ABSTRACT
Capitalizing on a previously developed Staudinger/azaWittig/Grignard (SAWG)-ring contraction sequence that furnished protected six-membered L-iminosugar C,C-glycosides bearing an allyl group and various substituents at the pseudoanomeric position, the synthesis and glycosidase inhibition of a small library of six- and seven-membered L-iminosugar C,C-glycosides is reported. Their hydrogenolysis or cyclization by RCM followed by deprotection afforded eleven L-iminosugars including spirocyclic derivatives. All compounds adopt a 1C4 conformation in solution according to NMR data. Compared to previously reported branched L-iminosugars, the L-iminosugar C,C-glycosides reported herein were less potent glycosidase inhibitors. However, some of these compounds showed micromolar inhibition of human lysosome ß-glucocerebrosidase suggesting that such iminosugars could be useful to access potent CGase inhibitors by adjusting the structure/length of the pseudoanomeric substituents.
Subject(s)
Enzyme Inhibitors , Imino Sugars , Humans , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Imino Sugars/pharmacology , Imino Sugars/chemistry , Glycosides/pharmacology , Glycoside Hydrolases/chemistryABSTRACT
We report the synthesis of iminosugar C,C-glycosides starting from 6-azidoketopyranoses. Their Staudinger-azaWittig-mediated cyclization provided bicyclic N,O-acetals, which were stereoselectively opened with AllMgBr to afford ß-hydroxyazepanes with a quaternary carbon α to the nitrogen. Their ring contraction via a ß-aminoalcohol rearrangement produced the six-membered l-iminosugars with two functional handles at the pseudoanomeric position. Inversion of the free OH at the azepane level furnished the d-iminosugars.
