67(P44) ダイバージェントな経路によるリピドA類縁体の合成と生物活性(ポスター発表の部)

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Novel lipid A analogues were synthesized in order to investigate the structural principles responsible for the biological activity of lipid A. Syntheses were achieved via divergent routes where various compounds were prepared from common synthetic intermediates. 1. In order to investigate the role of 1-O-phosphoryl group for the activity of lipid A, the 1-O-carboxymethyl analogues 4 and 5 were synthesized from disaccharide allyl glycosides which also serve as the common synthetic intermediates to natural lipid A. Ozonolysis of the allyl glycosides 8a,b afforded the formylmethyl glycosides 9a,b, which were then oxidized by NaClO_2 to give the desired carboxymethyl analogues 4 and 5, respectively. The 1-O-phosphonooxyethyl analogue 3 was synthesized more conveniently than our own previous route by reduction of the same formylmethyl glycoside 9a followed by phosphorylation. The E. coli-type analogue 4 showed strong IL-6 inducing activity and the biosynthetic-precursor-type analogue 5 exhibited antagonistic activity both with potency comparable to the respective natural type counterparts. These results showed the anionic moiety at 1-position is very important but monoanionic charge is sufficient for the expression of the activity. 2. In order to clarify the effect of the chain length of the acyl groups to the biological activity, the syntheses of precursor-type analogues which possess four (R)-3-hydroxyacyl moieties of shorter chains were effected via a new divergent synthetic route: 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 benzyl group by 1-pot reductive alkylation using benzaldehyde, TMS_2O, TMSOTf, and Et_3SiH. Both the glycosyl donor and the acceptor were synthesized by using novel method for the regioselective reductive opening of 4,6-O-benzylidene glucosamine derivatives with BH_3・Me_2NH and BF_3・OEt_2. On this reaction, the 3-O-allyloxycarbonylated compound in CH_3CN afforded the 6-O-benzylated product selectively, which was then converted to a glycosyl trichloroacetimidate as the donor. The 4-O-benzylated acceptor was synthesized by the same reductive opening of a 3-O-p-methoxybenzylated compound in CH_2Cl_2. A disaccharide 4'-phosphate was synthesized by coupling of the imidate donor and the acceptor using TMSOTf as a catalyst. Stepwise introduction of (R)-3-benzyloxyacyl groups at 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 of the synthetic analogues clearly showed the critical importance of the chain length of the acyl moieties in lipid A to its biological activity.
天然有機化合物討論会の論文
1997-07-20

67(P44) ダイバージェントな経路によるリピドA類縁体の合成と生物活性(ポスター発表の部)

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