Of 3-deoxy ulosonic acids

Such an important biological and immunological role of 3-deoxy ulosonic acids, as well as their unique chemical structure has emerged as an important area of many research fronts. Much attention has been also focused on enzymatic, chemoenzymatic, and stereocontrolled chemical syntheses of all of these compounds and their analogues. 

A more general approach to the synthesis of 3-deoxy-ulosonic acids has been presented by Dondoni [82]. The method consisted in the anti-aldol condensation of acyclic aldoses of type 61 with the lithiated 2-acetylthiazole as an equivalent of pyruvic acid to give 62 (Scheme 16). 

Numerous syntheses of 3-deoxy-ulosonic acids are based on the Wittig reaction and its modifications. For this purpose various Wittig-type ylides, shown in Fig.(3), were examined. 

It is obvious that monosaccharides in their hemiacetal form are the best substrates if they are able for the introduction of a-keto acid unit at the anomeric center. These substrates do not require tedious multistep selective protection-deprotection procedures to liberate the carbonyl function. A series of reactions were examined, what succeeded in developing of diverse routes to the construction of 3-deoxy-ulosonic acids. 

Scheme 41. Reductive decarboxylation of 3-deoxy-ulosonic acid glycosides.

V. Delest and C. Aug6, The use of Aspergillus terreus extracts in the preparative synthesis of 2-keto-3-deoxy-ulosonic acids, Tetrahedron Asymm. 6 863 (1995). 

RECENT ADVANCES IN THE CHEMISTRY OF BIOACTIVE 3-DEOXY-ULOSONIC ACIDS... 

Although the synthesis of seven carbon 3-deoxy-ulosonic acids are not as often presented as higher ones, there are some noteworthy examples published. 

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). 

N. Fraysse, B. Lindner, Z. Kaczynski, L. Sharypova, O. Holst, K. Niehaus, and V. Poinsot, Sinorhizobium meliloti strain 1021 produces a low-molecular mass capsular polysaccharide that is a homopolymer of 3-deoxy-D-manno-oct-2-ulosonic acid harbouring a phospholipidic anchor, Glycobiology, 15 (2005) 101-108. 

Several approaches have been developed for the synthesis of 3-deoxy-D-mararao-oct-2-ulosonic acid (Kdo, 123) the most common one involves the coupling of oxaloacetic acid with D-arabinose followed by decarboxylation. This aldol reaction takes place under basic conditions, but above pH 11 side reactions occur. The procedure is simple and Kdo is isolated as the crystalline ammonium salt.316... 

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. 

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]. 

S. David, B. Cavayd, and A. Malleron, Some derivatives of 3-deoxy-o-glycero-D-galacto-non-2-ulosonic acid (KDN), Carbohydr. Res. 260 233 (1994). 

ABSTRACT This article describes recent developments in the chemistry of an important family of complex monosaccharides which have diverse structures and participate in a wide range of biological processes. For example 3-deoxy-D-/n nno-2-octulosonic acid (KDO) is a key component of the lipopolysaccharides (LPS) of Grammnegative bacteria, 3-deoxy-D-araftmo-2-heptulosonic acid (DAH) is a key intermediate in the biosynthesis of aromatic amino acids in bacteria and plants. A number of their syntheses that were achieved by homologation reactions of the natural carbohydrate units using enzymatic or chemical methods, as well as by total synthetic approaches are here included. Special emphasis is placed on new methodologies and their correlation with the biosynthetic pathway of the corresponding 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],... 

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. 

The preparation of 3-deoxy-D-arai/ o-hept-2-ulosonic acid (Dahp) from P-d-glucopyranosyl cyanide peracetate is referred to in Chapters 7 and 16, and the syntheses of 2-deoxy-a- and -P-D-araiiho-hexopyranosyl phosphonic acids and related dicarboxylic acids from protected glycals are covered in Chapters 7 and 16, respectively. 

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... 

Ramage and co-workers have given full details of their Wittig approach to 2-ulosonic acids (see Vol. 22, p.l61) and have extended this route to the synthesis of 3-deoxy-D-eryt/iro-2-hexulosonic acid (KDG, 30), albeit in low yield in this case.33 A French group have developed two routes to KDG (30) (Scheme 5) involving, respectively, a Wittig synthesis of (28) 4 or P elimination from a gluconolactone derivative to yield (29) 35 the second approach could be modified to make 5- and 6-(2-methyl ethers of (30). 

No 3-azido, 3-amino, or Boc-protected mannosamine analogs 12 were accepted by the enzyme (Figure 5.11) [98] which suggests that the presence of a 3-hydroxyl group is a necessary precondition for substrates of the aldolase. Likewise, conformationally inflexible acrylate 13 was not accepted in cleavage direction. By use of fluoropyruvate 15 as the donor substrate a series of dia-stereomeric 3-deoxy-3-fluoro ulosonic acids such as 16 has been prepared in good yields (>49%) from pentoses or hexoses [82]. Such products are attractive for non-invasive in-vivo pharmacokinetic studies by NMR tomography ( F derivatives) or positron-emission spectroscopy ( F derivatives). 

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