DIVERGENT SYNTHESIS AND BIOLOGICAL-ACTIVITIES OF LIPID-A ANALOGS 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 grou ps to the biological activity: a disaccharide 4'-phosphate was first c onstructed as a common synthetic intermediate and all acyl moieties we re then introduced step by step to the respective positions. The hydro xy group in acyl moieties was protected with a benzyl group by novel 1 -pot reductive alkylation using benzaldehyde, TMS2O, TMSOTf, and Et3Si H. Both the glycosyl donor and acceptor were synthesized by using the new method recently reported by ourselves for the regioselective reduc tive opening of 4,6-O-benzylidene glucosamine derivatives with BH3 . M e2NH and BF3 . OEt2. In this reaction, a 3-O-allyloxycarbonylated 4,6- O-benzylidene compound in CH3CN afforded the 6-O-benzylated product se lectively, 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 CH2Cl 2. A disaccharide 4'-phosphate was synthesized by coupling of the imid ate donor and the acceptor using TMSOTf as a catalyst. (R)-3-Benzyloxy acyl groups were then introduced to the 3,3',2 and 2' positions follow ed by 1-O-phosphorylation and subsequent deprotection by Pd/H-2 afford ed the desired lipid A analogues. The present divergent route opens an efficient way toward the synthesis of lipid A libraries. Biological t ests (inhibition of IL-6 induction) clearly showed the critical import ance of the chain length of the acyl moieties in lipid A to the activi ty. (C) 1998 Published by Elsevier Science Ltd. All rights reserved.