Synthesis of the 4-acetamido-4-deoxy analogue of N-acetylneuraminic acid and its behaviour towards CMP-sialate synthase

✍ Scribed by Erich Zbiral; Erwin Schreiner; Rudolf Christian

• Publisher: Elsevier Science
• Year: 1989
• Tongue: English
• Weight: 206 KB
• Volume: 194
• Category: Article
• ISSN: 0008-6215
• DOI: 10.1016/0008-6215(89)85037-2

✦ Synopsis

To gain more insight into the structure-activity relationship of the enzymes of sialic acid metabolism we recently prepared a series of sialic acid analogues2-4 and determined their surface profiles 5,6. For CMP-sialate synthase to recognize its substrate, we found that the three hydrophilic functions 2-OH p, the NH of the NHAc group, and the coaxially aligned &OH group as well as both hydrophobic axial hydrogens H-4 and H-6 were necessary5,6. On the other hand, it is known that, for the recognition of a-glycosidically bound sialic acid and its release by a sialidase, the CO-group of the 5-acetamido group and the 4-OH group are required. Exchange of the latter group by hydrogen' or a methoxy groups, and the biochemical transformation into a 4-acetoxy group, prevents this cleavageq. Other structural relations concerning the a-face were studied systematically recentlylO.

The aforementioned data prompted us to propose that the 4-acetamido-4deoxy analogue of N-acetylneuraminic acid (NeuSAc) should be transformable into a CMP-derivative. In addition it should be possible to link it to glycoproteins by means of suitable transferases in similar manner to 4-O-Me-Neu5Ac8. Such artificial sialoglycoproteins would be stable not only against sialidases but also esterases, which are known to render a 4-O-acetyl-sialoglycoprotein sensitive to sialidases. The results on synthesis of the title compound are shown in the scheme.

First of all the sialic acid derivative 1 was transformed via the 4-oxo-derivative 2 into the 4-epi-sialic acid derivative' 3. Further reaction with triphenylphosphinediethylazodicarboxylate (DEAD)-3~ HN, (toluene) in THF yielded the expected compound 4 as the main product (65%) and the 3,4-didehydro sialic acid derivative 5 as a byproduct (15%)*. Hydrogenation in the presence of A%0 produced com-*Structural Variations on N-Acetylneuraminic Acid. Part 13. For part 12, see ref. 1.