Stereoisomeric Imidazolo-Pentoses − Synthesis, Chiroptical Properties, and Evaluation as Glycosidase Inhibitors

Abstract

The syntheses of all four imidazolo-piperidino-pentoses in the L-series ent-2 to ent-5, and of three out of the four possible stereomers in the D-series 3, 4, and 5, are reported. The linear imidazolo sugar precursors were prepared, either by double condensation of formamidine with protected aldohexoses, or by nucleophilic addition of a lithiated imidazole derivative to protected aldotetroses. Cyclisation of these linear imidazolo-carbohydrates was performed by intramolecular S N 2 reactions. These were followed by deprotection to

Stereomeric Pyrrolidinopentoses Bearing an Imidazole Ring − Synthesis, Chiroptical Properties, and Evaluation as Potential Sugar-Mimic Glycosidase Inhibitors

“…The synthesis of this compound had already been described in a previous publication. [10] The primary alcohol of 14 was selectively silylated (TBDPSCl/imidazole/DMF) to provide 15. Walden inversion occurred at once when Tf 2 O was added to 15 in pyridine, the secondary triflate intermediate undergoing spontaneous intramolecular nucleophilic attack by the nearest imidazole nitrogen atom to give 16.…”

“…[10] The linear synthetic sequence was very similar to the one that we used for the preparation of the -xylo compound 3. The primary alcohol of 18 was selectively silylated (TBDPSCl/imidazole/DMF) to afford 19.…”

“…This diol, the synthesis of which had already been described in a previous publication, [10] was selectively silylated (TBDPSCl/imidazole/DMF) at the primary alcohol to provide 27. Intramolecular Walden inversion occurred spontaneously when Tf 2 O was added to 27 in pyridine, the intermediate secondary triflate spontaneously undergoing S N 2 attack by the nearest N atom.…”

“…The same correlation between the sign of the long-wavelength CE and the absolute configuration of carbon atom C(8) Ϫ also directly connected to the imidazole chromophore Ϫ had also been observed with the analogous and isomeric imidazolopiperidino-pentose isomers of type 30 (Scheme 6), the (8R) configuration producing a positive CE and (8S) a negative one. [10] Similarly, Vasella and co-workers published some CD data for pyrrolo-piperidino-hexose derivatives, and showed that the -manno-pyrrolo-piperidino-hexose 31, which is (8R)-configured, appeared with a pronounced positive CE, whereas its (8S)-configured -gluco diastereomer 32 appeared with a negative CE (Scheme 6). [20] Furthermore, the imidazolo-pyrrolidino-tetroses 33 (-erythro), ent-33 (-erythro), and 34 (-threo), the syntheses of which we had described previously (the -threo enantiomer Scheme 6.…”

“…[8] Tested against a dozen human liver glycosidases, ent-3 proved to be inactive as a glycosidase inhibitor. [9] Nevertheless, having previously established that some imidazolo-piperidino-pentoses of type 30 Ϫ which are structural isomers of pyrrolidino-pentose ent-3 (see below: Scheme 6) Ϫ were selective and sometimes quite potent glycosidase inhibitors, [10] we surmised that some stereomers of ent-3 might show similar inhibitory properties. This assumption turned out to be true, as demonstrated here for some of the eight possible stereomers, the syntheses of which are described below.…”