Synthesis of 3- O-(alkyl-branched acyl)-2-deoxy-2 [(3 R)-3-hydroxytetradecanamido]-4- O-phosphono- d-glucose derivatives related to bacterial lipid A

Abstract

GLA-60 (2-deoxy-2-[(3R)-3-hydroxytetradecanamido]-4-O-phosphono-3-0[(3R)-3-tetradecanoyloxytetradecanoyl]-o-glucose)‘, which is an analog of the nonreducing sugar subunit of bacterial lipid A (ref 2), exhibits strong immunostimulatory activities without pyrogenicity”. In the course of an investigation1,4 into structure-activity relationships in the GLA-60 series, we showed that the chain length of the 3-acyloxyacyl group at C-3 is very important for the expression of immunopharmacological activity. For example, among the compounds differing from GLA-60 in this regard, GLA-63 (ref 4b), which carries a (3R)-3-dodecanoylo~tetradecanoyl group, was found to be the most beneficial, possessing strong immunomodulating activitiessd. However the derivatives& which respectively carry a (3R~)-3-acylo~decanoyl, (3RS)-3-acylo~dodecanoyl, or (3RS)-3-acyloxyhexadecanoyl group at O-3 in the sugar moiety were not significantly active. We have recently found 4d that 4-O-phosphono-g D lucosamine derivatives carrying an all&branched 2-tetradecylhexadecanoyl group instead of a 3-acyloxyacyl group stimulate the phagocytic activity of peritoneal macrophages and their antiviral activity as strongly as GLA-60. The aim of the present study was to investigate the biological influence of 2or 3-al~l-branched acyf groups of type I, II, or III (see formula chart), in which the length of the principal afkyi chain is varied. We synthesized a number of 3-O-(2or 3-alkyIacyl)-2-deoxy-2-[(3R)-3-hydroxytetradecanamido]-4-O-phosphono-o-gfucose derivatives, as shown in formulas 7a-m. The syntheses of compounds 7a-m all follow essentially the same pathway. 2-(Trimethyfsilyl)ethyl 2-deoxy-4,6-0-isopropylidene-2-{(3R)-3-[2-(trimethylsilyl)ethoxymethoxy]tetradecanamido)-P-D-glucopyranosides (1) was treated with alkyl-