Abstract
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 (4)C1 conformation.
Highlights
The pronounced hydrophilicity of carbohydrates is an inherent significant contributor to the typically low affinity found for protein−carbohydrate interactions.[1]
The step is the formylation of the remaining hydroxyl group in 22. This was previously achieved using diisopropyl carbodiimide (DIC) and formic acid in the presence of dimethylaminopyridine (DMAP), we serendipitously found that the use of a Vilsmeier−Haack-type reagent led to superior results
It has been shown that the intramolecular tetrafluoroalkylidene lithium addition to ester groups is a suitable method for the synthesis of tetrafluorinated monosaccharides, even on a large scale
Summary
The pronounced hydrophilicity of carbohydrates is an inherent significant contributor to the typically low affinity found for protein−carbohydrate interactions.[1]. While the isomerization of 49 to give 54 was reported to be complete in 3 h at −78 °C, it is interesting to observe that the anionic cyclization step starting from 46 as described above (Scheme 6), which took 4.5 h at temperatures up to −60 °C, only led to the formation of 48 in 11% yield. Supporting Information) shows that hydrogen bonding of the alcohol groups with oxygen-containing groups is maximized, an effect which presumably determines the anomeric configuration of the hemiacetals:[20] the benzyl ether 58 crystallizes as the αanomer, while 88 and 77 are obtained as the β-anomer Both unprotected 3,3,4,4-tetrafluorinated sugar derivatives 6 and 7 proved to be crystalline (Figure 4), and crystallization was achieved from hexane/acetone.
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