Synthesis of orthogonally protected bacterial, rare-sugar and D-glycosamine building blocks

Abstract

Bacterial glycoconjugates comprise atypical deoxy amino sugars that are not present on the human cell surface, making them good targets for drug discovery and carbohydrate-based vaccine development. Unfortunately, they cannot be isolated with sufficient purity in acceptable amounts, and therefore chemical synthesis is a crucial step toward the development of these products. Here we describe a detailed protocol for the synthesis of orthogonally protected bacterial deoxy amino hexopyranoside (2,4-diacetamido-2,4,6-trideoxyhexose (DATDH), D-bacillosamine, D-fucosamine, and 2-acetamido-4-amino-2,4,6-trideoxy-D-galactose (AAT)), D-glucosamine and D-galactosamine building blocks starting from β-D-thiophenylmannoside. Readily available β-D-thiophenylmannoside was first converted into the corresponding 2,4-diols via deoxygenation or silylation at C6, followed by O3 acylation. The 2,4-diols were converted into 2,4-bis-trifluoromethanesulfonates, which underwent highly regioselective, one-pot, double-serial and double-parallel displacements by azide, phthalimide, acetate and nitrite ions as nucleophiles. Thus, D-rhamnosyl- and D-mannosyl 2,4-diols can be efficiently transformed into various rare sugars and D-galactosamine, respectively, as orthogonally protected thioglycoside building blocks on a gram scale in 1-2 d, in 54-85% overall yields, after a single chromatographic purification. This would otherwise take 1-2 weeks. D-Glucosamine building blocks can be prepared from β-D-thiophenylmannoside in four steps via C2 displacement of triflates by azide in 2 d and in 66-70% overall yields. These procedures have been applied to the synthesis of L-serine-linked trisaccharide of Neisseria meningitidis and a rare disaccharide fragment of the zwitterionic polysaccharide (ZPS) A1 (ZPS A1) of Bacteroides fragilis.

Development of Rare Bacterial Monosaccharide Analogs for Metabolic Glycan Labeling in Pathogenic Bacteria

“…40,41 Accordingly, the 2,4-diol substrates (Scheme 1, compound 7 and Scheme 2, compound 8 ) for the one-pot double displacement reaction were first prepared starting from cheaply available d -mannose in six steps. 41 …”

“…Diol 8 upon similar triflation followed by sequential, one pot S N 2 reactions with TBAN 3 and with tetrabutyl ammonium nitrite (TBANO 2 ), at C2 and C4 respectively, afforded d -fucosamine derivative 12 in 60% overall yield. 41 Concomitant triflation of the axial 4-OH group and its displacement with NaN 3 furnished bacillosamine 13 . 41 Reduction of 2,4-azido groups in 13 followed by EDC coupling with azidoacetic acid afforded 14 in 72% yield over two steps.…”

“…A double displacement of the 2,4-bistriflate, obtained from 8 , with excess NaN 3 cleanly afforded di-azido derivative 15 in excellent overall yield. 41 The 3-O-benzoate group was cleaved using NaOMe to obtain 16 (96%). This step was deemed necessary in order to avoid the possible migration of benzoate (C3→C4) during the ensuing reduction of azides to corresponding amines.…”

Synthetic Oligosaccharide Libraries and Microarray Technology: A Powerful Combination for the Success of Current Glycosaminoglycan Interactomics

“…Although the entire synthesis of UroA building blocks involve multiple sub‐products and reactive steps, the yield of the final products are very high, about 30 % of the starting material . Besides synthesis of UroA building blocks, orthogonally protected d ‐GlcN building blocks can also be synthesized for assembly of heparin/heparan sulfate oligosaccharides . In this work d ‐GlcN building blocks was conveniently prepared from β‐ d ‐thiomannoside via a four‐step reactive sequence involving regioselective O3 acylation, 4,6‐ O ‐benzylidenation, and C2 inversion via azide displacement of the C2‐triflate.…”

Total synthesis of MECA-79

“…10 This sulfated tetrasaccharide is of signicant biological interest due to its unique expression at the site of chronic inammation. 15 In continuation of our studies directed towards the synthesis of glycosamine containing glycoconjugates, [16][17][18] we report herein a convenient synthesis of orthogonally protected Tn antigen and its application in the total synthesis of MECA-79 antigen. 11,12 Soon aer its isolation, Bélot and co-workers reported a synthesis of the n-octyl derivative of MECA-79.…”