Chemical Synthesis of Lipid A and Analogues
Chemical syntheses of lipid A and its analogues have made substantial contributions to our current understanding of the endotoxic active structures by providing homogeneous products with definite structures. Precise information has been obtained from the
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Chemical Synthesis of Lipid A and Analogues Shoichi Kusumoto
4.1
Introduction
Chemical syntheses of lipid A and its analogues have made substantial contributions to our current understanding of the endotoxic active structures by providing homogeneous products with definite structures. Precise information has been obtained from the use of synthetic lipid A derivatives, which exclude the possibility of influence by contaminants from bacterial or other sources. In this chapter, representative synthetic work on lipid A and analogues will be outlined with brief explanations of their significance for endotoxin research. After “lipid A” was first described as the endotoxically active principle of bacterial lipopolysaccharide (LPS) by Westphal and L€uderitz [1], it soon became an important target of research in microbiology, immunology, and related fields. However, more time was required until this particular molecule became attractive to organic chemists. This was because little was known on the structural features of lipid A mainly owing to difficulties in the purification of this amphiphilic and intrinsically heterogeneous molecule for the chemical characterization. Advances in the early 1970s towards the understanding of the structural features of lipid A made it possible to use synthetic approaches to build the proposed structures aiming at chemical reproduction of endotoxic activities with synthetic homogeneous molecular species. This body of early research, in part summarized in several articles in a book [2], was based on the incomplete structural information available at that time. Although these efforts did not lead to the production of definite synthetic endotoxic compounds, they contributed to resolve many important issues for the chemical construction of complex glycoconjugate molecules. In fact, this
S. Kusumoto (*) Suntory Institute for Bioorganic Research, Wakayamadai 1-1-1, Shimamoto-cho, Mishima-gun, Osaka 618–8503, Japan e-mail: [email protected] Y.A. Knirel and M.A. Valvano (eds.), Bacterial Lipopolysaccharides, DOI 10.1007/978-3-7091-0733-1_4, # Springer-Verlag/Wien 2011
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accumulated knowledge was soon utilized for the successful synthesis of lipid A derivatives once the lipid A structure was properly elucidated.
4.2
Early Chemical Syntheses of Endotoxic Lipid A
In the early attempts for chemical synthesis, the first molecule chosen as a target structure for synthesis was a tetraacylated glucosamine disaccharide bisphosphate, which corresponds to a disaccharide biosynthetic precursor to lipid A. This compound, designated precursor Ia or recently called more frequently lipid IVA, was first isolated from a temperature sensitive mutant of Escherichia coli and shown to contain 4 mol of (R)-3-hydroxytetradecanoic acid (D-b-hydroxymyristic acid) linked to the hydrophilic backbone [3]. The originally proposed backbone structure, 1,40 -bisphosphate of b-(1 ! 6) disaccharide of 2-amino-2-deoxy-D-glucose (D-glucosamine), was confirmed by structural studies of a purified major compo
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