6-O-glycosylation of a lipid A-subunit analog (GLA-27) with methyl (4,5,7,8-tetra-O-acetyl-3-deoxy-α-d-manno-2-octulopyranosyl bromide)onate (a KDO derivative)

✍ Scribed by Makoto Kiso; Masanori Tanahashi; Akira Hasegawa; Frank M. Unger

• Publisher: Elsevier Science
• Year: 1987
• Tongue: English
• Weight: 367 KB
• Volume: 163
• Category: Article
• ISSN: 0008-6215
• DOI: 10.1016/0008-6215(87)80190-8

✦ Synopsis

3Deoxy-D-manno-2-octulosonic acid (KDO) is a prominent constituent of the cell-surface macromolecules of Gram-negative bacterial, and recently has also been found* as a component of the cell walls of higher plants. In the bacterial lipopolysaccharides (US), KDO occurs as an cu-D-ketosidic component linked at O-6' of the D-glucosamine-disaccharide backbone OF-~ lipid A, but its distinct biological roles in LPS are still obscure.

In the course of a synthetic approa&-lo designed to clarify the relationship of the molecular structure and the biological activity of bacterial lipid A, and to obtain new sources of nontoxic biological-response modifiers (BRM), we have foundl' that a 4-0-phosphono-o-glucosamine derivative named6s7 GLA-27 distinctly shows some of the biological activities expressed by lipid A. In addition, it was also suggested** that the activities could be selectively expressed by modifying the lipophilic structure of GLA-27.

We now describe the 6-0-glycosylation of a diastereoisomeric pair, namely, Zdeoxy-4-0-phosphono-3-0-tetradecanoyl-2-[(3R)-and (3S)-3-tetradecanoyloxy tetradecanamidol-D-glucose (GLA-27-R and GLA-27-S)', with methyl (4,5,7,8tetra-O-acetyl-3-deoxy-cY-D-manno-2-octulopyranosyl bromide)onate13 (2). Condensation of lR or lS, which is a synthetic intermediate' of GLA-27, with the bromide 2 was accomplished by use of Hg(CN), and HgBr2 as the catalysts. The resulting 3R or 3s was a mixture of the (Y-(70-80%) and /3-(2&30%) glycosides, which were separated by chromatography after hydrogenolytic removal of the benzyl group at O-l. The anomeric configurations of 4R(a) and 4R(@ thus obtained were initially assigned on the basis of the glycosylation yields and the optical rotations. In their IH-n.m.r. spectra, the C-8 methylene protons of the KDO residue appeared at 6 4.00 and 4.59 for the major product, and at 4.24 and 4.36 for