First Total Synthesis of the Re‐Type Lipopolysaccharide

Lipopolysaccharides (LPS) are ubiquitous glycoconjugates located on the surface of Gram-negative bacteria such as Escherichia coli, and exhibit multiple and potent biological activity, both toxic and beneficial, towards higher animals.[1] LPS consist of a phosphorylated acyl glucosamine disaccharide covalently bonded to a polysaccharide. The former glycolipid, lipid A, is the entity responsible for most of the biological activity of LPS.[2, 3] Lipid A is therefore never present on living bacterial cells in the free form; it is an artificial product obtained only by the acid hydrolysis of LPS. The simplest LPS molecule that is known to be present on bacterial cells and that comes into contact with animal cells is the so-called Re-type LPS produced by the Escherichia coli Re mutant (Re LPS, 1).[4] This LPS derivative is composed of lipid A and two molar equivalents of 3-deoxy-d-manno-2octurosonic acid (formerly called 2-keto-3-deoxy-d-mannooctonic acid (Kdo)). The chemical synthesis of Re LPS is not only a highly challenging goal, but would also contribute towards the elucidation of the biological and physicochemical role of the sugar moieties linked to lipid A. It has often been implied that the polysaccharide portion enhances or modifies the activity of Re LPS.[5] In fact, Re LPS that only has two units of Kdo was reported to exhibit more potent antitumor and cytokine-inducing activity than lipid A.[6, 7] However, these observations have never been confirmed owing to the O O O HN HO O O HN O