Neuraminic acids, synthesis

Rodriguez-Aparicio LB, Ferrero MA, Reglero A. N-acetyl-D-neuraminic acid synthesis in Escherichia coli K1 occurs through condensation of N-acetyl-D-mannosamine and pyruvate. Biochem J 1995 308 501-505. 

Figure 10.7 Neuraminic acid derivatives accessible by NeuA catalysis, including an intermediate for alkaloid synthesis.

Carbon-carbon bond lyases, used in the reverse, synthetic direction have also enjoyed significant application in the pharmaceutical industry. For example 7/-acetyl-D-neuraminic acid (NANA), an intermediate in the chemoenzymatic synthesis of the influenza virus sialidase inhibitor zanamavir, may be synthesized using NANA aldolase. 

C-6,209,214 anhydro sugars,branched monosaccharides, fluori-nated amino sugars,difluorinated monosaccharides, and fluorinated monosaccharide phosphates,and phosphonates have been described. Further progress has been achieved in the synthesis and n.m.r.-spectral analysis of fluorinated avermectin Bu, tylono-lide, and neuraminic acid derivatives. " ... 

The Glaxo synthesis of zanamivir (2) started with the esterification of commercially available A-acetyl-neuraminic acid (88) with methanolic HCl to give the methyl ester as shown in Scheme 7.14 (Chandler and Weir, 1993 Chandler et ah, 1995 Patel, 1994 Weir et al., 1994). Global acetylation of all the hydroxyl groups with acetic anhydride in pyridine with catalysis by 4-(dimethylamino)pyridine (DMAP) led to the penta-acetoxy compound 89. Treatment of 89 with trimethylsilyl triflate in ethyl acetate at 52°C introduced the oxazoline as well as the 2,3-double bond to provide 86. Addition of trimethysilyl azide to the activated allylic oxazoline group led to the stereoselective introduction of azide at the C-4 position to afford 83 as in Scheme 7.13. 

A. Oseltamivir inhibits neuraminidase, an enzyme that cleaves neuraminic acid from oligosaccharides. Neuraminidase activity aids the movement of viral particles through neuraminic acid-rich respiratory secretions and is required for the release of progeny virions. Inhibition of viral DNA polymerase is the mechanism of action of nucleoside analogue antiviral drugs. Interferons do stimulate the JAK-STAT signaling pathway but do not stimulate proliferation of immune cells. Ribavirin inhibits GTP synthesis, and the antiretroviral protease inhibitors (e.g., ritonavir) inhibit HIV protease. 

Vasella has applied the concept of anomeric anion stabilization by a nitro group to the /3-D-JV-acetyl-D-glucosamine derivative 177, available in four steps from N-acetyl-n-glucosamine [52] (Scheme 39). Reaction of the tetraethylammonium nitronate derived from 177 with aldehyde 178 provides anti-179 which then undergoes stereoselectively reduction (see Sect. 2.2.1) to provide -C-glycoside 180, intermediate in a synthesis of N-acetyl-neuraminic acid. 

Other useful nucleophiles for this type of substitution include azide and thiolacetic acid. Glaxo researchers utilized such a strategy in their synthesis of the neuraminic acid analogue 346 (Scheme 8.109). ° Itzstein and co-workers used a similar strategy to synthesize a thio analogue of neuraminic acid 347 °" and reported that thiolacetic acid was also a suitable nucleophile. ° ... 

T. J. Martin and R. R. Schmidt, Efficient sialylation with phosphites as leaving group, Tetrahedron Lett. 33 6123 (1992) T. J. Martin, R. Brescello, A. Toepfer, andR. R. Schmidt, Synthesis of phosphites and phosphates of neuraminic acid and their glycosyl donor properties— convenient synthesis of GM3, Glycoconjugate J. 70 16 (1993), and references therein. 

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]. 

M.-J. Kim, W. J. Hennen, H. M. Sweers, and C.-H. Wong, Enzymes in carbohydrate synthesis 79-Acetylneuraminic acid aldolase catalyzed reactions and preparation of 7V-aceiyl-2-deoxy-D-neuraminic acid derivatives, J. Am. Chem. Soc. 770 6481 (1988). 

U. Kragl, D. Gygax, O. Ghisalba, and C. Wandrey, Enzymatic two-step synthesis of W-acetyl-neuraminic acid in the enzyme membrane reactor, Angew. Chem. Int. Ed. Engl. 30 827 (1992). 

C. Aug6 and C. Gautheron, The use of an immobilized aldolase in the first synthesis of a natural deaminated neuraminic acid, J. Chem. Soc., Chem. Commun. p. 860 (1987). 

A. Schrell and G. M. Whitesides, Synthesis of the a-methyl ketoside of 5-amino neuraminic acid methyl ester and its corresponding 5-myristoyl and 5-cyclopropanoyl derivative, Liebigs Ann. Chem. p. 1111 (1990). 

J. O. Nagy and M. D. Bednarski, The chemical-enzymatic synthesis of a carbon glycoside of W-acetyl neuraminic acid, Tetrahedron Lett. 32 3953 (1991). 

Banwell M, De Savi C, Watson K (1998) Diastereoselective Synthesis of (-)-W-Acctyl-neuraminic Acid (Neu5Ac) from a Non-Carbohydrate Source. J Chem Soc Perkin Trans 1 ... 

J. C. Wilson, R. J. Thomson, J. C. Dyason, P. Florio, K. J. Quelch, S. Abo, and M. von Itzstein, The design, synthesis and biological evaluation of neuraminic acid-based probes of Vibrio cholerae sialidase, Tetrahedron Asymmetry, 11 (2000) 53-73. 

M. Murakami, K. Ikeda, and K. Achiwa, Chemoenzymatic synthesis of neuraminic acid analogs structurally varied at C-5 and C-9 as potential inhibitors of the sialidase from influenza vims, Carbohydr. Res., 280 (1996) 101-110. 

Sugar derivatives that contain double bonds have been developed and used so extensively that they almost certainly constitute the most versatile category of carbohydrate compounds available for use in synthesis. They may be applied both in the synthesis of complex members of the family and of a myriad enantiomerically pure noncarbohydrate compounds—notably, many of interest in medicinal chemistry. Furthermore, some unsaturated sugar derivatives have themselves been found to possess important therapeutic properties. For example, the unnatural L-nucleoside 1 inhibits reverse transcriptase and shows potent and selective anti-AIDS activity,1 and the unsaturated neuraminic acid analogue 2 is the sialidase-inhibitory... 

The 4 9-bis-0- and 4>8,9-tris-0-t-butyldimethyl-silylether derivatives 2J and 8 of the biologically important neuraminic acid represent useful starting points for the synthesis of the new structurally varied nonulosonic acid derivatives 2 9 (figure 3) j5C and 21 (figure 6). Opening of the oxirsne ring of 29 with Hl. j leads to the 8-d.esoxy-8-azido-neuraminic acid derivative which corresponds completely 23. 

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