3- Deoxy-ulosonic acids

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). 

Dondoni A, Marra A, Merino P (1994) Installation of the pyruvate unit in gly-cidic aldehydes via a Wittig olefination-Michael addition sequence utilizing a thiazole-armed carbonyl ylide. A new stereoselective route to 3-deoxy-2-ulosonic acids and the total synthesis of DAH, KDN, and 4-epi-KDN. J Am ChemSoc 116 3324... 

Li LS, Wu YL (2002) Synthesis of 3-deoxy-2-ulosonic acid KDO and 4-epi-KDN, a highly efficient approach of 3-C homologation by propargylation and oxidation. Tetrahedron 58 9049... 

Sialic acids are a family of 3-deoxy-2-ulosonic acids found most frequently as a-glycosidically linked terminal residues of glycoproteins and glycolipids. The most abundant sialic acid is N-acetylneuraminic acid (5-acetamido-3,5-di-deoxy-D-glycero-D-galacto-nonu osonic acid, NeuSAc, 1), which was first isolated in the 1930s. To date, 36 sialic acids have been isolated, many of which are 0-acetylated derivatives of N-acylated neuraminic acid [1]. 

Assuming that the recent review articles concern mainly sialic acid (Neu5Ac) and its deaminated counterpart KDN, as well as their modified analogs [12], we found as not reasonable describing them in this review. Instead, more attention will be focused on the remaining 3-deoxy-2-ulosonic acids. 

The aldolases which have been investigated for their synthetic utility can be classified on the basis of the donor substrate accepted by the enzyme. For the synthesis of 3-deoxy-2-ulosonic acids pyruvate- and phosphoenolpyruvate dependent aldolases are the most desirable enzymes as they are involved in the metabolism of sialic acids (or structurally related ones) in vivo. They use pyruvate or phosphoenolpyruvate as a donor to form 3-deoxy-2-keto acids (Table 1). Both of them add a three-carbons ketone fragment onto a carbonyl group of an aldehyde. The pyruvate dependent aldolases have a catabolic function in vivo, whereas the phosphoenolpyruvate dependent aldolases are involved in the biosynthesis of the keto acids. For synthetic purpose the equilibrium of the pyruvate dependent aldolases is shifted toward the condensation products through the use of an excess of pyruvate. 

Much effort towards stereoselective synthesis of 3-deoxy-2-ulosonic acids resulted in the development of several strategies based on the diverse building units. Among them aldol reaction between D-arabinose derivative 50 and methyl dichloroacetate (51) deserves some attention [78] (Scheme 14). The condensation product isolated as oxirane derivative 52 reacted smoothly with Mgk to give the intermediate 53, easily convertible into 3-deoxy-D-ara6mo-2-heptulosonic acid methyl ester 56 in high yield. 

By this course of reactions a series of 3-deoxy-2-ulosonic acids were synthesized, including DAH [105], DRH [105] and 4-epi-KDN [103],... 

All previously described approaches to 3-deoxy-2-ulosonic acids started from advanced carbohydrate precursors, and thus they are not easily applicable to the synthesis of structurally diverse analogues. This concerns chemical syntheses relying on sugar-derived stereocenters and enzymatic ones, providing only very limited access to some naturally occurring compounds. In contrast, de novo syntheses starting from simple, achiral compounds offer much more flexible alternative approaches to synthesis of unnatural ulosonic acid analogues. 

Syntheses of 3-deoxy-2-ulosonic acids have again been the subject of a number of reports. The cycloheptene derivative 46 was made by enzymic desymmetrization of the neso-compound and employed in a multistep synthesis of the doivadve 47 of 3-deoxy-D-ara6ino-heptulosonic acid (Dah), dihydroxylation being used to establish the required chirality at C-S and C-6 of the sugar relative to that at C-4.39 if, in the chemistry of Scheme 6, the final rhodium-catalysed reaction was replaced by MCPBA oxidation, Kdo could be obtained. Application of the earlier stages of... 

Kdn). Dondoni s group have extended their earlier woik on the use of a diiazolyl phosphtnane as a masked C3 synthon for making 3-deoxy-2-ulosonic acids (Vol. 25, p. 187), and have now described this approach as applied to Dah, Kdn and A-epi- jAaM... 

A paper has described interesting studies on the use of sialic acid aldolase with unnatural substrates to make various 3-deoxy>2-ulosonic acids. When the aldolase is used to catalyse the reaction of D-arabinose with pyruvate, both 4-ep/-Kdo, the product of the enzyme s nonnal stereoselectivity, and Kdo, the product of inverted selectivity, are produced. Use of a large excess of arabinose increased the proportion of Kdo. Similarly, condensation of pyruvate with L-xylose, D-altrose and D-ribose gave isomeric mixtures, and use of L-xylose in excess gave a good yield of 7-ept-Kdo, the product of inverted stereoselectivity. With L-allose as substrate, just the nonnal product, 7,8-di-ep/-Kdn, was obtained. Relationships between the enzyme stoeoselecdvity and the conformation and C-3 stereochemistry of the substrate were discussed. ... 

There have been further reports on routes to 3-deoxy-2-ulosonic acids. A new synthesis of Kdo involves the synthesis of epoxyester 35 (X=Br or Cl) by a Darzens reaction, followed by reaction with magnesium iodide and subsequent reduction of the 3-iodocompounds with bisulfite to give 36 deprotection by sequential acid and base treatment led to the isolation of Kdo ammonium salt (38) in 63% overall yield from the a/deAydo-sugar.34 another approach (Scheme 6) a hetero-Diels-Alder reaction was employed, followed by hydroxylation and then inversion at both C-4 and C-5 conversion of 37 to Kdo ammonium salt (38) involved functionalization at C-2 by phenylsulfenylation of an enolate.33... 

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