An approach for direct synthesis of biologically significant 2-deoxy-β-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-β-tetrasaccharide.

Dedicated to Professor Samuel J. Danishefsky 2-Deoxysugars, especially 2,6-dideoxy-and 2,3,6-trideoxysugars, are an important class of carbohydrates and exist in numerous biologically active natural products and clinical agents, including anthracyclines, [1] angucyclines, [2] aureolic acid antibiotics, [3] avermectins, [4] enediynes, [5] pluramycins, [6] lomaiviticins, [7] vancomycin, [8] and cardiac glycosides. [9] These sugars play a critical role in the biological activity of these compounds as well as their stability and solubility. [10] As a result, considerable effort has been devoted to the stereoselective synthesis of 2-deoxyglycosides and the study of their structure-activity relationships. [11] Despite the significance of 2-deoxysugar subunits, the glycosidic linkage of 2deoxyglycosides has been found to be susceptible to hydrolysis in acid media or by glycosyl hydrolases. This reactivity has made it difficult to pinpoint the biological role of these 2deoxysugars, has resulted in toxicity [12] and reduced activity [13] of the parent molecules, and has limited their use as clinical agents.Thioglycosides (S-linked glycosides), [14] in which the glycosidic oxygen atom is replaced with a sulfur atom, are resistant towards enzymatic cleavage as well as chemical degradation. Furthermore, thioglycosides maintain the biological activity of their parent O-linked glycosides and are tolerated by most biological systems. Therefore, they are an important tool for structural biology [15] and attractive therapeutic agents. Because of these characteristics, the preparation of S-linked 2-deoxysugars for comparison of their physical, chemical, and biological properties with those of their natural O-linked counterparts is beneficial. Although a number of protocols are available for the synthesis of thioglycosides, [14,16] there is no efficient method for the stereoselective construction of S-linked 2-deoxyoligosaccharides, [17] and in particular, S-linked 2-deoxy-b-oligosaccharides. Previously, 2-deoxythioglycosides 3 were obtained with moderate to good anomeric stereoselectivity through the thioglycosylation of 2-deoxyglycosyl acetates [18] /chlorides 1 [19] or 2-deoxyglycals 2 [20] with simple thiol-containing nucleophiles (Scheme 1 a). Herein, we report an unprecedented sulfenylation of stereochemically defined 2-deoxyglycosyl lithium species with asymmetric sugar-derived disulfide acceptors for the stereoselective synthesis of both a-and b-S-linked 2-deoxyoligosaccharides (Scheme 1 b).According to our approach, the reductive lithiation of a mixture of 2-deoxy a-and b-glycosyl phenylsulfide 4 with a suitable radical-anion reductant should afford predominantly intermediate 5 with an axial lithium substituent at low temperature. [21,22] The 2-deoxyglycosyl lithium species 5 may then react with a sugar-derived asymmetric disulfide (e.g. 6) to afford the desired S-linked 2-deoxy-a-oligosaccharide (in this case 7). [23] We used a steric effect to promote the desired regioselectivity by installing a tertiary alkyl group (e...

A mild and atom-economic gold(I)-catalyzed glycosylation for stereoselective synthesis of 2-deoxy αglycosides using bench-stable 2-deoxy S-But-3-ynyl thioglycoside donors has been described. Under optimal conditions, 2deoxy and 2,6-dideoxy thioglycoside donors were able to react with a variety of primary, secondary, and tertiary alcohol acceptors to afford α-selective glycosides in good to excellent yields.

A mild and atom-economic rhenium(V)-catalyzed stereoselective synthesis of β-D-digitoxosides from 6-deoxy-D-allals has been described. This β-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.

The complex sulfation motifs of heparan sulfate glycosaminoglycans (HS GAGs) play critical roles in many important biological processes. However, an understanding of their specific functions has been hampered by an inability to synthesize large numbers of diverse, yet defined, HS structures. Herein, we describe a new approach to access the four core disaccharides required for HS/heparin oligosaccharide assembly from natural polysaccharides. The use of disaccharides rather than monosaccharides as minimal precursors greatly accelerates the synthesis of HS GAGs, providing key disaccharide and tetrasaccharide intermediates in about half the number of steps compared to traditional strategies. Rapid access to such versatile intermediates will enable the generation of comprehensive libraries of sulfated oligosaccharides for unlocking the “sulfation code” and understanding the roles of specific GAG structures in physiology and disease.