2-Deoxy-P-KDO

Burke, S. D., Sametz, G. M. Total Synthesis of 3-Deoxy-D-manno-2-octulosonic Acid (KDO) and 2-Deoxy-p-KDO. Org. Lett. 1999, 1, 71-74. 

Among various modifications of KDO, 2-deoxy-P-KDO which is believed to be inhibitor of CMD-KDO synthetase has attracted great interest as a potential antibiotic [142], Another importance of 2,3-dideoxy ulosonic acids comes from the possibility of using them as the precursors of glycosyl donors. 

Treatment of the NeuNAc derivative 40 with Stnl2 in ediylme ycol and THF gave stereoselectively the product 41 with an axial carboxymethyl groiqt. The same sdectivi was found in the reduction of the equivalent Kdo derivative, leading to 2-deoxy P-Kdo.34... 

In a new route to 2-deoxy-P-KDO, the key step was the intramolecular alkylation of 23, made from D-mannose, in the presence of LDA, to give 24 steteospecifically.28... 

Analogues of 2-deoxy-p-KDO and 2-deoxy-a-NeulVAc continue to attract attention. A range of compounds has been reported which involve modification of 2-deoxy-p-KDO at C-8, including the chain extended analogues of type (IS), " and the same group has also prepared the C-glycosidic analogues (19) by methods complementary to those used earlier by other... 

The anhydroribonlc acid derivative (12) has been prepared from isopro-pylidene-D-glyceraldehyde.ib Several 8-substituted analogues (13) of 2-deoxy-P-KDO have been prepared and shown to be inhibitors of CMP-KDO synthetase, although they did not display antibacterial activity. A number of similar 2-deoxy compounds are discussed together with their ulosonic analogues in the next section. 

A. Dondoni and P. Merino, Chemistry of the enolates of 2-acetylthiazole Aldol reactions with chiral aldehydes to give 3-deoxy aldos-2-uloses and 3-deoxy-2-ulosonic acids. A short total synthesis of 3-deoxy-D-manno-2-octulosonic acid (KDO), J. Org. Chem. 56 5294 (1991). 

Neszmelyi, A., Jann, K., Messner, P. and Unger, F.M. (1982) Constitutional and configurational assignements by JC NMR spectroscopy of Escherichia coli capsular polysaccharides containing ribose and 3-deoxy-D-manno-2-octulosonic acid (KDO). J. Chem. Soc. Chem. Commun. 1017-1019... 

P. A. McNicholas, M. Batley, and J. W. Redmond, Synthesis of methyl pyranosides and furanosides of 3-deoxy-D-marcrco-oct-2-ulosonic acid (KDO) by acid-catalysed solvolysis of the acetylated derivatives, Carbohydr. Res., 146 (1986) 219-231. 

The research team of J. Tadanier prepared a series of C8-modified 3-deoxy-P-D-manno-2-octulosonic acid analogues as potential inhibitors of CMP-Kdo synthetase. One of the derivatives was prepared from a functionalized olefinic carbohydrate substrate by means of the Wohl-Ziegler bromination. The stereochemistry of the double bond was (Z), however, under the reaction conditions a cis-trans isomerization took place in addition to the bromination at the allylic position (no yield was reported for this step). It is worth noting that the authors did not use a radical initiator for this transformation, the reaction mixture was simply irradiated with a 150W flood lamp. Subsequently the allylic bromide was converted to an allylic azide, which was then subjected to the Staudinger reaction to obtain the corresponding allylic amine. 

Molin, H., and Pring. B.G., Regio- and stereoselective synthesis of the carbocychc analogue of 3-deoxy-P-D-mann-2-octulopyranosonic acid (P-KDO) from (-)-quinic acid. Tetrahedron Lett., 26, 677, 1985. 

Waglund, T., Luthman, K., and Orbe, M., Synthesis of C-(P-D-glycosyl) analogues of 3-deoxy-D-manno-2-octulosonic acid (Kdo) as potential inhibitors of CMP-Kdo synthetase, Carbohydr. Res., 206, 269, 1990. 

The 5-0-a-L-rhamnopyranosyl derivative of KDO and KDO 7-(2-aminoethylphosphate) have both been isolated from the inner core region of the lipopolysaccharide (LPS) of E.coli K12. The syntheses of KDO-7-phosphate and 7-(2-acetamidoethyl phosphate) have been carried out by phosphorylation of an appropriately-protected derivative. It has been shown that in solution KDO 8-phosphate exists as a mixture of a-pyranose (66%), P-pyranose (3%), a-furanose (19%) and P-furanose (12%) forms. By use of the two isomeric 2-deoxy analogues of KDO 8-phosphate it was shown that KDO 8-phosphate phosphatase is speciflc for the a-pyranose form of the substrate, so that a mutarotation must be involved before the next stage in the formation of LPS, since CMP-KDO synthetase is specific for the P-pyranose form of KDO. 0 Other references to 2-deoxy-KDO and 2-deoxy-NeuNAc can be found in Section 1 of this Chapter. 

The synthesis of 3-deoxy-D-manno-2-octulosonic acid (KDO) and its derivatives continues to attract attention. The Cornforth-type synthesis of KDO from D-arabinose and oxaloacetic acid has been improved by the use of NiCl2 to effect rapid decarboxylation, and similarly S-deoxy-D-glycero-D-galacto-2-nonulosonic acid (KDN) could be made in high yield from D-mannose and oxaloacetate.24 Schmidt and coworkers have given a full account of their route to KDO (Vol. 18. p.l52), and also describe various O-acylated derivatives and... 

Some examples of transformations involving carbonyl ylides are listed in Table 4.20. Entry 1 illustrates the conversion of P-acyloxy-a-diazoesters into a-acyloxyacrylates by ring fission of a cyclic carbonyl ylide [978]. This reaction has been used for the synthesis of the natural aldonic acid KDO (3-deoxy-Z)-manno-2-octulosonic acid), which is an essential component of the cell wall lipopolysaccharide of gram-negative bacteria (Figure 4.15). 

M. D. Bednarski, D. C. Crans, R. Dicosimo, E. S. Simon, P. D. Stein, and G. M. Whitesides, Synthesis of 3-deoxy-i>manno-2-octulosonate-8-phosphate (KDO-8-P) from D-arabinose Generation of D-arabinose-5-phosphate using hexokinase, Tetrahedron Lett. 29 427 (1988). 

Scheme 4.1 (a) Structure of the lipopoly saccharides of Gram-negative bacteria, (b) The structure of the lipid A from E. coli. (c) The structure of Kdo residue (a-3-deoxy-D-manno-oct-2-ulopyranosonic acid). For all structures, where not stated otherwise, sugars are a-D-pyranosides. Residues in bold are present as non-stoichiometric substitutions. Common abbreviations P, Phosphate, PPEtn, 2-aminoethanol diphosphate, PEtN, 2-aminoethanol phosphate, PCho, 2-trimethylaminoethanol phosphate Gly, glycine, Ac, Acetyl, Cm, Carbamoyl, Pyr, Pyruvic Acid... 

Allen, NE, Nonclassical targets for antibacterial agents, Annu. Rep. Med. Chem., 20,155-162,1985. Ray, P H, Kelsey, J E, Bigham, E C, Benedict, C D, Miller, T A, Synthesis and use of 3-deoxy-D-manno-2-octulosonate (KDO) in Escherichia coli. Potential sites of inhibition, ACS Symp. Ser., 231, 141-169, 1983. 

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