A Simple and Efficient Stereoselective Synthesis of a 2,3-Difluorosialic Acid-Based Influenza Virus Neuraminidase Inhibitor

Abstract

3-Fluoroneuraminosyl fluorides are invaluable probes for studying the catalytic mechanism of sialidases (neuraminidases), and as sialidase inhibitors. Significantly, when a C-3 equatorial fluorine is installed on a C-4 functionalised N-acylneuraminic acid (Neu)-based template, the compounds are potent and selective inhibitors of both influenza and parainfluenza sialidases, and of virus replication. Typically, the reported syntheses of 3-fluoroneuraminosyl fluorides involve either an enzymatic or a chemical synthesis that have uncontrolled stereoselectivity in the introduction of fluorine at C-3 of Neu and consequently yield a mixture of C-3 ax and C-3 eq fluoro derivatives. We now report a simple approach for the exquisitely stereo-controlled introduction of the C-3 equatorial fluorine on Neu by incorporation of steric bulk at C-4. Through this method, we have elaborated a novel synthetic route that exclusively produces the potent anti-influenza drug candidate; 2,3-difluoro-zanamivir analogue with C-3 eq fluoride.