Synthesis of 3-azido-3-deoxy-b-D-galactopyranosides Christopher T. Öberg, Ann-Louise Noresson, Tamara Delaine, Amaia Larumbe, Johan Tejler, Henrik von Wachenfeldt, Ulf J. Nilsson * Organic Chemistry, Lund University, PO Box 124, SE-22100 Lund, Sweden article info Article history: Received 30 March 2009 Accepted 7 May 2009 Available online 9 May 2009 Keywords: Galactose Gulose Epimerization Azide abstract Three efficient routes to 3-azido-3-deoxy-b-D-galactopyranosides were developed relying on a double inversion protocol at C3. Two of the routes were demonstrated to work with both O- and S-glycosides. In all three routes, the 2-O-acetyl-3-azido-4,6-O-benzylidene-3-deoxy-b-D-galactopyranosides were obtained by an azide inversion of the key intermediates 2-O-acetyl-4,6-O-benzylidene-3-O-trifluoro- methanesulfonyl-b-D-gulopyranosides. The intermediate gulopyranosides were in turn obtained from 2-O-acetyl-4,6-O-benzylidene-3-O-trifluoromethanesulfonyl-b-D-galactopyranosides, installed in one pot from the 4,6-O-benzylidene-b-D-galactopyranosides, by inversion with nitrite or acetate. For O-glyco- sides, the gulopyranoside configuration could alternatively be obtained from the 4,6-O-benzylidene-b-D- galactopyranoside by elimination to give the 2,3-dianhydro derivative followed by a highly stereoselec- tive cis-dihydroxylation. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction D-Galactopyranose is ubiquitous to mammalian glycoconju- gates, where it can be glycosidically linked via O1–O4 and O6 oxy- gen atoms. The HO2 is fucosylated in blood group determinants, the HO3 is glycosylated with various monosaccharides, including sialic acid, as well as sulfated, HO4 is glycosylated with b-D-GalNAc or a-D-Gal in the ganglio- and globo-series of glycolipids, HO6 is sialylated or sulfated in glycolipid or glycoprotein glycans. The diversity of galactose glycosylation and modification in mamma- lian glycoconjugates most often play critical roles in controlling the function of the glycoconjugate. The chemical properties of the glycosidic atom linked to galactopyranose can be expected to influence conformational preferences, as well as interactions with, for example, proteins, which in turn affects biological activities. Hence, replacement of oxygens of glycosidic bonds involving galac- topyranose with other atoms is an important strategy for decipher- ing the biological importance of the glycosidic oxygens in galactose-containing glycans. Within this context, various oxygen replacements of HO3, HO4, and HO6 have been reported, while HO2 oxygen replacements are less frequent. Galactose HO4 have been readily prepared, for example, by substituting glucose 4-O- sulfonate leaving groups with nucleophiles. 1,2 Galactose HO6 is maybe even more readily accessible via substitutions of a, for example, galactose 6-O-sulfonate. In contrast, replacement of the galactose HO3 oxygen is more challenging. A reliable route for replacement of this oxygen starts from di-isopropylidene-D-gluco- furanose in which C3 is doubly inverted together with a single inversion at C4. This route has been used, for example, in the syn- thesis of 3-amino-gal-UDP, which still is one of the most potent GalT inhibitors reported to date. 3 Synthesis strategies toward gan- glioside GM 3 analogs incorporating a galactose 3-thio linkage were developed based on the discovery that 4,6-O-benzylidene-2-O- acyl-b-D-galactopyranoside derivatives readily undergo double inversions at C3 and thus, via the gulo-epimer, provide access to the galactose 3-thio analogs that either act as neuraminidase inhibitors 4,5 or can be used as vaccine constituents with improved hydrolytic stability. 6 More recently, the Ramström group has made substantial contributions to our general understanding of the influ- ence of protecting group pattern, relative configuration, solvent, and nucleophile on carbohydrate hydroxyl inversion efficiency, which in turn has led to the development of highly efficient and practical protocols for carbohydrate epimerizations including C4. 7–9 We have reported on efficient galectin inhibition with galactose 3C-amides or 3C-triazoles. 10–16 These inhibitors have all been derived from the 3-azido-3-deoxy-galactopyranose originally described by Lowary and Hindsgaul 3 and later developed into a thioglycoside donor by us. 10 However, the synthesis of 3-azido-3- deoxy galactosides from di-isopropylidene-D-glucofuranose involves several steps of which a majority requires column chro- matography for purification of intermediates, PCC oxidations, and hydrogenations that are laborious on large scale. This prompted us to investigate the possibility to introduce the 3-azido-function- ality by double inversions at C3 of 4,6-O-benzylidene-b-D-galacto- pyranosides. Apart from being potentially more efficient and easier to handle on large scale, this route would allow for installation of 0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2009.05.005 * Corresponding author. E-mail address: ulf.nilsson@organic.lu.se (U.J. Nilsson). Carbohydrate Research 344 (2009) 1282–1284 Contents lists available at ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres