Synthesis of fluoro- and seleno-containing d-lactose and d-galactose analogues

Abstract

Synthetic deoxy-fluoro-carbohydrate derivatives and seleno-sugars are useful tools in protein–carbohydrate interaction studies using nuclear magnetic resonance spectroscopy because of the presence of the ¹⁹F and ⁷⁷Se reporter nuclei. Seven saccharides containing both these atoms have been synthesized, three monosaccharides, methyl 6-deoxy-6-fluoro-1-seleno-β-D-galactopyranoside (1) and methyl 2-deoxy-2-fluoro-1-seleno-α/β-D-galactopyranoside (2α and 2β), and four disaccharides, methyl 4-O-(β-D-galactopyranosyl)-2-deoxy-2-fluoro-1-seleno-β-D-glucopyranoside (3), methyl 4-Se-(β-D-galactopyranosyl)-2-deoxy-2-fluoro-4-seleno-β-D-glucopyranoside (4), and methyl 4-Se-(2-deoxy-2-fluoro-α/β-D-galactopyranosyl)-4-seleno-β-D-glucopyranoside (5α and 5β), the three latter compounds with an interglycosidic selenium atom. Selenoglycosides 1 and 3 were obtained from the corresponding bromo sugar by treatment with dimethyl selenide and a reducing agent, while compounds 2α/2β, 4, and 5α/5β were synthesized by the coupling of a D-galactosyl selenolate, obtained in situ from the corresponding isoselenouronium salt, with either methyl iodide or a 4-O-trifluoromethanesulfonyl D-galactosyl moiety. While benzyl ether protecting groups were found to be incompatible with the selenide linkage during deprotection, a change to acetyl esters afforded 4 in a 17% overall yield and over 9 steps from peracetylated D-galactosyl bromide. The synthesis of 5 was performed similarly, but the 2-fluoro substituent led to reduced stereoselectivity in the formation of the isoselenouronium salt (α/β ∼ 1 : 2.3). However, the β-anomer of the uronium salt could be obtained almost pure (∼98%) by precipitation from the reaction mixture. The following displacement reaction occurred without anomerisation, affording, after deacetylation, pure 5β.