Synthesis and L-fucosidase inhibitory potency of a cyclic sugar imine and its pyrrolidine analogue Jean-Bernard Behr a, * , Morwenna S. M. Pearson a , Claudia Bello b , Pierre Vogel b , Richard Plantier-Royon a a Institut de Chimie Moléculaire de Reims, UMR 6229, UFR Sciences—CNRS, BP 1039, 51687 Reims Cedex 2, France b Laboratoire de Glycochimie et Synthèse Asymétrique, Ecole Polytechnique Fédérale de Lausanne (EPFL), BCH CH-1015 Lausanne, Switzerland article info Article history: Received 11 June 2008 Accepted 16 June 2008 Available online 16 July 2008 abstract The synthesis of a fully deprotected ketimine-type iminosugar is reported, starting from commercial D-mannose diacetonide. An appropriate solvent system was critical for the success of the key tandem addition/cyclization reaction. Reduction of the imine was also achieved to yield the corresponding pyrrolidine in a stereoselective manner. The cyclic sugar imine displayed modest fucosidase inhibitory activity when compared to the saturated analogue. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Glycosidases are involved in a wide range of biochemical trans- formations, such as digestion, lysosomal catabolism of polysaccha- rides and glycoconjugates or biosynthesis of glycoproteins and glycolipids. 1 Hence, the control of these processes by specific inhibitors in vivo is of great therapeutic interest. Iminosugars are an important class of glycosidase inhibitors that have attracted considerable attention as antidiabetics, as well as anticancer or anti-infective agents. 2 The strong affinity of iminosugars for glyco- sidases is generally attributed to a structural analogy with the oxocarbenium-like transition state involved in the enzymatic reac- tion. 3 As a part of our search for potent a-L-fucosidase inhibitors, we have recently introduced the spirocyclopropyl moiety in the structures of fucose-derived iminosugars to flatten the heterocyclic ring in the proximity of the nitrogen atom to mimic the distorted half-chair conformation of the fucosyl cation (Fig. 1). 4 Promising results were obtained with pyrrolidine 1, which displayed potent inhibition of a-L-fucosidase (K i = 1.6 lM). 5 Another chemical motif might force the structures of iminosugars into the required conformation, that is, the C@N unsaturation as found in cyclic sugar imines. 6 Continuing our interest in more varied a-L-fucosi- dase inhibitors, we herein report the rapid synthesis of such an unsaturated iminosugar (compound 2) and its hydrogenated ana- logue 3, structurally related to the potent inhibitor 1. The compar- ison of their inhibitory potencies will provide a first set of SAR studies. 2. Results and discussion Despite their resemblance to the putative transition state of glycosidases, only a few, fully deprotected sugar ketimines have been reported in the literature and assayed against glycosidases. 6f We have recently described a general approach to polyhydroxy- pyrrolines, which was based on the tandem addition/cyclization reaction of Grignard reagents to the easily available x-methane- sulfonyl-glycononitriles. 7 We wished to apply this methodology to the synthesis of the fucose-configured pyrroline 2. In this regard, the addition of MeMgBr to the mannononitrile 4 might afford an intermediate imide salt 5a that could undergo an intra- molecular nucleophilic displacement to give the target ketimine 6 (Scheme 1). The starting mannononitrile mesylester 4 was obtained from commercially available D-mannose diacetonide by reaction with hydroxylamine and subsequent treatment with an excess of meth- anesulfonyl chloride, as reported earlier. 5 Our initial attempts were focused on bringing about the addition/cyclization reaction in the optimized conditions from the literature. 7 Nevertheless, when glycononitrile 4 was treated with 1.5 equiv of MeMgBr in toluene 0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2008.06.019 * Corresponding author. E-mail address: jb.behr@univ-reims.fr (J.-B. Behr). NH HO OH 1 (K i = 1.6 μM) O HO OH OH N HO OH 2 NH HO OH OH OH 3 H H H OH OH OH OH Fucosyl cation Figure 1. Structures of compounds 1–3. Tetrahedron: Asymmetry 19 (2008) 1829–1832 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy