3- Deoxy-ulosonic acids synthesis

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). 

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). 

Analogous cycloaddition reaction of sodium glyoxylate, in water, onto penta-2,4-dienol has been used for synthesis of seven carbon 2-deoxy-ulosonic acid analogues as depicted in Scheme 56 [145]. 

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). 

Deoxy-D-araZhrao-hept-2-ulosonic acid-7-phosphate ( DAHP, 122) is the precursor for the synthesis of aromatic amino acids in all microorganisms and plants (shikimic pathway).306,307... 

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. 

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... 

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. 

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. 

The developed by Burke route to ulosonic acid has been also utilized for the synthesis of 2-deoxy compounds [143] (Scheme 54). 

Szabo and his colleagues have prepared 3-deoxy-D-crj f/iro- and U-threo-hcx-2-ulosonic acid 5-phosphate in the ratio 2 1 as illustrated in Scheme 1. The products were isolated in 37 and 23% yield, respectively, as their magnesium salts.In parallel fashion, Russian workers have developed a synthesis of 3-deoxyaldulosonic acids as depicted in Scheme Studies by n.m.r. spectroscopy of ot- and /3-A-acetylneuraminic acid derivatives and determination of /c-i-H-3 e values allowed the conclusion that, in cytidine 5-phospho-iV-acetyl-neuraminic acid, a key intermediate in the biosynthesis of glyconoconjugates, the neuraminic acid moiety has the 3-configuration. ... 

An enantioselective synthesis of 18 was achieved. This is a deoxy analogue of naturally occurring 3-deoxy-D-gf/yccro-D-firu/acm-2-non-2-ulosonic acid (KDN). ... 

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... 

A chemicoenzymatic synthesis of l-dcoxy-D-xylo-bexose is discussed in Chapter 2, and the occurrence of 2-<9-methyl-6-deoxy-L-talose in an O-linked glycopeptide in Chapters 3 and 5. Syntheses of 2-deoxykanosamine and methyl a-D-evalopyranoside are mentioned in Chapters 9 and 14 respectively, and deoxyanalogues of ulosonic acids are covered in Chapter 16. 

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). 

A synthesis of 3-deoxy- D-glycero-D-galacto-2-nonu osonic acid from d-mannose involved use of a keto-thiazole Wittig reagent,while addition of lithiated thiazole to a 2-deoxy-hexono-1,4-lactone featured in a synthesis of 3-deoxy-D-ara )j>io-hept-2-ulosonic acid. 

Considerable attention has been given to the synthesis of dlsaccharldes with ulosonic acid non-reducing compounds - particularly 3-deoxy-D-manno-octulosonlc acid (KDO). The a-l- -4 linked... 

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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