Iminosugars are a family of polyhydroxylated heterocycles with an endocyclic nitrogen atom. Inhibitory activity of these compounds against a number of enzymes of medicinal interest, including glycosidases, has led to the development of iminosugars as therapeutic agents in a wide range of diseases.1 Iminosugar based peptidomimetics have been synthesised as ligands for somatostatin receptors and HIV protease. The use of iminosugars as scaffolds, compared with pyranosides, offers the possibilty of incorporating a charged hydrogen bond donor through ring protonation of the ring nitrogen atom.2
A novel route in the stereoselective preparation of iminosugar C-glycosides including the tandem allylic azide rearrangement3 – Huisgen cycloaddition as a key step has been studied. Investigations have been carried out towards the syntheses of homonojirimycin (HNJ), homomannojirimycin (HMJ) and homogalactostatin (HGJ) (Fig 1).
A summary of results with mannose derivatives is shown (Fig 2). The final step, an oxidation of the alkene to the alcohol is being investigated. The importance of a 1,2-diol constraint in promoting the 1,3-dipolar cycloaddition has been realised. Molecular dynamics has been used to rationalise the stereochemistry of the key reaction. Syntheses from ᴅ-galactose and ᴅ-glucose have also been investigated and will be presented.
(1) (a) Stütz, A. E.; Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH: New York, 1999. (b) Compain, P.; Martin, O. R.; Iminosugars: from synthesis to therapeutic applications; John Wiley and Sons, 2007.
(2) Murphy, P. V., Eur. J. Org. Chem., 2007, 4177-4178.
(3) Feldman, A. K. et. al.; J. Am. Chem. Soc. 2005, 127, 13444.
(4) Zhou, Y.; Murphy, P. V. Org. Lett. 2008, 10, 3777.
