A-acetyl-D-mannosamine

Commercial A -acetylneuraminic acid aldolase from Clostridium perfringens (NeuAcA EC 4.1.3.3) catalyzes the addition of pyruvate to A-acetyl-D-mannosamine. A number of sialic acid related carbohydrates are obtained with the natural substrate22"24 or via replacement by aldose derivatives containing modifications at positions C-2, -4, or -6 (Table 4)22,23,25 26. Generally, a high level of asymmetric induction is retained, with the exception of D-arabinose (epimeric at C-3) where stereorandom product formation occurs 25 2t The unfavorable equilibrium constant requires that the reaction must be driven forward by using an excess of one of the components in order to achieve satisfactory conversion (preferably 7-10 equivalents of pyruvate, for economic reasons). 

In nature, NANA arises through condensation of phosphoenolpyruvic acid with A-acetyl-D-mannosamine (NAM) catalysed by the biosynthetic enzyme NANA synthase. Owing to the labile nature of phosphoenolpyruvate, the use of this reaction in the synthesis of NANA has been limited to whole-cell systems where this substance can be generated biosynthetically in situ Most recently, the NANA synthase reaction forms the basis of fermentation processes for total biosynthesis of NANA. ... 

N-acetyl D-glucosamine A/-acetyl D-mannosamine N-acetyl D-galactosamine... 

By virtue of the aldehyde at the reducing end, sugars are susceptible to deprotonation and isomerization. The rearrangement from an aldose sugar to a ketose sugar, shown in Scheme 6.80, is a direct result of this property [123]. Based on the initial enolization step, this chemistry is easily applied to the direct C-2 epimerization of 2-deoxy-2-aminosugars. Scheme 6.81 illustrates this reaction in the conversion of A-acetyl-D-glucosamine to A-acetyl-D-mannosamine [124,125]. 

The nitroaldol condensation with nitromethane (Henry s reaction), followed by Nef decomposition of the resultant nitronate under strongly acidic conditions, has been used to elongate aldehydes. For instance, A-acetyl-D-mannosamine has been converted into A-acetylneuraminic acid applying this method iteratively [69]. Chikashita and coworkers [70] have reported good levels of anti diastereoselectivity better than 99% in an iterative homologation sequence using 2-lithio-l,3-dithiane [71] with 2,3-O-cyclohexylidene-D-glyceraldehyde R)-62. In the case of the BOM-protected tetrose derivative, the addition of 2-lithio-l,3-dithiane was syn selective (synlanti 82 18) (Scheme 13.30). 

The nitroaldol condensation with nitromethane (Henry s reaction), followed by Nef decomposition of the resultant nitronate under strongly acidic conditions has been used to elongate aldehydes. For instance, A-acetyl-D-mannosamine has been converted into A-acetylneu-... 

Generally, syntheses of DAHP, KDO and Neu5Ac are based on chain extension of an appropriate sugar unit electrophiles by a C3 nucleophiles, according to the biosynthetic pathway, shown in Scheme 1. Thus, the reaction of D-erythrose 4-phosphate (13) acting as a C4 electrophile with phosphoenolpyruvate (14, C3 nucleophile) creates DAHP [6]. Mutual relationship to this pathway concerns the biosynthesis of KDO and Neu5Ac, which are produced on the reaction of phosphoenolpyruvate with D-arabinose 5-phosphate (C5 electrophile) or A-acetyl-D-mannosamine 6-phosphate (C6 electrophile), respectively [5,12]. 

In contrast, Neu5Ac aldolase turned out to be very useful for synthetic purpose because it tolerate wide range of unnatural substrates [21,23]. The enzyme also named sialic acid aldolase (EC 4.1.3.3.) catalyze reversible reaction of A/-acetyl-D-mannosamine (15) and pyruvate (Scheme 3) [33-35],... 

A -acetyl-D-mannosamine-6-phosphate + phosphoenolpyruvate - -iV-acetyl neuraminic-9-phosphate + phosphate... 

A -acetyl-D-neuraminic acid is biosynthesized from A -acetyl-D-mannosamine and phosphoenol pyruvate, catalyzed by N-acetyl-D-neuraminic acid synthase. The first step involves the addition of an electron pair from the double bond of the phosphoenol pyruvate to the aldehyde group to give an aldol-type condensation (see Fig. 10.8A). The product is the nine-carbon sugar acid, A -acetyl-D-neuraminic acid [23]. In some instances the enzyme requires A-acetyl-D-mannosamine-6-phosphate as the substrate and forms A-acetyl-D-neuraminic acid-9-phosphate. Various hydroxyl groups on C-4, -7, -8, and -9 can be acetylated by specific acetyl transferases using acetyl CoAas the donor. KDO (2-keto-3-deoxy-D-mannooctulosonic acid) is biosynthesized by a very similar condensation between D-arabinose-5-phosphate and pyruvic acid, catalyzed by KDO synthase (see Fig. 10.8B) [24]. 

Carroll, P. M., and Comforth, J. W., 1960, Preparation of N-acetylneuraminic acid from A-acetyl-D-mannosamine, Biochim. Biophys. Acta 39 161. 

A-Acetylneuraminic acid aldolase (NeuA EC 4.1.3.3) catalyzes the reversible addition of pyruvate to A-acetyl-D-mannosamine (1) to form the parent sialic acid (3) (Fig. 4). The NeuA lyases found in both bacteria and animals are type I enzymes that form an enamine intermediate with pyruvate and promote a j/-face attack to the aldehyde carbonyl group with formation of a (4S) configurated stereo center. Enzyme preparations from Clostridium perfringens and E. coli are commercially available, and the latter enzyme has been cloned, overexpressed [44,45], and its three-dimensional structure determined [46]. The enzyme has a broad pH optimum around 7.5 and is quite stable in solution at ambient temperature [47]. 

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