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

Abstract

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.