Preparation of a Protected 3‑Deoxy‑D-manno-oct-2-ulosonate Glycal Donor for the Synthesis of β‑KDO-Containing Oligosaccharides Tapan Kumar Pradhan, † Chun Cheng Lin, ‡ and Kwok-Kong Tony Mong* ,† † Applied Chemistry Department, National Chiao Tung University, 1001 Ta Hsueh Road, Taiwan ‡ Chemistry Department, National Tsing Hua University, Guang Fu Road, Taiwan * S Supporting Information ABSTRACT: A practical method for the synthesis of KDO glycal donors was developed. The prepared KDO donors exhibited excellent disastereoselectivity of glycosylation in a CH 2 Cl 2 -CH 3 CN solvent mixture, which was found to be associated with the isopropylidene protection at the C-4 and C-5 hydroxyls. The synthetic use of the KDO donor was demonstrated in the preparation of β-KDO-containing oligosaccharides. G lycosides of 3-deoxy- D- manno-oct-2-ulosonoic acid (KDO) are prominent in bacteria. 1 Natural KDO glycosides are present in α- and β-anomeric configurations. α- KDO glycosides are found in the core oligosaccharides of lipopolysaccharides (LPS) in Gram-negative bacteria, whereas β- KDO glycosides commonly occur in capsular polysaccharides (CPSs) of Gram-positive and Gram-negative bacteria. 2,3 Recent studies have shown that the reducing-end terminus of CPSs from various pathogenic bacteria, including Escherichia coli 4 and Neisseria meningitides, 5 is composed of a β-KDO-containing oligosaccharide linker. 6 The CPSs of pathogenic bacteria play defensive roles in the prevention of phagocytosis and comple- ment-mediated killing of the immune system, indicating their potential as new therapeutic targets. 3a,7-9 The chemical synthesis of KDO-containing oligosaccharides is nontrivial. As the KDO sugar is not commercially available, a practical method is needed to provide the starting material required for the preparation of the KDO-glycosyl substrates that are used to assemble the oligosaccharides. More challenging is the absence of a C-3 hydroxyl function in the KDO sugar which can be used to control the stereochemistry of glycosylation through neighboring group participation (NGP). 10 The first synthesis of a KDO glycoside can be traced back to 1978. 8a Later studies mainly focused on the synthesis of an α- KDO glycoside. 11 Although an increasing number of β-KDO- containing oligosaccharides have been identified in pathogenic bacteria, 4-6 glycosylation methods for the synthesis of β-KDO glycosides remain scarce. 12-14 Therefore, a practical synthetic route to stereoselective KDO glycosyl donors and β-KDO- containing oligosaccharides is highly desirable. Sinaÿ et al. described the synthesis of a β-KDO-containing disaccharide through Wittig condensation of a mannose-derived aldehyde and a glycosyl phosphonate, but only the E-isomeric product could be used for β-glycoside formation. 12 Ling et al. prepared 1-C-aryl β-KDO glycoside analogues from a 1-C- arylglycal, yet dearomatization was needed to obtain the natural KDO glycosides; thus, elaboration to oligosaccharide synthesis would be tedious. 13 Herein, we report a synthetic route for the preparation of β-selective KDO glycal donors that can be used for the synthesis of simple β-KDO glycosides and bacterial-related β- KDO-containing oligosaccharides. Our synthetic route to the various KDO glycal donors started with the diacetonide-protected mannofuranose 1, which was prepared via known procedures that included the addition of lithiated trimethylsilylacetylide and desilylation to give the alkyne derivative 2 (Scheme 1). 15 Subsequent benzylation of the hydroxyl groups and bromination transformed 2 into the Received: January 27, 2014 Published: February 26, 2014 Scheme 1. Synthesis of KDO Glycal 6 Letter pubs.acs.org/OrgLett © 2014 American Chemical Society 1474 dx.doi.org/10.1021/ol500275j | Org. Lett. 2014, 16, 1474-1477