KDO synthesis

U. Kragl, A. Godde, C. Wandrey, N. Lubin, and C. Auge, New synthetic applications of sialic acid aldolase, a useful catalyst for KDO synthesis. Relation between substrate conformation and enzyme stereoselectivity, J. Chem. Soc. Perkin Trans. 7 119 (1994). 

The six-carbon chain of ManNAc 6-P can be extended by three carbon atoms using an aldol-type condensation with a three-carbon fragment from PEP (Eq. 20-7, step c) to give N-acetylneuraminic acid (sialic acid).48 Tire nine-carbon chain of this molecule can cyclize to form a pair of anomers with 6-membered rings as shown in Eq. 20-7. In a similar manner, arabi-nose 5-P is converted to the 8-carbon 3-deoxy-D-manno-octulosonic acid (KDO) (Fig. 4-15), a component of the lipopolysaccharide of gram-negative bacteria (Fig. 8-30), and D-Erythrose 4-P is converted to 3-deoxy-D-arafrmo-heptulosonate 7-P, the first metabolite in the shikimate pathway of aromatic synthesis (Fig. 25-1).48a The arabinose-P used for KDO synthesis is formed by isomerization of D-ribulose 5-P from the pentose phosphate pathway, and erythrose 4-P arises from the same pathway. 

Enzymes of KDO Synthesis and Metabolism and Their Inhibition. The KDO pathway can be thought of as a minor branched pathway in carbohydrate metabolism initiating with the key intermediate in the hexose-monophosphate shunt, D-ribulose-5-phosphate. As shown in Figure 2 the biosynthesis and utilization are known to involve at least five sequential reactions ... 

In vivo measurements of lipopolysaccharide synthesis in E. coli B have indicated that two nanomoles of KDO must be synthesized per minute per mg of protein in order to meet the cellular requirement for LPS synthesis under the normal conditions of growth on glucose-minimal medium (27). We have measured the specific activities of the enzymes involved in KDO synthesis in crude extracts of E. coli B including those enzymes responsible for the synthesis of D-ribulose-5-phosphate, the precursor of D-arabinose-5-phosphate. D-Ribulose-5-phosphate is a key intermediate in carbohydrate metabolism as shown in Figure 2, since it is the direct precursor of both D-ribose-5-phosphate and D-arabinose-5-phosphate... 

The isolation of mutants in S. typhimurium by Rick and Osborn (11,12) and mutants in E. coli by Nishijima and Raetz (44) that accumulate the Lipid A precursor indicate that KDO synthesis and Lipid A synthesis are not coordinately controlled. The initial steps in the synthesis of the Lipid A precursor are totally unknown. The temperature sensitive mutants of E. coli isolated by Nishijima and Raetz (44) that are defective in phosphaditylglyc-erol phosphate synthesis at 42°C and accumulate the Lipid A precursors indicate that there is some relationship between the synthesis of phosphatidylglycerol and LPS. The reasons for the acu-cumulation of the Lipid A precursors in this E. coli mutant are not obvious. We have shown that CDP-diglyceride, one of the substrates for phosphatidylglycerol phosphate synthesis, is an inhibitor of D-arabinose-5-phosphate isomerase with an 1 value... 

It is worth to note that enantiomer of 221 is an intermediate in the KDO synthesis. For the purpose of synthesizing KDO R enantiomer of aldehyde 218 was used as a starting material (Scheme 49). Thus obtained dihydropyranes 227 were converted into KDO in nine steps elaborated previously during Neu5Ac synthesis. 

Steps KDO synthesis from furan presented Martin et al. [150]. The reaction started from addition of 2-lithiofuran to isopropylidene-D-glyceraldehyde (Scheme 59). 

Different concept of 2-deoxy-KDO synthesis was presented by Craig [151]. The synthetic route started from epoxide 281 and 3,3-dimethoxy-l-(phenylsulfonyl)-propane which were transformed, after several manipulation, to bicyclic alcohol 284 (Scheme 60). 

Asymmetric Sharpies epoxidation was applied by Schreiber to the synthesis of epoxide 286 being starting material for KDO synthesis [152] (Scheme 61). Aldehyde 287, obtained from 286, underwent aldol type condensation with a-(bromomethyl)acrylate to 8-carbons skeleton of KDO and its C-4 epimer (1 1) mixture. 

D-mannose derivatives, (see Vol. 22, p. 161).29 a new stereoselective total synthesis of (+)-KDO (27) proceeds via the adduct (28) from 2-furyllithium and isopropylidene-D-glyceraldehyde (Scheme 10).3O A full account has been given of a KDO synthesis by free-radical extension of a mannose derivative at C-6 (see Vol. 22, p. 162),31 and there has been a further report on the preparation of 3-deoxy-L-5(ulo-2-octulosonic acid [the C-7 epimer of (27)] by similar methods to those previously used (see Vol. 22, p. 162).32... 

The derivative (31) of 3-deoxy-D-arabj o-2-heptulosonic acid (DAH) has been prepared by interaction of the cyclic sulfate of 2,3,5-tri-O-benzyl-D-arabinitol with the lithium derivative of 2-carboethoxy-l,3-dithiane (an approach used for KDO synthesis Vol. 21, p.l61-2),36 and the D-gluco-heptulosonic and derivative (32) is accessible by hydroxylation of the 2,3-ene.37 The chloroglycidate (33) gives the bromoderivative (34) of DAH on treatment with MgBr2 or PhMgBr, and a similar reaction was also observed from a precursor of L-g /o-configuration.3 8... 

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