Stereoselective synthesis of a-glucosides from 3-O-propargyl protected glucal exploiting the alkynophilicity of AuCl 3 Sudhir Kashyap and Srinivas Hotha * Division of Organic Chemistry: Synthesis, Combi Chem—Bio Resource Center, National Chemical Laboratory, Pune 411 008, India Received 23 November 2005; revised 20 December 2005; accepted 12 January 2006 Available online 3 February 2006 Abstract—The stereoselective synthesis of 2,3-unsaturated a-D-glucosides by the S N 2 0 addition of diverse aglycones onto 4,6-di-O- benzyl-3-O-propargyl glucal was achieved using a catalytic quantity of AuCl 3 . The Au catalyzed reaction was explored using various aliphatic, aromatic, alicyclic and monosaccharide aglycones. The current protocol tolerates diverse functional groups and is highly stereoselective, fast, catalytic and mild. Ó 2006 Elsevier Ltd. All rights reserved. Glycals are excellent templates for initiating diversity oriented synthesis 1 to achieve stereochemically pure compound libraries possessing unique structural archi- tecture and complexity. 2 One type of important chiral intermediate that can be obtained from glycals is 2,3-unsaturated glycosides. Various natural products, 3 glycopeptides, 4 natural product-like compounds, 2b modified carbohydrate derivatives, 5 nucleosides and oligosaccharides 6 were synthesized involving 2,3-unsatu- rated glycosides as key intermediates. The 2,3-olefinic group in the pyran rings can be diversified by a number of complexity generating reactions such as asymmetric dihydroxylation, amino hydroxylation, hydrogenation and epoxidation in order to achieve structural diversity. 7 2,3-Unsaturated glycosides are routinely synthesized via S N 2 0 addition of alcohols onto per-O-acetylated glycal in the presence of a Lewis acid, a process known as the Ferrier reaction. 8 In our programme 2b,8c,9 directed towards the develop- ment of diversity oriented synthesis of oxygen-rich chemical scaffolds, we considered performing alkoxycyc- lization 10 on 3-O-propargyl bearing glucal 1 by chemo- selective activation of the terminal alkyne exploiting the alkynophilicity of Au to afford scaffold 2 (Fig. 1). 11 We disclose in this letter our observations which demonstrated that a Ferrier-like reaction takes place even with a propargyl group in the C-3 position of the glucal. To begin our investigation, the easily accessible glucal 3 was converted to 4,6-di-O-benzyl glucal 4 12 which was then transformed to the corresponding 3-O-propargyl derivative 5 using NaH/propargyl bromide/n-Bu 4 NI in 90% yield (Scheme 1). Subsequently, an acetonitrile solution of 5 was treated with 3 mol % AuCl 3 in aceto- nitrile in the presence of methanol at 80 °C for 4 h. Surprisingly, we found that the reaction did not result in the formation of any alkoxycyclized product but instead the S N 2 0 addition product 6a in 38% yield with 50% recovery of the starting material 5. In the 1 H NMR spec- trum of the product of the Au-mediated reaction, reso- nances due to the olefin moiety were observed between d 5.62 and 6.10 ppm and the methoxy group was identi- fied at d 3.44 ppm as a sharp singlet. Furthermore, the 13 C NMR spectrum showed that the olefinic carbons were at d 126.5 and 130.8 ppm and the anomeric carbon was evident at d 95.7 ppm. However, the DEPT NMR spectrum revealed that there was no methylene group in the olefinic region which confirmed that the resultant product was the 2,3-unsaturated methyl glucoside 6a. 13,8c Mechanistically, the alkynophilic Au 3+ activated the triple bond to make the propargyl moiety a leaving 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.01.048 * Corresponding author. Tel.: +91 20 2590 2401; fax: +91 20 2589 3153; e-mail: s.hotha@ncl.res.in O O RO Au 3+ O RO O Nu Nu 1 2 Figure 1. Au-mediated alkoxycyclization. Tetrahedron Letters 47 (2006) 2021–2023