Divergent synthesis and biological activities of lipid A analogues of shorter acyl chains

Novel lipid A analogues which possess four (R)-3-hydroxyacyl moieties of shorter chain length were synthesized via a new divergent synthetic route in order to clarify the effect of the chain length of acyl groups to the biological activity: a disaccharide 4'-phosphate was first constructed as a common synthetic intermediate and all acyl moieties were then introduced step by step to the respective positions. The hydroxy group in acyl moieties was protected with a benzyl group by novel 1-pot reductive alkylation using benzaldehyde, TMS2O, TMSOTf, and Et3SiH. Both the glycosyl donor and acceptor were synthesized by using the new method recently reported by ourselves for the regioselective reductive opening of 4,6-O-benzylidene glucosamine derivatives with BH3 . Me2NH and BF3 . OEt2. In this reaction, a 3-O-allyloxycarbonylated 4,6-O-benzylidene compound in CH3CN afforded the 6-O-benzylated product selectively, which was then converted to a glycosyl trichloroacetimidate used as the donor. The 4-O-benzylated acceptor was synthesized by the same reductive opening of a 3-O-p-methoxybenzylated compound in CH2Cl2. A disaccharide 4'-phosphate was synthesized by coupling of the imidate donor and the acceptor using TMSOTf as a catalyst. (R)-3-Benzyloxyacyl groups were then introduced to the 3,3',2 and 2' positions followed by 1-O-phosphorylation and subsequent deprotection by Pd/H-2 afforded the desired lipid A analogues. The present divergent route opens an efficient way toward the synthesis of lipid A libraries. Biological tests (inhibition of IL-6 induction) clearly showed the critical importance of the chain length of the acyl moieties in lipid A to the activity. (C) 1998 Published by Elsevier Science Ltd. All rights reserved.