FULL PAPER DOI: 10.1002/ejoc.200600440 Stereoselective Glycosylations Using (R)- or (S)-(Ethoxycarbonyl)benzyl Chiral Auxiliaries at C-2 of Glycopyranosyl Donors Jin-Hwan Kim, [a] Hai Yang, [a] Vishal Khot, [a] Dennis Whitfield,* [b] and Geert-Jan Boons* [a] Keywords: Carbohydrates / Glycosylation / Anomeric control / Chiral auxiliary The stereoselective introduction of a glycosidic bond pres- ents the greatest challenge to complex oligosaccharide syn- thesis. Important developments such as automated polymer- supported oligosaccharide synthesis will not realize their full potential until this problem is addressed. In this paper, a novel approach for stereoselective glycosylations is de- scribed whereby a chiral auxiliary at C-2 of a glycosyl donor controls the anomeric outcome of a glycosylation. It was found that participation of an (S)-ethoxycarbonylbenzyl aux- iliary led to the formation of 1,2-cis glycosides, probably Introduction It is now well established that protein- and lipid-bound saccharides play essential roles in many molecular processes impacting eukaryotic biology and disease. [1–3] Examples of such processes include fertilization, embryogenesis, neu- ronal development, hormone activities, the proliferation of cells and their organization into specific tissues. Remark- able changes in cell-surface carbohydrates occur with tumor progression, an event that appears to be intimately associ- ated with the dreaded state of metastasis. Furthermore, carbohydrates are capable of inducing a protective antibody response, which is a major contributor to the survival of an organism during infection. In plants, oligosaccharides have been found to control development and defense mecha- nisms. A major obstacle to advances in glycobiology is the lack of pure and structurally well-defined carbohydrates and gly- coconjugates. These compounds are often found in low con- centrations and in microheterogeneous forms, greatly com- plicating their isolation and characterization. In many cases, well-defined oligosaccharides can only be obtained by chemical synthesis. [4] [a] Complex Carbohydrate Research Center, University of Geor- gia, 315 Riverbend Road, Athens, GA 30602, USA E-mail: gjboons@ccrc.uga.edu [b] National Research Council of Canada, Institute for Biological Sciences, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada E-mail: dennis.whitfield@nrc-cnrc.gc.ca Supporting information for this article is available on the WWW under http://www.eurjoc.org or from the author. Eur. J. Org. Chem. 2006, 5007–5028 © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5007 through a trans-fused dioxolenium ion intermediate. On the other hand, the use of an auxiliary with (R) configuration gave 1,2-trans glycosides, and this glycosylation proceeds through a cis-fused dioxolenium ion intermediate. The auxil- iary could conveniently be removed by Birch reduction. Computational studies support the formation of the proposed ethoxy-carbonium ion intermediate with all pseudo-equato- rial substituents. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) The last two decades have witnessed dramatic improve- ments in the methods available for the synthesis of complex oligosaccharides. New anomeric leaving groups such as an- omeric fluorides, trichloroacetimidates, and thioglycosides have been introduced which can be prepared under mild conditions, are sufficiently stable for purification, may be stored for a considerable period of time and undergo glyco- sylations under mild conditions. These beneficial features permit the synthesis of complex oligosaccharides by highly convergent strategies in which most synthetic efforts are di- rected towards the preparation of monomeric glycosyl ac- ceptors and donors, which can be assembled into complex structures using a minimum number of synthetic steps. The synthesis of complex oligosaccharides has been further streamlined by one-pot multi-step glycosylations [5,6] and automated polymer-supported syntheses, [7–9] which reduces the need for time-consuming purification protocols. Despite these important developments, the problem re- mains that there is no general method for the preparation of complex oligosaccharides of biological importance. One of the main stumbling blocks in complex oligosaccharide synthesis is the formation of mixtures of α/β-anomers dur- ing glycosylations. Separation of these anomers requires time-consuming purification protocols resulting in loss of material. The formation of anomeric mixtures also severely limits the use of one-pot multi-step glycosylations or poly- mer-supported syntheses. Currently, the most reliable method for stereoselective glycosylations is based on neighboring-group participation by a 2-O-acyl functionality (Scheme 1, a). [10] In these reac- tions, a promoter activates an anomeric leaving group re- sulting in its departure and the formation of an oxacarben-