ANOMERIC O-ALKYLATION .10. SYNTHESIS OF KDO-ALPHA-GLYCOSIDES OF LIPID-A DERIVATIVES

The synthesis of the lipopolysaccharide fragment O-(4,5,7,8-tetra-O-acetyl-O-acetyl-3-N-methyl-alpha-D-manno-2-octulopyranosylonamide)-(2 --> 6)-O-{2-deoxy-2-[(3R)-3-dodecanoyloxytetradecanamido]-4-O-phosphono-3-O-tetradecanoyl-beta-D-glucopyranosyl}-(1 --> 6)-1-O-acetyl-2-deoxy-2-[(3R)-3-dodecanoyloxytetradecanamido]-3-O-tetradecanoyl-alpha-D-glucopyranose (35alpha) is performed via anomeric O-alkylation. With this objective, the 2-azido-3-O-benzyl-2-deoxy-6-O-trifluoromethanesulfonyl-beta-D-glucopyranosides 5, 7, and 19alpha, beta were synthesized from D-glucal and employed as alkylating agents. Reaction of 5 with the O-cyclohexylidene-protected Kdo-derivative 10 afforded the desired alpha-linked disaccharide, tert-butyldimethylsilyl 4-O-allyl-2-azido-3-O-benzyl-2-deoxy-6-O-(4,5:7,8-di-O-cyclohexylidene-3-deoxy-N-methyl-alpha-D-manno-2-octulopyranosylonamide)-beta-D-glucopyranoside (11); even better yields of the structurally related disaccharide 12 were obtained with the 4-O-unprotected 7 as alkylating agent. 1-O-Desilylation of 12 furnished the lactol 20, which could be alkylated at the anomeric position with 1-O-allyl protected alkylating agents 19alpha and 19beta, both of which furnished exclusively the desired beta-(1 --> 6)-linked trisaccharides allyl O-(4,5:7,8-di-O-cyclohexylidene-3-deoxy-N-methyl-alpha-D-manno-2-octulopyranosylonamide)-(2 --> 6)-O-(2-azido-3-O-benzyl-2-deoxy-beta-D-glucopyranosyl)-(1 --> 6)-2-azido-3, 4-di-O-benzyl-2-deoxy-alpha- (21alpha) and -beta-D-glucopyranoside (21beta), respectively. Phosphorylation with diphenyl phosphorochloridate, replacement of the O-cyclohexylidene protective group by O-triethylsilyl (TES) protective groups, removal of the 1-O-allyl group, azido group reduction, subsequent N-acylation, and then O-acetylation provided the key 1-O-acetyl protected intermediate 30alpha. Removal of the O-TES groups, subsequent O-acetylation, and hydrogenolytic O-debenzylation furnished O-[4,5:7,8-tetra-O-acetyl-3-deoxy-N-methyl-alpha-D-manno-2-octulopyranosylonamide]-(2 --> 6)-O-(2-deoxy-4-O-diphenoxyphosphoryl-2-[(3R)-3-dodecanoyloxytetradecanamido]-beta-D-glucopyranosyl}-1 --> 6)-1-O-acetyl-2-deoxy-2[3R) dodecanoyloxytetradecanamido]-alpha-D-glucopyranose (33alpha), which underwent the required selective O-tetradecanoylation at the 3-O- and 3'-O-position, thus furnishing, after hydrogenolytic O-dephenylation of the diphenoxyphosphoryl group, the target molecule 35alpha.