Interest in cationic benzimidazoles has been stimulated by the extensive use of Hoechst 33258 (1) and analogs as DNA fluorophores* 1 and by the fact that bis-benzimidazoles (e.g., 2) have potent activity against a number of microorganisms including those that lead to AIDS-related opportunistic infections.2 Both 1 and 2 bind to DNA in the minor groove at ATrich sequences.2c•3 Interest in the molecular basis for specific minor groove interactions has been stimulated by theoretical studies,4 by extensive experimental analysis including X-ray studies of complexes,3•5 and by the need to develop a broad range of ligands with DNA recognition specificity. The latter idea led to development of "lexitropsins"6 and to dimer recognition agents.7 The dimer motif recognizes a sequence-
3,4,5‐Trihydroxypiperidines represent a family of biologically active natural products, found to modulate principally the glycosidase enzymes. This is ascribed to their structural and electronic resemblance to the pyranose monosaccharides, their natural counterparts. Expedient syntheses are crucial to access these valuable high Fsp3 index drug leads. In this review we present the literature strategies to this class of iminosugars to spur further research into drug leads targeting the glycobiological machinery of living systems.
Stereoselective and biocatalysed synthetic routes to 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatisations are reviewed. These iminosugars effectively modulate glycosidase enzymes and display biological activities in immunosuppression, as anti‐inflammatory agents and as anti‐viral agents. Syntheses to these building blocks and their N‐ and O‐derivatives are predicted to produce drug leads of high Fsp3 index. This is also crucial in the collection of structure‐activity relationship data, particularly for diseases dependant on glycosidase modulation.
Short syntheses to high Fsp
3 index natural-product analogues such as iminosugars are of paramount importance in the investigation of their biological activities and reducing the use of protecting groups is an advantageous synthetic strategy. An isopropylidene group was employed towards the synthesis of seven-membered ring iminosugars and the title compound, C9H15N3O5, was crystallized as an intermediate, in which the THF ring is twisted and the dioxolane ring adopts an envelope conformation: the dihedral angle between the rings is 67.50 (13)°. In the crystal, the hydroxyl groups participate in O—H...(O,O) and O—H...N hydrogen-bonding interactions, which generate chains of molecules propagating parallel to the a-axis direction. There is a notable non-classical C—H...O hydrogen bond, which cross-links the [100] chains into (001) sheets.
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