Towards the synthesis of a 2-deoxy-2-fluoro-d-mannose building block and characterisation of an unusual 2-S-phenyl anomeric pyridinium triflate salt via 1 → 2 S-migration

Abstract

Regio- and stereo-selective synthetic routes to 2-deoxy-2-fluoro-d-mannose building blocks are often experimentally challenging when using Selectfluor with the corresponding glycal. We targeted a late-stage method to introduce fluorine in a stereospecific manner using inversion via a triflate. Accordingly, synthesis of a conventionally protected 2-deoxy-2-fluoro-d-mannose β-thioglycoside donor, directly applicable to oligosaccharide synthesis, was attempted using C2-triflate inversion of the corresponding d-glucoside with TBAF. Unexpectedly, an anomeric pyridinium salt was isolated when attempting to form the C2-triflate using Tf₂O in pyridine. Indicatively, this proceeds via a 1 → 2 S-migration delivering a 1,2-trans product with α-d-manno configuration and the anomeric pyridinium in a pseudo-equatorial position. The structure of this unexpected intermediate was confirmed in the solid-state using X-ray crystallography. Omission of the pyridine solvent led to dimer formation. Switching the aglycone to an O-para-methoxyphenyl enabled smooth C2 inversion to the desired 2-deoxy-2-fluoro d-mannose system, suitably equipped for further anomeric manipulation.