Ulosonic acid synthesis

Fig. (3). Various Wittig ylide applied for the ulosonic acids synthesis.

Synthesis of anomeric phosphates of aldoses and 2-ulosonic acids 71... 

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. 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. 

By analogy with the synthesis of /V-acetylneuraminic acid,63 di-A-acetyl derivatives of 5,7-diamino-3,5,7,9-tetradeoxynon-2-ulosonic acids could be obtained by condensation of 2,4-diacetamido-2,4,6-trideoxyhexoses with oxaloacetic acid under basic conditions. Four chiral centers in the C precursors, C-2 C-5, correspond to the centers C-5-C-8 in the target C9 products, and the fifth asymmetric center, C-4, is formed upon condensation. At present, derivatives of twelve 2,4-diamino-2,4,6-trideoxy-hexoses with the d-gluco, o-manno, L-allo, r>-galacto, D- and L-altro, D- and L-talo, D- and l-gulo, D- and L-ido configurations have been prepared by multistep chemical syntheses.11,17,18,64,65... 

Proline-Catalyzed Asymmetric Synthesis of Ulosonic Acid... 

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 preference of glyeopyranosan-l-yl radicals for axial attack by an inter-molecular hydrogen donor has been exploited in a p-mannoside synthesis (Figure 7.26) the ulosonic acid was obtained by oxidative destruetion of a furan ring. 

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. 

Development of the chemical synthesis of ulosonic acids which mimics the enzymatic condensation is an interesting target [70]. As a model a reaction leading to KDO 8-phosphate (22) has been evaluated. In this reaction mediated by KDO 8-P synthetase D-arabinose 5-phosphate (A5P, 21) is reacted with phosphoenolpyruvate (PEP) (Scheme 7) [71]. 

The introduction of the a-keto acid function on the way to the ulosonic acids is a main problem of their syntheses. By analogy with the biosynthetic pathway, the aldol reaction between sugar aldehydes and a pyruvate equivalents seems to be the most simple and versatile. As it has been demonstrated by Comforth [74] in the first chemical synthesis, the reaction of arabinose and oxalacetic acid as pyruvate equivalent, followed by decarboxylation afforded KDO, albeit in low yield. This condensation has been optimized by use of Ni(II) catalyst for the decarboxylation [75], In this case, reaction of D-mannose and oxalacetic acid gave KDN (11) and its D-manno epimer 37 in 70% yield [75] (Scheme 12). 

However, the lack of stereochemical control at C-4 of newly created asymmetric center, resulting in the formation of two diastereomers, is the great disadvantage. Despite this, Comforth s methodology remains still the best choice for preparation of the selected ulosonic acids. It is a case of synthesis of nine stereoisomeric 5,7-diacetamido-3,5,7,9-tetradeoxy-2-nonulosonic acids [76]. The synthesis was performed by condensation of an appropriate 2,4-diacetamido-2,4,6-trideoxy-hexopiranoses with oxalacetic acid under basic conditions (Scheme 13), used previously in the preparation of Neu5Ac [77]. 

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. 

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