FULL PAPER z Achiral Cyclodextrin Analogues** Peter R. Ashton, Stuart J. Cantrill, Giuseppe Gattuso, Stephan Menzer, Sergey A. Nepogodiev, Andrew N. Shipway, J. Fraser Stoddart," and David J. Williams Abstract: zyxwvutsrqpon The synthesis of a new family of cyclodextrin (CD) analogues is described. This family consists of novel cyclic oligosaccharides built from monosaccha- rides that possess the same relative but opposite absolute (D- and L-) configura- tions. The alternation of such D- and L- residues-specifically, D- and L-rhamnose or D- and L-niannose-in a macrocyclic structure results in &-type symmetry and, consequently, optical inactivity. The syn- thesis of these cyclic oligosaccharides was achieved by an economical polycondensa- tion/cycloglycosylation approach that re- lies on an appropriately-derivatized disac- charide monomer and that avoids the time-consuming, and often low-yielding, stepwise growth of long linear oligosac- charide precursors. In the cases reported, the key precursors are the disaccharide monomers I-RR and I-MM, which bear both a glycosyl donor (cyanocthylidene function) and a glycosyl acceptor (trity- loxy group). These compounds are able to undergo Tr+-catalyzed polycondensation which, under appropriate dilution condi- tions, can be terminated by cycloglycosyl- ation. Thus, compound 1-RR was con- verted into a range of protected cyclic rhamnooligosaccharides 15- 19 in 64% overall yield. All these products. including the unique cyclic dodeca- and tetrade- casaccharides 18 and 19, have been isolat- ed by preparative HPLC. Unexpectedly, treatment of the zyxwvuts manno analogue of the Keywords carbohydrates cyclodextrin ana- logues cyclooligomerizations zyxwvu * glyco- sylations nanostructures Introduction Cyclodcxtrins (CDs), which are composed of (1 +4)-linked X-D- glucose residues, are the most well-known family of compounds in the class of cyclic oligosaccharides. They have been studied extensively['] as a result of their unique ability to form inclusion complexes with a very broad range of guest molecules. Along with CDs, a limited number of examples of naturally produced cyclic oligosaccharides are known: either they are formed as a rsJ Prof. J. F. Stoddart. Dr G. Gattoso, Dr. S. A. Nepogodiev. Dr A. N. Shipway, P. R. Ashton, zyxwvutsrqpon S. J. Cantrill School of Chemistry, Univcrsity of Birmingham Edgbaston, Birmingham, B152TT (UK) Fax: Int. code +(121)434-3531 Prof. D. J. Williamr, Dr. S. Menrer Chemical Crystallography Laboratory, Department of Chemistry, Imperial Collcgc South Kensington. London, SW72AY (UK) Fax: Int. code +(171)594-5804 [**I Part zyxwvutsrqponmlk 2 of a series on Synthetic Cyclic Oligosaccharide,. For Part 1, see: P. zyxwvuts K. Ashton. C. L. Brown, S. Mcnar. S. A. Ncpogodicv, J. F. Stoddart, D. J. Williams, zyxwvutsrqponmlkj Chrm. Eur J 1996, 2, 580~-591. disaccharide I-RR (compound I-MM) undcr the same conditions produced only the cyclic hexasaccharidc 28 and numer- ous apparently linear oligomers. Removal of the protecting groups from 16-19 af- forded the free cyclic oligosaccharides 21 - 24, which exhibited the predictcd Lcro optical rotation and very simple NMR spectra, indicating highly symmetrical structures. X-ray crystallography reveals that in the solid state the cyclooctxxide 21 possesses a C, symmetric structure, on account of a slight deformation of its cylindrical shape. The channel-type crys- tal packing of molecules of 21 forms nanotubes with an internal diameter of around 1 nm. Conversely, the cyclic hexa- saccharide 29 possesses a Ci symmetric solid-state structure and its molecules pack to form a parquct-likc superstruc- ture. result of enzymatic degradation of polysaccharides['] or they are produced by microorganisms.[31 Therefore, it appears that total chemical synthesis is the only feasible method for the produc- tion of cyclic oligosaccharides with different structural and chemical properties. The chemical synthesis of X-CD and 7-CD was a remarkable achievementL4] as it was the first successful attempt at the total synthesis of cyclic oligosaccharidcs. How- ever, CDs themselves do not represent extremely interesting synthetic targets as they can bc easily obtained from enzymatic action on a low-cost natural raw material, that is, starch. Unnat- ural cyclic oligosaccharides are obviously more attractivc syn- thetic targets, and numerous studies on the synthesis of both %-(I -4)-linked CD analogues''] and compounds with different interglycosidic linkages["] have been reported during the past decade. In order to develop a practical route to the preparation of complex cyclic oligosaccharides, we have employed a poly- condensation/cyclization approach that uses a small saccharide precursor for the synchronous preparation of a series of cyclic oligosaccharides composed of different numbers of repeating units (Figure 2). The basic structural requirement for the pre-