Synthesis of Cluster N-Glycosides Based on a b-Cyclodextrin Core Juan J. García-Lo  pez, [b] Francisco Santoyo-Gonza  lez,* [a] Antonio Vargas-Berenguel,* [b] and Juan J. Gime  nez-Martínez [b] Abstract: A convenient method for the synthesis of b-d-gluco-, b-d-galacto-, 2-acetamido-2-deoxy-b-d-gluco- and a- d-mannopyranosylamine clusters based on cyclomaltoheptaose (b-cyclodextrin) is presented. The synthesis involves: 1) the one-pot synthesis of the acety- lated chloroacetyl N-glycoside deriva- tives of d-glucose, d-galactose, 2-acet- amido-2-deoxy-d-glucose and d-man- nose from the corresponding glycosyl azides, 2) conversion of the chloroacetyl N-glycosides into their isothiouronium derivatives, then 3) attachment of the N- glycosides onto heptakis(6-deoxy-6-io- do) and heptakis(6-chloroacetamido-6- deoxy) b-cyclodextrin by means of nu- cleophilic displacement with caesium carbonate in dimethylformamide, and 4) de-O-acetylation of b-cyclodextrin derivatives. The chloroacetyl N-glyco- side derivatives were easily prepared by mild reduction of the azide function by one of two methods: a) by the Stauding- er reaction, with nBu 3 P, and b) with 1,3- propanedithiol, as reducing reagents. Keywords: carbohydrates ´ cluster glycosides ´ cyclodextrins ´ glycosyl- amines ´ Staudinger reaction Introduction The construction of systems that can selectively deliver bioactive molecules to their sites of action within the organism is currently a challenge in therapeutics. In this respect, much effort has been focused on exploitation of the host-guest properties of certain molecules such as cyclodextrins. [1±3] The cyclodextrins (CDs) are cyclomaltooligosaccharides with six (a-CD), seven (b-CD) and eight (g-CD) a-(1 !4)-d-gluco- pyranosyl units, respectively, that are formed during the enzymatic degradation of starch. [1, 2] Most applications of CDs are based on their ability to include spatially compatible molecules (guest molecules) in their hydrophobic cavity to yield inclusion complexes [3] without formation of any covalent bonds. This supramolecular property can be used for the solubilization, encapsulation and transport of bioactive mol- ecules by CDs and their derivatives. [4] Nevertheless, CD ± drug inclusion complexes exhibit very poor target specificity owing to the lack of biologically recognizable sites. Several research- ers are addressing this problem using CDs conjugated with target molecules with promising results, for example, increas- es in both water solubility and recognition properties of the carrier systems. [5] Oligosaccharides are known to play important roles in many biological events, for example as cell-surface receptors which enable adhesion of bacteria, parasites, and viruses in the early stages of infection. [6] Therefore, carbohydrates involved in recognition processes are good candidates for targetting molecules. However, unlike protein ± protein inter- actions, carbohydrate ± protein interactions usually have low dissociation constants. [7] An effective means to increase binding interactions between carbohydrates and proteins is the use of clusters of carbohydrates. [8] With the aim of achieving much stronger affinity between receptors and saccharides, several authors have reported the synthesis of multivalent glycoconjugates on scaffolds of polymers and oligomers, [9±10] dendrimers, [10±13] calix[4]arenes, [14] crown ethers, [15] surfactant aggregates, [16] and metal complexes. [17] The well-defined torus-shaped structures of CDs provide a versatile scaffold for the construction of branched structures of bioactive molecules. In our research project we intend to combine the scaffolding potential of the CDs for building multivalent or dendrimerlike molecules with their host ± guest properties, in order to develop drug carrier systems. Previ- ously we have reported the synthesis of a variety of persubstituted b-CD derivatives branched with O- and S- glycosides and their recognition studies towards cell-wall specific lectins. [18] [a] Dr. F. Santoyo-Gonza Âlez Instituto de Biotecnología, Facultad de Ciencias Universidad de Granada E-18071 Granada (Spain) Fax: ( 34) 958-243186 E-mail: fsantoyo@goliat.ugr.es [b] Dr. A. Vargas-Berenguel, J.J. García-Lo  pez, Dr. J. J. Gime  nez-Martínez A  rea de Química Orga  nica, Universidad de Almería E-04120 Almería (Spain) Fax: ( 34) 950-215481 E-mail: avargas@ualm.es Supporting information for this article is available on the WWW under http://www.wiley-vch.de/home/chemistry/ or from the author. FULL PAPER Chem. Eur. J. 1999, 5, No. 6  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999 0947-6539/99/0506-1775 $ 17.50+.50/0 1775