Synthesis of C-glycosyl phosphonate derivatives of 4-amino-4-deoxy-α-L-arabinose

Submitting author affiliation:
University of Natural Resources and Life Sciences, Vienna, Austria

Beilstein Arch. 2019, 2019129.

Published 24 Oct 2019

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Incorporation of basic substituents into the structurally conserved domains of cell-wall lipopolysaccharides has been identified as a major mechanism contributing to antimicrobial resistance of Gram-negative pathogenic bacteria. Inhibition of the corresponding enzymatic steps, specifically the transfer of 4-amino-4-deoxy-L-arabinose would thus restore the activity of cationic antimicrobial peptides and several antimicrobial drugs. C-glycosidically linked phospholipid derivatives of  4-amino-4-deoxy-L-arabinose have been prepared as hydrolytically stable and chain-shortened analogues of the native undecaprenyldonor.  The C-phosphonate unit was installed via a Wittig-type reaction of benzyl-protected 1,5-arabinonic acid lactone with the lithium salt of dimethyl methylphosphonate followed by an elimination step of the resulting hemiketal leading to the corresponding exo- and endo-glycal derivatives. The ensuing selective mono-demethylation and hydrogenolysis of the benzyl groups and reduction of the 4-azido group gave the α-L-anomeric arabino- and ribo-configured methyl phosphonate esters. In addition, the monomethyl phosphonate glycal intermediates were converted into n-octyl derivatives followed by subsequent selective removal of the methyl phosphonate ester group and hydrogenation to give the octyl-phosphono derivatives. These intermediates thus will be of value for future conversion into transition state analogues as well as for introduction of various lipid extensions at the anomeric phosphonate moiety.

Keywords: Glycosyl phosphonate, lipid A, lipopolysaccharide, glycosyl transferase, antibiotic resistance

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Kerner, L.; Kosma, P. Beilstein Arch. 2019, 2019129. doi:10.3762/bxiv.2019.129.v1

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