary electrophiles.

An approach for direct synthesis of biologically significant 2-deoxy-ß-glycosides has been developed via O-alkylation of a variety of 2-deoxy-sugar-derived anomeric alkoxides using challenging secondary triflates as electrophiles. It was found a free hydroxyl group at C3 of the 2-deoxy-sugar-derived lactols is required in order to achieve synthetically efficient yields. This method has also been applied to the convergent synthesis of a 2-deoxy-ß-tetrasaccharide.

Catalytic stereoselective synthesis of ß-digitoxosides: direct synthesis of digitoxin and C1'-epi-digitoxin.

A mild and atom-economic rhenium(V)-catalyzed stereoselective synthesis of ß-D-digitoxosides from 6-deoxy-D-allals has been described. This ß-selective glycosylation was achieved probably because of the formation of corresponding α-digitoxosides disfavored by 1,3-diaxial interaction. In addition, this method has been successfully applied to the synthesis of digitoxin trisaccharide glycal for the direct synthesis of digitoxin and C1'-epi-digitoxin.

Synthesis of S-linked trisaccharide glycal of derhodinosylurdamycin A: Discovery of alkyl thiocyanate as an efficient electrophile for stereoselective sulfenylation of 2-deoxy glycosyl lithium.

Stereoselective synthesis of S-linked trisaccharide glycal of angucycline antitumor antibiotic derhodinosylurdamycin A is described. The synthesis has been accomplished employing our previously reported umpolung S-glycosylation strategy - stereoselective sulfenylation of 2-deoxy glycosyl lithium. It was found that sugar-derived thiocyanate was a better electrophile than corresponding asymmetric disulfide in this type of stereoselective sulfenylation.

Stereoselective Synthesis of S-Linked Hexasaccharide of Landomycin A via Umpolung S-Glycosylation.

Stereoselective synthesis of carbohydrate mimics resistant toward acid-mediated or enzymatic hydrolysis is chemically challenging and biologically interesting. In this Letter, the first stereoselective synthesis of a "non-hydrolyzable" S-linked hexasaccharide of antitumor antibiotic landomycin A is described. This synthesis was accomplished through the utilization of our recently developed umpolung reactivity-based S-glycosylation-sulfenylation of stereochemically defined glycosyl lithium species with asymmetric sugar-derived disulfides.