Total Synthesis of the Lipid-Anchor-Attached Core Trisaccharides of Lipoteichoic Acids of Streptococcus pneumoniae and Streptococcus oralis Uo5

Abstract

Herein we report an efficient total synthesis of lipid-anchor-appended core trisaccharides of lipoteichoic acids of Streptococcus pneumoniae and Streptococcus oralis Uo5. The key features include the expedient synthesis of the rare sugar 2,4,6-trideoxy-2-acetamido-4-amino-D-Galp building block via one-pot sequential S N 2 reactions and the α-selective coupling of D-thioglucoside with the diacyl glycerol acceptor to construct a common disaccharide acceptor, which was utilized in the total synthesis of target molecules 1 and 2.B acteria often contain unique deoxy amino glycans on their surfaces that are absent in host cells. 1 The bacterial raresugar-containing carbohydrates play important roles in the bacterial growth, survival and motility, entry of pathogen, infection, as well as the immune response. 2 For example, the Gram-positive bacteria Streptococcus pneumoniae and Streptococcus oralis Uo5 both contain lipoteichoic acids (LTAs) as major components of the cell wall, with core trisaccharides 1 and 2 composed of a common disaccharide unit containing a rare 2,4,6-trideoxy-2-acetamido-4-amino-D-Galp (AAT) sugar unit α-linked to diacylglycerol (Figure 1). 3 Streptococcus pneumoniae causes a variety of life-endangering diseases such as severe infection in the upper respiratory track, pneumonia, bacteremia, and meningitis, thereby resulting in high mortality rates. 4−6 The teichoic acid of Streptococcus pneumoniae performs a crucial role in cell division, cation homeostasis, and the regulation of cell-wall elongation. 7,8 Moreover, the

Stereoselective Synthesis of Diglycosyl Diacylglycerols with Glycosyl Donors Bearing a β-Stereodirecting 2,3-Naphthalenedimethyl Protecting Group

“…Retrosynthetic analysis of the targeted DGDGs 1 – 3 indicated that they could be synthesized by the β-selective glycosylation reaction of MGDG 12 with the 2,3- O -NapDM-protected glycosyl imidate 11 , with subsequent global deprotection under acidic conditions (Scheme ). In a recent report from Kulkarni et al, a MGDG acceptor has been used in the synthesis of the lipid-anchor-attached core trisaccharide of lipoteichoic acids of Streptococcus pneumonia and Streptococcus oralis Uo5 . Acceptors with the structure 12 could be accessed from glycosyl thioglycoside 13 and glycerol 14 via the following three steps: β-selective glycosylation reaction, removal of the p -nitrobenzylidene group on the glycerol moiety, and introduction of unsaturated fatty acyl chain(s).…”

Total Synthesis of the Repeating Unit of Streptococcus pneumoniae Zwitterionic Polysaccharide Sp1

“…Retrosynthetically (Scheme ), the target molecule 1 can be synthesized through global deprotection of fully protected trisaccharide 2 , which in turn can be assembled via the formation of the 1,2- cis -glycosidic linkage between protected disaccharide acceptor 3 and β-thiogalactoside donor 4 . Disaccharide 3 can be synthesized through glycosylation of the known AAT donor 5 , with the d -galactosyl 4-OH acceptor 6 followed by selective oxidative cleavage of the 2-naphthylmethyl (Nap) group from O3. Obtaining 1,2- cis -selectivity in consecutive glycosylations is the main challenge of the synthesis.…”

“…The known AAT building block 5 was procured following our reported protocol starting from d -mannose via C6-deoxygenation, tin-mediated selective Nap protection at O3, followed by sequential S N 2 displacements of the C2 and C4 trifluoromethane sulfonates by TBAN 3 and then CbzNH 2 in a one-pot reaction in 26% yield over 11 steps …”

“…The known AAT building block 5 was procured following our reported protocol 10 starting from D-mannose via C6deoxygenation, tin-mediated selective Nap protection at O3, 19 followed by sequential S N 2 displacements of the C2 and C4 trifluoromethane sulfonates by TBAN 3 and then CbzNH 2 in a one-pot reaction in 26% yield over 11 steps. 14 The remaining building block 6 was synthesized from known 2,3-di-O-benzyl β-D-thiogalactoside 10 20 (Scheme 3). Glycosylation of D-galactopyranoside with p-methoxyphenol (PMPOH) as an acceptor proved to be difficult.…”

Total Synthesis of the Phosphorylated Zwitterionic Trisaccharide Repeating Unit of Photorhabdus temperata cinerea 3240

“…On the contrary, at a lower temperature of −60 °C, the reaction is likely to proceed through an S N 2-like pathway via the formation of α-glycosyl triflate or a contact-ion pair, which leads to the β-product, exclusively. Under the optimized conditions, glycosylation of 3-O-Nap-protected AAT donor 6a with diol acceptor 5 (entry 8) cleanly furnished a Nap-protected trisaccharide derivative 16a that is an important synthetic intermediate for the chain elongation of the trisaccharide. The regioselectivity of glycosylation was confirmed by performing acetylation on the 4′-OH group in 16 .…”