Synthesis of a D,D- and L,D-heptose-containing hexasaccharide corresponding to a structure from Haemophilus ducreyi lipopolysaccharides

The synthesis of a linear hexasaccharide, 2-(4-trifluoroacetamidophenyl)ethyl (beta-D-galactopyranosyl)-( 1--4)-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-(1 --> 3)-(beta-D-galactopyranosy1)-(1-->4)-(D-glycero-alpha-D-manno-heptopyranosyl)-(1-->6)-(beta-D-glucopyranosyl)-(1-->4)-L-glycero-alpha-D-manno-heptopyranoside, corresponding to a structure found in Haemophilus ducreyi LPS, is described. A Barbier reaction between benzyloxymethyl chloride and a properly protected 6-aldo-1-thio-mannopyranoside yielded both the D,D- and the L,D-heptopyranoside (2 and 3, ratio 2:3), which were separated and both used in the synthesis, p-Methoxybenzyl and chloroacetyl groups were employed as temporary protecting groups, selectively removed in the presence of the persistent benzyl, acetyl, benzoyl and isopropylidene groups by treatment with DDQ/H2O and hydrazine dithiocarbonate, respectively. Thioglycosides were utilised as donors throughout using either NIS/TfOH or DMTST as promoters. The introduction of the spacer into thioglycoside 5 was high-yielding (95%) but with low stereoselectivity (alpha:beta 5:3). All other glycosylations are completely stereoselective. The target hexasaccharide is obtained via a 3+3 block approach with the yield in the final NIS/TfOH-promoted coupling between an N,N-diacetyl-trisaccharide thioglycosyl donor 20 and a 4 "-OH trisaccharide acceptor 13 being 75%. (C) 2000 Elsevier Science Ltd. All rights reserved.