Synthesis of Highly Condensed Polycyclic Carbohydrates by Reaction of a Spirocyclic Enamino Sulfonate Derived from D-Xylofuranose with Bifunctional Reagents Alessandra Cordeiro, ² Marı ´a Luisa Jimeno, ‡ Miguel A. Maestro, § Marı ´a-Jose ´ Camarasa, ² Ernesto Quesada, ² and Ana San-Fe ´lix* ,² Instituto de Quı ´mica Me ´ dica (CSIC), Juan de la CierVa 3, 28006 Madrid, Spain, Centro de Quı ´mica Orga ´ nica “Manuel Lora Tamayo” (CSIC), Juan de la CierVa 3, 28006 Madrid, Spain, and Departamento de Quı ´mica Fundamental, Facultade de Ciencias, UniVersidade da Corun ˜ a, 15071 La Corun ˜ a, Spain anarosa@iqm.csic.es ReceiVed August 14, 2007 The appropriately substituted 5-O-tosyl derivative (1), easily prepared from 1,2-O-isopropylidene-R-D- xylofuranose, serves as a useful precursor for the preparation of highly condensed cyclic carbohydrates. The synthesis involves a first cyclization of the 5-O-tosyl sugar derivative 1 to a highly reactive cyclic enamine, which subsequently undergoes the nucleophilic attack of a bifunctional reagent X(CH 2 ) n Z in a regio- and stereospecific way. Finally, a spontaneous cyclization step allows the formation of a stereochemically defined extra ring, fused to the sugar backbone. The functionalization and size of this ring can be varied by the proper choice of the bifunctional reagent. X-ray diffraction analysis and intensive NMR studies with one of these carbohydrates were performed to highlight the strained nature of these compounds. Introduction Carbohydrates are natural products of great interest, due to their widespread occurrence, structural diversity, well-defined stereochemistry, and high functional (mostly hydroxyl) group density. These properties make this class of compounds particularly attractive as chiral scaffolds for the synthesis of naturally occurring 1 as well as carbohydrate 2 and non- carbohydrate bioactive compounds. 3-5 After the successful use of carbohydrates as scaffolds to mimic particular peptide folds 6 there has been a growing interest in these compounds as tools for the drug-discovery process. 7 More recently, solution- 8 and solid-phase libraries 9 have been generated by using carbohy- drates and carbohydrate-derived scaffolds as molecular templates to display pharmacophoric groups in well-defined spatial orientations. A potential disadvantage in the application of monosaccharide scaffolds may be their propensity, depending on the nature and spatial orientation of the substituents, to adopt more than one conformation. One possible method for the reduction of mo- lecular flexibility is the introduction of a second or even further ² Instituto de Quı ´mica Me ´dica (CSIC). ‡ Centro de Quı ´mica Orga ´nica “Manuel Lora Tamayo” (CSIC). § Universidade da Corun ˜a. (1) (a) Hanessian, S. In Total Synthesis of Natural Products; The “Chiron” approach; Organic Chemistry Series; Pergamon: Oxford, UK, 1983; Vol. 3. (b) For a review see: Nicolau, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576. (2) (a) Sears, P.; Mitchell, H. J. Angew. Chem., Int. Ed. 1999, 38, 2300. (b) Cipolla, L.; Peri, F.; Ferla, B. L.; Redaelli, C.; Nicotra, F. Curr. Org. Synth. 2005, 2, 153. (3) Nicolau, K. C.; Trujillo, J. I.; Chibale, K. Tetrahedron 1997, 53, 8751. (4) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. ReV. 2002, 102, 491. (5) Chakraborty, T. K.; Srinivasu, P.; Tapadar, S.; Mohan, B. K. J. Chem. Sci. 2004, 116, 187. 10.1021/jo701775a CCC: $37.00 © 2007 American Chemical Society J. Org. Chem. 2007, 72, 9713-9721 9713 Published on Web 11/14/2007