Zanamivir, analogues synthesis

Scheme 13 Application to the synthesis of of zanamivir analogues 46 and 49 and 2,3-unsaturated sialic acid 45 and 46.

Andrews DM, Cherry PC, Humber DC, Jones PS, Keeling SP, Martin PE, Shaw CD, Swanson S (1999) Synthesis and influenza virus siahdase inhibitory activity of analogues of 4-guanidino-Neu5Ac2en (Zanamivir) modified in the glycerol side-chain. Eur J Med Chem 34 563-574... 

The discovery, in the early 1990s, that zanamivir was a potent and selective inhibitor of influenza virus sialidase prompted several researchers to investigate the synthesis of Neu5Ac2en based analogues of zanamivir. Much of this effort was a consequence of the fact that zanamivir (12) must be administered as a nasal spray, due to its poor oral bioavailability and rapid excretion [101,102], and the desire to identify new sialidase inhibitors with modified physicochemical properties. Several researchers have described structure-activity relationship studies based on zanamivir (vide infra), with most modifications reported at C-4, C-5, and the glycerol side-chain. 

Scheme 12 Completion of the synthesis of zanamivir and 2,3-unsaturated sialic acid (Neu5Ac2en) analogues. Reagents and conditions a) Me3SiN3 (1.5 equiv), t-BuOH, 90 °C, 13 h 96% b) i) ln(0) (2 equiv), NH4CI, EtOH, 80 °C, 12 h ii) LiOH, THE, rt, 2 h 90% for the 2 steps c) aminoiminomethanesulfonic acid, K2CO3, water, 77% d) LiOH (2 equiv), THE, rt, 2 h 90%.

---