Building Multivalent Iminosugar-Based Ligands on Calixarene Cores via Nitrone Cycloadditions Francesca Cardona, ‡ Giovanni Isoldi, ‡ Francesco Sansone, † Alessandro Casnati,* ,† and Andrea Goti* ,‡ ‡ Dipartimento di Chimica “Ugo Schiff”, Polo Scientifico e Tecnologico, Universita ̀ di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy † Dipartimento di Chimica Organica e Industriale, Universita ̀ degli Studi, Parco Area delle Scienze 17/A, 43124 Parma, Italy * S Supporting Information ABSTRACT: A novel and challenging approach for the construction of multivalent iminosugar architectures directly on calixarene scaffolds is presented, which exploits multiple cycloaddition reactions of a carbohydrate-derived nitrone on diversely functionalized calix[4]arenes. Regardless of the 4-fold reiteration on a single calixarene, the reactions take place with high regio- and stereoselectivity, demonstrating this method as an appealing one for the synthesis of calixarene-based neoglycoconjugates. ■ INTRODUCTION Carbohydrate-lectin interactions are intensively investigated as they play a pivotal role in a host of biological events. Monovalent carbohydrates typically bind to their lectin receptors with low affinity. 1 Nature has circumvented this tight binding limitation by exposing sugar residues in a multivalent fashion at the surface of cells. This multivalent or cluster glycoside effect is the affinity enhancement obtained with multivalent ligands compared to their monovalent counterparts, which is greater than predicted from the sum of every single saccharide-receptor recognition event. 2 On this basis, hundreds of multivalent glycomimetics have been synthesized for studying carbohydrate-lectin interactions. 3,4 Conversely, the concept of multivalency has remained essentially unexplored concerning specific glycosidase inhib- ition using iminosugars as glycomimetics. The different nature of the enzyme receptors involved, which usually have a single and deep active site and therefore do not appear prone to accept multivalent substrates, reasonably accounts for the paucity of studies on this subject. However, although a strong multivalent or cluster effect is generally associated with the interaction of receptors bearing multiple recognition sites with multivalent sugar ligands, significant affinity enhancements have also been observed for systems where the receptors possess a single binding site. In this case, an “intrinsic” multivalent effect associated with local concentration effects may be producti- ve. 2c,5 Early attempts to use multivalent iminosugar inhibitors were not encouraging, 6 apart from the results reported with a trivalent derivative of 1-deoxynojirimycin, which showed a 6- fold affinity enhancement toward jack bean-α-mannosidase. 7 Conversely, dramatic enhancement effects were reported more recently for a fullerene decorated with 12 iminosugar residues (up to 2150-fold) 8 and for a series of cyclodextrins conjugated with 7 and 14 iminosugars (up to 4 orders of magnitude). 9,10 These results demonstrated that the use of multivalent ligands can be applied, beyond carbohydrate-lectin recognition processes, to glycomimetic-enzyme inhibition for modulating the activity as well as the selectivity in the design of more potent glycosidase inhibitors from iminosugars, a class of compounds with several therapeutic applications. 11 Following these findings, we wish to report here our results on the synthesis of novel enantiopure iminosugars linked to calix[4]arenes via highly selective 1,3-dipolar cycloaddition reactions of enantiopure cyclic nitrones to calix[4]arenes functionalized at the upper or the lower rim. ■ RESULTS AND DISCUSSION Multiple glycosylations of calix[4]arene platforms to give glycoclusters have been extensively investigated in recent years. 12,13 Concerning the synthetic strategies adopted, they usually involve conjugation of a preformed sugar moiety to the calixarene scaffold through suitable linkers. In contrast, our approach to iminosugar decorated calixarenes is particularly innovative and challenging, regarding the direct construction of nascent iminosugars on the calixarene skeleton. Thus, an intriguing selectivity issue arises: several novel stereogenic centers are created in the same key step when the iminosugar moieties are generated on the calixarene. For the success of this strategy, availability of a highly selective reaction for formation of the iminosugars was essential in order to avoid complex Received: June 10, 2012 Article pubs.acs.org/joc © XXXX American Chemical Society A dx.doi.org/10.1021/jo301155p | J. Org. Chem. XXXX, XXX, XXX-XXX