The biochemistry and synthesis of sialidase inhibitors, in particular influenza virus sialidase inhibitors, has been of great interest to us [1][2][3]. The synthesis of a number of S-acetamido-2,6-anhydro-3,5-dideoxy-o-glycero-o-galacto-non-2-enonic acid (Neu5Ac2en, 1) analogues has received considerable attention over the past decade [4][5][6]. These compounds are thought to be transition-state analogues of the enzyme reaction [1,2]. We have recently reported the design and biological evaluation of S-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-o-glycero-o-galacto-non-2enonic acid (4-amino-NeuSAc2en, 2) and 5-acetarnido-2,6-anhydro-4-guanidino-3,4,S-trideoxy-o-glycero-o-galacto-non-2-enonic acid (4-guanidino-NeuSAc2en, 3) as influenza virus sialidase inhibitors [7]. Both of these compounds, in particular 3, have been shown, not only to be potent inhibitors of influenza virus sialidase and influenza virus replication, but also of the virus in a number of animal models [7].
The synthetic strategy that we adopted for the preparation of 3 required the introduction of nitrogen at C-4 of 1. We have previously reported the preparation of 4 in good yield, and this was achieved by treatment of 1 with BF 3 β’ EtzO, followed by reaction with azide [8]. The synthesis of 3 was succesfully completed as detailed in Scheme 1. Thus, reduction of 4 was best achieved by hydrogenation at atmospheric pressure in the presence of Pd-C (10%) in toluene, methanol, and glacial acetic acid for 1 h, which afforded, following work-up and purification, methyl 5-acetamido-7,8,9-tri-O-acetyl-4-amino-2,6-anhydro-3,4,5-trideoxy-og/ycero-o-galacto-non-2-enonate (4-amino-NeuS,7,8,9Ac 42enlMe, 5) in 72% over-* Corresponding author.