1) The esterification of N-acetylmuramyl-L-alanyl-D-glutaminyl-L-alanine (I) with N-hydroxysuccinimide (II) by means of dicyclohexylcarbodiimide in dimethylacetamide gives the corresponding N-hydroxysuccinimide ester (III), which is then to condensed with O-(1,2-dipalmitoyl-sn-glycero-3-phosphoryl)ethanolamine (IV) by means of triethylamine in the same solvent.
The reaction of N-(tert-butoxycarbonyl)-3-hydroxyvaline (I) with O-benzylhydroxylamine (II) by means of hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DCC) in THF gives the corresponding benzyloxyamide (III), which is treated with the pyridine.SO3 complex (IV) in pyridine to yield N-(tert-butoxycarbonyl)-3-(sulfooxy)-N2-(benzyloxy)valinamide (V). The cyclization of (V) by means of K2CO3 in ethyl acetate - water affords 1-(benzyloxy)-3-(tert-butoxycarbonylamino)-4,4-dimethylazetidin-2-one (VI), which is debenzylated by hydrogenation with H2 over Pd/C in methanol to give the N-hydroxyazetidine (VII). The reaction of (VII) with the sulfonating complex (IV) affords the 1-azetidinyl sulfuric ester (VIII), which is deprotected by reaction with trifluoroacetic acid in anisole - dichloromethane yielding 3-amino-4,4-dimethyl-2-oxoazetidinyl-1-sulfate (IX). The condensation of (IX) with 2-(2-aminothiazol-4-yl)-2(Z)-(diphenylmethoxycarbonylmethoxyimino)acetic acid (X) by means of diphenyl chlorophosphate (PCP) and triethylamine in DMF gives the diphenylmethyl ester (XI) of the final product, which is finally deprotected by hydrolysis with trifluoroacetic acid and anisole.
2) The esterification of N-acetyl-L-alanyl-D-glutamine (V) with N-hydroxysuccinimide (II) as before gives the corresponding N-hydroxysuccinimide ester (VI), which is then condensed with N-alanyl-O-(1,2-dipalmitoyl-sn-glycero-3-phosphoryl)ethanolamine (VII) by means of triethylamine as before.