Synthesis and biological evaluation of ether bridged bicyclic iminosugar derivatives
Introduction
N-Alkylated iminosugars have been clinically applied as potent glycosidase inhibitors for the treatment of diabetes and glycosidase-deficiency diseases.1 For example, N-hydroxyethyl 1-deoxynojirimycin (Miglitol)2 and N-butyl 1-deoxynojirimycin (Miglustat)3 have been used in the treatment of type II diabetes and type I Gaucher’s disease, respectively. Previous studies suggest that even better selectivity of inhibition may be achieved by modification of the iminosugars, including alteration of the alkyl chain length, saturation, hydroxylation, and ring hydroxyl residues.4, 5 Recently, researchers have focused considerable effort on the preparation of bicyclic iminosugars6, 7, 8 and bridge bicyclic iminosugar derivatives9, 10 for glycosidase inhibition.
The N-substituted derivatives of 8-oxa-3-azabicyclo-[3,2,1]octanes 1 and 2 are types of an ether bridged bicycle azasugar, and they exhibit analgesic and anti-inflammatory activities in mice and rats.11, 12, 13, 14 In addition, [2,2,2]-bicyclic iminosugar analogue 3, which lacks both the 2- and 6-hydroxyl groups, shows weak inhibition of several glycosidase enzymes.15 Fuentes and co-workers synthesized related derivatives of ether bridged bicyclic iminosugars 4,16 prompting us to synthesize other ether bridged bicyclic iminosugar analogues for the current study. Recently, we described the preparation of N-alkylated iminosugar derivatives.17 Now, we report the syntheses of various ether bridged bicyclic iminosugars (5a, 5b, 6a,6b, and 22) and their biological evaluation.
Section snippets
Results and discussion
The synthetic route to the ether bridged bicyclic iminosugars 5a and 5b started with the conversion of C-glycoside 78 to azido-C-glycoside 8 by mesylation and azido substitution (Scheme 1).18 Compound 8 was further converted to an amine by hydrogenation and subsequently treated with base to promote intramolecular amidation between the amino group and the ester. This process produced ether bridged bicyclic iminosugar 9 (63%) as a major product, together with aza-C-glycoside 1017 (35%). An allyl
General methods
All reagents were obtained from commercial suppliers and were used without further purification. DCM was distilled over CaH2. CH3OH was distilled over magnesium and iodine. Analytical thin-layer chromatography was performed using Silica Gel 60 F254 plates (Merck). The 1H and 13C NMR spectra were recorded with Bruker AM 300 (300 MHz) spectrometers. Chemical shifts are expressed in ppm with residual CHCl3 or CD3OD as reference. Low- and high-resolution mass spectra were recorded under fast atom
Acknowledgment
This work was supported by the National Science Council of Taiwan.
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