Stereoselective β,β-1,1’ glycosylation for the synthesis of lipid a mimetics

S5.1 Glycomimetics
Location (hall): 
Start/end time: 
Tuesday, July 2, 2019 - 15:00 to 15:15

Sebastian Strobl1, Karin Hofbauer1, Alla Zamyatina1

1University of Natural Resources and Life Sciences, Vienna, Vienna, Austria

Toll-like Receptor 4 (TLR4)-mediated pro-inflammatory signaling plays a crucial role in the pathogenesis of numerous inflammatory and autoimmune diseases, which highlights its significance as a target for therapeutics as well as vaccine adjuvants [1;2].  Our preliminary immunobiological tests proved that Lipid A mimetics based on the β,β-1,1’-linked diglucosamine act as powerful TLR4 agonists. Chemical glycosylation towards 1,1’-linked disaccharides is challenging due to possible formation of four diastereomeric products. Existing approaches to 1,1’-linked disaccharides focus on establishing α,α-1,1’ and α,β-1,1’ linkages using mostly simply protected monosaccharides. In our case an orthogonal protective group pattern was crucial for the synthesis of Lipid A mimetics with complex substitution pattern. 

The 1,2-trans selectivity on the side of the glycosyl donor was readily achieved by application of 2-N-carbamate protected imidate donors, whereas the β-stereoselectivity on the side of the glycosyl acceptor required preparation of the anomerically enriched hemiacetals where the β-configuration was trapped via quick glycosylation reaction to afford β,β-1,1’ diglucosamines. We established a facile approach towards β-configured GlcN hemiacetals which includes deallylation of protected β-allyl glycosides with retention of configuration via terminal olefin isomerization and ozonolysis followed by methanolysis of the formyl group [3]. The latter were glycosylated with retention of β-configuration by reaction with GlcN-imidate donors. Alternatively, the superior reactivity of the β-configured anomeric OH-group in 2-azido protected GlcN-hemiacetal acceptors which were obtained by NBS-mediated hydrolysis of thioglycosides allowed for stereoselective high-yielding β,β-1,1’ glycosylation. Application of conformation-constraining protecting groups (4,6-O-DTBS- or 4,6-O-benzylidene acetal) in both acceptor and donor molecules was decisive for attaining high β,β-1,1’ stereoselectivity. Non-symmetric orthogonally protected β,β-1,1’-linked diglucosamines were used as scaffolds for the divergent synthesis of bioactive Lipid A mimetics. 


Financial support by Austrian Science Fund (Grant FWF P-28915) is gratefully acknowledged.

  1. F. Adanitsch, J. Shi, F. Shao, R. Beyaert, H. Heine, A. Zamyatina, Chem.Sci. 2018, 9, 3957-3963.
  2. T. Kawai, S. Akira, Nat. Immunol 2010, 11, 373-384.
  3. R. Hollaus, P. Kosma, A. Zamyatina, Org.Lett. 2016, 19, 78-81