Glycosyl thioimidates in a highly convergent one-pot strategy for oligosaccharide synthesis Papapida Pornsuriyasak and Alexei V. Demchenko * Department of Chemistry and Biochemistry, University of Missouri––St. Louis, One University Boulevard, St. Louis, Missouri, MO 63121, USA Received 8 November 2004; accepted 16 November 2004 Available online 8 January 2005 Abstract—Application of two classes of thioimidoyl derivatives, S-benzoxazolyl (SBox) and S-thiazolyl (STaz) glycosides to selec- tive activation over thioglycosides is described. These results allowed us to synthesize a tetrasaccharide derivative using a leaving group differentiated one-pot strategy in 73% yield over three sequential glycosylation steps. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction Recent understanding of the involvement of carbohy- drate molecules and conjugates in many vital biological processes 1 and, consequently, the appreciation of their tremendous therapeutic potential 2 has stimulated the development of new methods for the synthesis of this class of compounds. The main efforts in the field of syn- thetic carbohydrate chemistry have been focused on the development of new glycosylation methodologies and convergent strategies for oligosaccharide synthesis, in which the number of synthetic and purification steps is reduced. As a result, many efficient approaches have been developed both on the solid phase 3 and in solu- tion. 4 The most efficient solution-based techniques include armed–disarmed, 5 active–latent, 6 orthogonal/ semi-orthogonal, 7,8 and one-pot strategies. 9,10 Amongst these, one-pot strategies perhaps offer the shortest path- way to oligosaccharides, as the sequential glycosylation reactions are performed in a single flask (pot) and do not require isolation and purification of the intermediates. Although many variations of the one-pot strategy have been developed, 11 there are two major concepts these protocols are based upon. The first approach is relying on the chemoselectivity principle, according to which the reactivity difference be- tween the glycosyl donor and the glycosyl acceptor is achieved by varying the electronic properties of protect- ing groups in either or in both of the reaction compo- nents. 9,10,12 It is now well known that electron- withdrawing groups deactivate (disarm) the leaving group while electron-donating moieties activate (arm) the leaving group. 13 As illustrated in Scheme 1a, this ap- proach in its conventional mode requires a set of build- ing blocks with the same type of a leaving group, the reactivity of which is differentiated by the protecting group pattern. In this context, the reactivity difference between similarly protected sugars of different series has to be also taken into consideration. For example, the reactivity ratio between per-benzylated S-(p-methyl- phenyl) glycosides of L-fuco, D-galacto, and D-gluco ser- ies was found to be 27.1/6.4/1, respectively. 10 The second concept is based on selective activation of one leaving group over another (Scheme 1b). 14 Since this 0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2004.11.029 * Corresponding author. Tel.: +1 314 516 7995; fax: +1 314 516 5342; e-mail: demchenkoa@umsl.edu O LG OP 1 O LG OH OP 2 O LG OH OP 3 O OH Oligosaccharides O LG 1 OP O LG 2 OH OP O LG 3 OH OP O OH (a) (b) O O O O O O O P - protecting group; LG - leaving group Scheme 1. Two concepts for one-pot oligosaccharide assembly: (a) chemoselective activation (reactivity is differentiated by protecting groups) and (b) selective activation (reactivity is differentiated by leaving groups). Tetrahedron: Asymmetry 16 (2005) 433–439 Tetrahedron: Asymmetry