3-Deoxy-2-keto 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. 

Type B aldolases use pyruvic acid as the nucleophile to form a 3-deoxy-2-keto acid product. 

The 2-keto-3-deoxy-aldonic acid (phosphate) aldolases from Pseudomonas strains - 3-deoxy-2-keto-L-arabonate (F.C 4.1.2.18), 3-deoxy-2-keto-D-xylonate (EC 4.1.2.28), 3-deoxy-2-keto-6-phospho-D-gluconate (EC 4.1.2.14) and 3-deoxy-2-keto-6-phospho-D-galactonate aldolase (EC 4.1.2.21) - appear to be specific even for the acceptor components, but allow stereoselective syntheses of the respective natural substrates29. 

Pyruvate-dependent lyases serve catabolic functions in vivo in the degradation of sialic acids and KDO (2-keto-3-deoxy-manno-octosonate), and in that of 2-keto-3-deoxy aldonic acid intermediates from hexose or pentose catabolism. 

Labeling experiments with l-deoxy-l-(dibenzylamino)-D-[l- C]-aruI>-mo-2-hexulosuronic acid [l- C] 112 indicated that the C label corresponded to the 5-methyl group of 111 (see Ref. 234). This is also consistent with a l-deoxy-2,3-dicarbonyl intermediate (115), and indicates that 111 is a decarboxylation product (see Scheme 22). The precise step entailing decarboxylation has not yet been determined. The carboxyl group could be carried through to ring closure (furanone formation). Such a step would provide a 2-carboxylate which is a /3-keto acid subject to ready decarboxylation. The labeling information and the initial steps of the mechanism in Scheme 22 are also consistent with the formation of 111 from D-[l- C]ribose and a secondary amine. ... 

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). 

Comparable to the situation for the sialic acid and KDO lyases (vide supra), sets of stereochemically complementary pyruvate lyases are known, e,g. in Pseudomonas strains, which act on related 2-keto-3-deoxy-aldonic acids [112]. The enzymes cleaving six-carbon sugar acid phosphates—the KdgA and 2-keto-3-deoxy-6-phospho-D-galactonate (20) aldolases (KDPGal aldolase EC 4.1.2.21) [139] — are typified as class I enzymes, whereas those acting on non-phosphorylated five-carbon substrates — 2-keto-3-deoxy-L-arabonate (21) (KDAra aldolase EC 4.1.2,18) [140, 141] and 2-keto-3-deoxy-D-xylonate (22)... 

Further support for 3-deoxy-D-arofefno-heptulosonic acid 7-phosphate as an intermediate in aromatic biosynthesis was given by the isolation of a phosphorylated keto acid from filtrates of a mutant of E. cali, blocked before 5-dehydroquinate. This compound was shown to be identical with synthetic 3-deoxy-D-ara wno-heptulosonic acid 7-phosphate by its chromatographic behavior, chemical properties, and conversion to 5-dehydroquinate by a purified enzyme-preparation. ... 

The oxidative decarboxylation of 6-phosphogluconic acid occurs in a stepwise mechanism involving a )8-keto acid intermediate 64). However, it appears that no metal ion is required in the reaction (66). 2-Deoxy-6-phosphogluconate is also a substrate for this enzyme, but the reaction is about two orders of magnitude slower than reaction of the natural substrate. The keto acid produced in the initial oxidation is released into solution and subsequently undergoes slow enzyme-catalyzed decarboxylation (67). 

The term sialic acid (Sia) refers to a group of nine-carbon a-keto acids derived from Neu5Ac, 5-glycolylneur-aminic acid (Neu5Gc), and deaminated neuraminic acid (KDN) (Figure 20). A closely related keto-deoxy acid,... 

By an analogy to the radical syntheses above, the carbon chain elongation reaction was achieved by Barton et al. [109] in the reaction with ethyl a-trifluoroacetoxy acrylate 165. Under radical conditions 165 was coupled with the ester 164 prepared from pentaacetyl gluconic acid and /V-hydroxy-2-thiopiridone (Scheme 35) to afford an unstable intermediate 166, readily convertible to the unsaturated a,p-keto acid 167. The methoxymercuration-demercuration of 167 gave a low selectivity, providing the mixture of 3-deoxy-4-methoxy-D-man/jo and D-g/wco-octulosonic acids (4 3) in a moderate yield [110]. 

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. 

K. Hatton, K. Takahashi, M. Uematsu, N. Sakai, Multiple interactions between host cyclodextrin and guest compound assisting asymmetrically selective reduction with NaBH4 in aqueous media, Chem. Lett., 1990, 19, 1463-1466 K. Hattori, K. Takahashi, N. Sakai, Enantioface differentiating reduction of keto-acid in the presence of 6-deoxy-6-amino-j3-cyclodextrin with NaBHi in aqueous media. Bull. Chem. Soc. Jpn., 1992,65,2690-2696 K. Hattori, K. Takahashi, Asymmetric reduction of prochiral inclusion complex in aqueous media, Supramol. Chem., 1993, 2, 209-213. 

Reduction of 1-nitro-l-alkene derivatives such as 65 provided 2-deoxy-aldose oximes and their elimination products such as 66 and 67, respectively (Scheme 11). The oxime 66 could be converted into the corresponding free 2-deoxy-sugar, 2-deoxy-aldononitrile and 2-deoxy-aldonic acid. Radical cyclization of 5-keto-aldose aldoximes to give aminocyclopentitol derivatives is covered in Chapter 18. 

This keto acid was first identified in beef bile by Wieland and Kishi (36). It had been obtained earlier as a molecular complex with chenodeoxycholic acid (152). 12-Ketolithocholic acid has been identified as a fecal acid in several species (4). The acid may be prepared by direct oxidation of deoxy-cholic acid (153) but better overall yields are obtained by protection of the hydroxyl group at carbon 3 (154). 

The chemistry and analysis of sialic acids have been reviewed. Picomole quantities of sialic acids have been measured by the fluorescence produced by the periodate-oxidized acid in the thiobarbituric acid reaction. " Contamination of the sialic acids with 2-deoxy-D-eryt/iro-pentose (derived from cellular material) could be detected by a downfield shift of the excitation maximum. Fluorescent derivatives are also produced when free sialic acids react with pyridoxamine, a procedure that compares favourably with the thiobarbituric acid reaction for determining sialic acids. Keto-acids e.g. pyruvic acid) interfere with the determination, but 2-deoxy-D-arabmo-hexose and 2-deoxy-D-c/-ytliro-pentose do not. A nonfading chromophore is produced when DMSO is used instead of n-butanol in the thiobarbituric acid ssay for sialic acids. A new histochemical method for the visualization and identification of unmodified or 0-acylated sialic acids has been reported. ... 

B Biosynthesis of 2-keto-3-deoxy-octuiosonic acid (KDO) by KDO synthase... 

Kdn 2-keto-3-deoxy-nononic acid, formally 5-desamino-5-hydroxy-neuraminic acid... 

Sialic acids (Sia) are a family of monosaccharides comprising about 40 members which can be considered as derivatives of 2-keto-3-deoxy-nononic acid (Kdn), the 5-amino derivative representing the long-known neuraminic acid [1]. However, Kdn formally is a 5-desamino-5-hydroxy-neuraminic acid. Thus, all sialic acids are derivatives of neuraminic acid with different substituents at the amino or hydroxyl... 

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