KDO analogs

Another interesting antibiotic constmct is a peptide-conjugated form of j8-KDO. jS-KDO is an inhibitor of the CMP-KDO synthetase that is involved in lipopolysaccharide (LPS) synthesis, a major constituent of the bacterial cell wall. Antibacterial activity is thus accomplished by interference with cell wall construction. /3-KDO is incapable of membrane permeation, and therefore is not useful as an antibiotic in its native form. Hammond et al. have shown that conjugation of a /3-KDO analog to certain dipeptides resolves this problem [184] (O Fig. 14). Attachment of the /3-KDO analog to a dipeptide allows the glycopeptide constmct to permeate the bacterial membrane. Inside the cell, proteases hydrolyze the peptide and release the inhibitor, resulting ultimately in bacterial cell death. 

The 2-keto-3-deoxyoctosonate (KDO) aldolase (KdoA EC 4.1.2.23) is an inducible enzyme in gram-negative microorganisms [78] where d-KDO 8 is a core constituent of the outer membrane lipopolysaccharide. The aldolases from Aerobacter cloacae and an Aureobacterium barkerei strain have been studied for synthetic applications [72,79]. Similar to the NeuA, the KdoA enzyme has a broad substrate specificity for aldoses in place for the natural acceptor D-arabinose (Table 2) while pyruvate was found to be irreplaceable. Preparative applications, e.g., that for the synthesis of KDO analogs 13/14 (Fig. 9), suffer... 

NeuA, has broad substrate specificity for aldoses while pyruvate was found to be irreplaceable. As a notable distinction, KdoA was also active on smaller acceptors such as glyceraldehyde. Preparative applications, for example, for the synthesis of KDO (enf-6) and its homologs or analogs (16)/(17), suffer from an unfavorable equilibrium constant of 13 in direction of synthesis [34]. The stereochemical course of aldol additions generally seems to adhere to a re-face attack on the aldehyde carbonyl, which is complementary to the stereoselectivity of NeuA. On the basis of the results published so far, it may be concluded that a (31 )-configuration is necessary (but not sufficient), and that stereochemical requirements at C-2 are less stringent [71]. 

The biosynthesis of Kdo and neuraminic acid is known to involve enol-pyruvate phosphate and D-arabinose or 2-acetamido-2-deoxy-D-mannose, respectively. Nothing is known about the biosynthesis of all the other glycu-losonic acids. One interesting problem is, for example, whether the two 5,7-diamino-3,5,7,9-tetradeoxynonulosonic acids are synthesized analogously to neuraminic acid, from a three- and a six-carbon fragment, by modification of neuraminic acid on the sugar nucleotide level, or by a third, less obvious route. 

As shown in Eq. 12.54, with glyoxylate as the dienophile, if the attack is on the si face of the diene, it would lead to the skeleton of KDO if the attack is on the re face, it would lead to the skeleton of KDN. C-Disaccharide analogs of trehalose were prepared using an... 

On studying the KDO content of LPS from Xanthomonas sinensis, Volk and coworkers64 found that only one KDO residue per LPS chain is present in this organism. Moreover, the authors observed the formation of 4,7- and 4,8-anhydro derivatives (39 and 40) of KDO (see Scheme 14) under the conditions used for mild hydrolysis of the LPS with acetic acid. Free KDO was also shown to yield the anhydro derivatives under analogous conditions. The structures of these unusual side-products were identified by mass spectrometry, as follows. Reduction of 39 and 40 with sodium borohydride gave the two epimeric mixtu.es, 41 and 42. These were subjected to periodate treatment followed by borohydride reduction, the products separated by paper electrophoresis, and their trimethylsilyl ether derivatives analyzed by... 

Following the synthesis by Comforth and his associates18 of NeuAc from oxalacetate and 2-acetamido-2-deoxy-D-mannose, Ghalambor and Heath29,31 prepared KDO (isolated as the crystalline methyl 2,4,5,7,8-penta-0-acetyl-3-deoxy-D-manno-2-octulopyranosonate, 70) from D-arabinose and oxalacetate by an analogous reaction (see Scheme 20). 

Several observations regarding this aspect have been published, and are briefly mentioned here. 5,6-Dideoxy-6-C-phosphono-D-arabino-hexofuranose (135), an isosteric phosphonate analog of D-arabinose 5-phosphate, is apparently converted, in the presence of enolpyruvate phosphate, into 3,8,9-trideoxy-9-C-phosphono-D-mcmno-2-nonulosonic acid (136) under catalysis by KDO 8-phosphate synthetase from Escherichia coli K 235. Compound 136, an isosteric phosphonate analog of KDO 8-phosphate, is a product inhibitor of the synthetase, and, by the nature of the phosphonate group, is not subject to dephosphorylation as catalyzed by KDO 8-phosphate phosphatase156 (see Scheme 40). Compound 119 (see Scheme 33) is a weak inhibitor of KDO 8-phosphate synthetase.81 KDO inhibits KDO 8-phosphate phosphatase,139 and D-ribose 5-phosphate has an inhibitory... 

For example, data obtained by this technique are shown in Table VIII and Fig. 12a for HDS of dibenzothiophene catalyzed by a CoMo/carbon (41). In these experiments, 3,3 -dimethylbiphenyl was used as the biphenyl analog, as the chemistries are identical and only small differences in adsorption behavior are expected. As shown in Table VIII, the ratio of rate constants ((kDo + /chs / hpi) was estimated to be 62. With this ratio held constant, the other rate constants in the HDS pathway matrix were estimated using curve-fitting techniques. 

T. Sugai, G.-J. Shen, Y. Ichikawa, and C.-H. Wong, Synthesis of 3-deoxy-D-monno-2-octulosonic acid (KDO) and its analogs based on KDO aldolase-catalyzed reactions, J. Am. Chem. Soc. 775 413 (1993). 

Tadanier, J., Lee, C. M., Whittern, D., Wideburg, N. Synthesis of some C-8-modified 3-deoxy-]3-D-manno-2-octulosonic acid analogs as inhibitors of CMP-Kdo synthetase. Carbohydr. Res. 1990, 201, 185-207. 

Coutrot, P., Grison, C., and Lecouvey, M., Preparation of the phosphonic acid analog of 3-deoxy-D-manno-2-octulosonic acid (KDO), Tetrahedron Lett., 37, 1595, 1996. 

The aqueous oxa-Diels-Alder reaction has been successfully exploited in the synthesis of sesbanimides A and B [70], carbovir [71], mevinic acids [72], aris-teromycin and carbodine [73], ketodeoxyoctulosonic acid (KDO) and analogs... 

Such an aqueous hetero Diels-Alder reaction, which was extended to other dienes [42], was applied in various syntheses, including sesbanimides A and B [43], carbovir [44], mevinic acids [45], aristeromycin and carbodine [46], ketodeoxyoctu-losonic acid (KDO) and analogs [47], and sialic acids [48]. Pyruvaldehyde, glyoxal, and even ketones like pyruvic acid also react with dienes in water [42],... 

---