Mannosamine synthesis

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-Acetvlneuraminic Acid Aldolase. A new procedure has also been developed for the synthesis of 9-0-acetyl-N-acetylneuraminic acid using the aldolase catalyzed reaction methodology. This compound is an unusual sialic acid found in a number of tumor cells and influenza virus C glycoproteins (4 ). The aldol acceptor, 6-0-acetyl-D-mannosamine was prepared in 70% isolated yield from isopropenyl acetate and N-acetyl-D-mannosamine catalyzed by protease N from Bacillus subtilis (from Amano). The 6-0-acetyl hexose was previously prepared by a complicated chemical procedure (42.) The target molecule was obtained in 90% yield via the condensation of the 6-0-acetyl sugar and pyruvate catalyzed by NANA aldolase (Figure 6). With similar procedures applied to KDO, 2-deoxy-NANA and 2-deoxy-2-fluoro-NANA were prepared from NANA. 

The free nitriles of iV-methyl-L-glucosaminic acid and iV-methyl-L-mannosaminic acid have been prepared by Wolfrom, Thompson and Hooper by the Kiliani-Fischer cyanohydrin synthesis. 

The Sowden homologation [21], based on the nitroaldol condensation (Henry reaction) [22] between the aldehydo sugar and nitromethane in basic medium, followed by the Nef decomposition [23] of the resultant nitronate in strongly acidic conditions, has been employed in a more limited number of cases than the cyanohydrin synthesis. A recent example in this area is shown by the stepwise homologation of (V-acetyl-D-mannosamine (11) into /V-acetylneuraminic acid (12) [24] (Scheme 4). Also, this procedure has found... 

Having set up a protocol for the aminohomologation of various aldehydo sugars, the value of the method was tested by the synthesis of simple natural products. The firsl example involved [57a] the conversion of 2,3 4,5-di-0-isopropylidene-D-arabinose 59 (Scheme 18) through the nitrone 60 into the W-acetyl-D-mannosamine diacetonide 61 and the deprotected compound 11, both well-known key intermediates for the synthesis of /V-acetylneuraminic acid (Neu5Ac) [59,60]. Unfortunately, in this case the addition of 2-LTT (25b) to the nitrone 60 occurred with modest selectivity (ds 75% to the best) therefore, the overall yield of 61 was quite low (29%). 

The reversed configuration of these adducts that was mistakenly assigned in our first report (Ref 57a) was timely corrected in a second paper (Ref 57b). For a commentary to this reaction, see A. Zamojski, Stereoselective aminohomologation of chiral a-alkoxy aldehydes via thiazole addition to nitrones. Application to the synthesis of W-acetyl-D-mannosamine, Chemtracts Org. Chem. 6 172 368 (1993). 

The sialic acid aldolase-catalyzed condensation of D-mannose 8 and pyruvate led, in an excellent yield, to the synthesis of KDN 9 [33], a natural deaminated neuraminic acid first isolated from rainbow trout eggs [34] and then discovered in other species. The discovery that sialic acid aldolase accepts as substrates D-mannose substituted on the 2-position, even by bulky substituents such as phenyl, azido, or bromine, opened the route to novel unnatural sialic acid derivatives [35-39]. Pentoses also are substrates. N-Substituted neuraminic acids could be prepared either directly from the corresponding Af-substituted mannosamine, such as N-thioacyl derivatives [40], or after reduction and acylation of 5-azido-KDN [41]. Recently, AT-carbobenzyloxy-D-mannosamine was converted, in a good yield, into the N-carbobenzyloxy-neurarninic acid, further used as a precursor of a derivative of castanospermine [42]. 

Scheme 11.—Chemical Synthesis of Differently Substituted W-Acetyl-D-mannosamine Derivatives.

Scheme 12.—Chemical Synthesis of the Furanose Derivative of N-Acetyl-D-mannosamine.

Scheme 4.26 Glycosyl hydrolases in oligosaccharide synthesis, (i) = /V-acetylhexo from A. oryzae, (ii) = p-mannosamine from A. orzyae.

The second pathway for the formation of 3-deoxyulosonic acids is, at present, represented only by the condensation of pyruvate with iV -acetyl-n-mannosamine to form a nonulosaminic acid (iV-acetylneuraminic acid). - This reaction is readily reversible, but the point of equilibrium is 90 per cent toward degradation and 10 per cent toward synthesis of the iV-acetyl-neuraminic acid. ... 

Figure 17-33. Synthesis of N-acetylneuraminate (Neu5Ac) from N-acetyl-D-glucosamine (GIcNAc) and pyruvate through N-acetyl-D-mannosamine (ManNAc) with N-acetylneuraminate and N-acetyl-D-glucosamine 2-epimerase. Reprinted from Maru et al.I259].

N-Acetyl-D-mannosamine serves as the in situ generated substrate for the synthesis of N-acetylneuraminic acid. Since N-acetyl-D-mannosamine is quite expensive it is synthesized from N-acetyl-D-glucosamine by epimerization at C2. This biotransformation is integrated into the production of N-acetylneuraminic acid (Neu5Ac). 

By application of N-acylglucosamine 2-epimerase it is possible to start with the inexpensive N-acetyl-D-glucosamine instead of N-acetyl-D-mannosamine (Fig. 19-42). The epimerase is used for the in situ synthesis of N-acetyl-D-mannosamine... 

The Sia synthase, or aldolase, is responsible for the reversible aldol reaction that occurs between six-carbon mannosamines and pyruvate (Figure 22). In the forward direction, this condensation reaction creates a new carbon-carbon bond to produce nine-carbon Sias. Aldolases capable of Sia synthesis are found in a variety of bacteria. The E. coli enzyme has proven to be extremely adaptable in chemoenzymatic reactions. Its substrate scope has been studied extensively and is described in a large body of literature published in the late 1980s and early 1990s. Taken together, these reports indicate that the enzyme exhibits a strong preference for pyruvate as... 

In Banwell s de novo synthesis of Neu5Ac [136] cis-1,2-dihydrocatechol 228, a product of microbial oxidation of chlorobenzene, has been converted into a protected form of Neu5Ac via a fifteen steps reaction sequence (Scheme 50). Synthesis started from azido alcohol 229, obtained from catechol 228 by an established procedure [137]. This was subjected to ozonolytic cleavage and a reductive work-up to afford diol 230. Protection-deprotection reaction sequence led to alcohol 232 which was then oxidized to D-mannosamine derivative 233 using the Swem protocol. Condensation with the organozinc reagent derived from... 

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