Synthesis of Novel Iminosugar-Based Trehalase Inhibitors by Cross-MetathesisReactions

The synthesis of a novel class of trehalase inhibitors composed of iminopyranose or iminofuranose residues linked at the pseudoanomeric carbon through an alkyl chain is described. A set of six novel compounds was prepared by the same reaction sequence involving the Grubbs Ru-carbene-catalyzed cross-metathesis (CM) of different N-Cbz-protected allyl C-iminoglycosides as the key step in homo- or heterodimerization reactions. The target products, obtained with the CM reaction, were fully hydrogenated by catalytic hydrogenolysis, and preliminary biological screening of the products as inhibitors of commercially available porcine trehalase was performed. Several iminosugar-based trehalase inhibitors were synthesized by homo- and heterodimerization mediated by Grubbs Ru-carbene-catalyzed cross-metathesis reactions. Preliminary biological evaluation ofthe synthesized compounds for their inhibitory activity against commercially available porcine trehalase showed nojirimycin dimer as the most active compound, possessing a Ki value of 44 μM. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.