First example of 5/6-O-linked pseudosaccharides: synthesis of bicyclic nucleosides containing azido or extended carbohydrate moiety Joy Krishna Maity, a Subhranshu Mukherjee, a Michael G. B. Drew, b Basudeb Achari a and Sukhendu B. Mandal a, * a Division of Chemistry, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India b Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK Received 2 July 2007; received in revised form 23 July 2007; accepted 19 August 2007 Available online 23 August 2007 Abstract—Treatment of the D-glucose-derived substrate 1 with sodium hydride in tetrahydrofuran provided 3,6-anhydro monosac- charide 2, along with the 5,6-ether linked pseudodisaccharide 3, and pseudotrisaccharide 4. However, reaction of 1 with sodium ethoxide in ethanol afforded 2 as the sole product, elaborated to the bicyclic azidonucleosides 9 and 16. Acetylated bicyclic nucleo- sides 17–19 with extended carbohydrate residues have been synthesized from 3. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Pseudosaccharides; Synthesis; Azido bicyclic nucleosides; Carbohydrate; D-Glucose 1. Introduction Bicyclic nucleosides 1 are derived by the replacement of the natural furanose sugar moiety with a bicyclic ring structure. Such replacement results in the diminution of the conformational freedom of the nucleosides. 2 A pleth- ora of conformationally restricted bicyclic nucleosides have been synthesized for potential antiviral, antitumor, and other biological activities. Bicyclic nucleosides have been encountered in natural sources too. Among them, the most notable are the griseolic acids 3 (having fur- ano-furan skeleton), which are known to inhibit the 3 0 ,5 0 -cyclic nucleotide phosphodiesterase. Other bicyclic nucleosides such as ezomycins, quantamycin, and malay- amycins (all with furanopyran skeleton) are antibiotics having interesting properties. 4 The common structural motif present in some of these products is an extended carbohydrate moiety. The fact that the location of such structural features in the nucleosides imparts various antibiotic properties encouraged researchers to take up programs on the synthesis of conformationally restricted glycotriazole-tethered nucleoside/nucleotide analogues, 5 which have not been adequately explored so far. Keeping this in mind, we took up the synthesis of glucose-derived bicyclic nucleosides with azido functionality at C-2 0 and C-5 0 . In the process, we could also synthesize the hitherto unknown 5,6-ether linked pseudosaccharides and char- acterize a representative member unequivocally through X-ray crystallographic structure determination. It is per- tinent to mention here that a 5,4-ether linked disaccha- ride has been identified as a structural element of the exotoxin of Bacillus thuringiensis and synthesized by Pry- stas ˇ and S ˇ orm, 6 while 6,6 0 -ether linked disaccharides have been synthesized by Ikegami’s group 7 and by Haines 8 to establish the structure of a natural product 9 having antidiabetic activity. 2. Results and discussion 2.1. Synthesis of pseudosaccharides 2–4 from 1 We initially treated the glucose-derived precursor 1 10 with sodium hydride in tetrahydrofuran, hoping to 0008-6215/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2007.08.013 * Corresponding author. Tel.: +91 33 2473 3491; fax: +91 33 24735197; e-mail: sbmandal@iicb.res.in Available online at www.sciencedirect.com Carbohydrate Research 342 (2007) 2511–2521