Carbohydrates typically have low affinities to protein binding sites, and the development of carbohydrate mimetics with improved binding is therefore of interest. Tetrafluorination of monosaccharides is one of the strategies currently under investigation for that purpose. The synthesis of the required tetrafluorinated monosaccharides is achieved by a fluorinated building block approach. The enantioselective synthesis of tetrafluorinated hexose derivatives is described here, in both pyranose and furanose forms. In particular, the optimization of the enantioselective synthesis of the previously reported 2,3-dideoxy-2,2,3,3-tetrafluoro-d-threo-hexopyranose 3, 2,3-dideoxy-2,2,3,3-tetrafluoro-d-threo-hexofuranose 4, and 2,3-dideoxy-2,2,3,3-tetrafluoro-d-erythro-hexopyranose 5 is described as is the synthesis of two novel sugar derivatives, 3,4-dideoxy-3,3,4,4-tetrafluoro-d-threo-hexopyranose 6 and 3,4-dideoxy-3,3,4,4-tetrafluoro-d-erythro-hexopyranose 7. The key step of all syntheses is a perfluoroalkyl lithium-mediated C–C bond formation, either intramolecular or intermolecular, which proceeds in good to excellent yields. NMR and X-ray crystallographic analyses of the tetrafluorinated methyl pyranoside derivatives confirm their 4C1 conformation.