Synthesis of New Sialidase Inhibitors, 6‐Amino‐6‐Deoxysialic Acids

The synthesis of the 6‐amino‐6‐deoxysialic‐acid analogues 4, 5, and 6, is described. Mitsunobu reaction of the 1‐C‐nitroglycal 8, (PPh3, HCOOH, DEAD) gave the formiate 10 with inversion of configuration at C(3) (Scheme 2). Treatment of 10 with aq. NH3 and subsequent protection of the amino function gave the imines 14 and 15 (Scheme 3), which were transformed into the triflates 17. Substitution by azide, deprotection, and N‐acetylation gave the anormeric 2‐acetamido‐3‐azido‐1‐deoxy‐1‐nitro‐D‐mannoses 16 and the enol ether 18. Chain elongation of the nitro azides 16 followed by hydroylsis gave the nonulosonates 20/22, which upon reduction yielded the diols 23 and 24, respectively (Scheme 4). The diol 23 was transformed into the sialic‐acid analogues 5, 6, and 32 by ozonolysis, transfer hydrogenation, hydorgenolysis, and deprotection (Scheme 5), and the diol 24 into 4 by a similar reaction sequence. The sialic‐acid analogues 4 and 6 inhibit bacterial and viral sialidases competitively. The inbibitor constants for this enzyme from Vibrio cholerae are 0.12 mm for 4 and 0.19 mm for 6, respectively. The activity of fowl plague virus sialidase was reduced by 17% and 36% under the influence of 4 and 6, respectively, at a concentration of 0.1 mM. Compound 5 was inactive.