Synthesis of mannose-6-phosphate analogs: large-scale preparation of isosteric mannose-6-phosphonate via cyclic sulfate precursor

A scale-up synthesis of isosteric phosphonate analog of mannose-6-phosphate (M6P) is presented via regioselective nucleophilic displacement of the protected 4,6-cyclic sulfate precursor by dialkyl lithiomethylphosphonates in the key step. The five-step synthesis requires only simple purification procedures after each step excluding chromatography separations. The usage of proper nucleophiles makes the method also applicable for the preparation of other isosteric M6P analogs, e.g. α,β-unsaturated phosphonate, sulfonate, etc., with the potential to expand the method for analogs of other sugar-phosphates.