Thermal effect in b-selective glycosylation reactions using glycosyl iodides Mohamed H. El-Badry and Jacquelyn Gervay-Hague * Department of Chemistry, University of California, Davis, CA 95616, USA Received 8 July 2005; revised 18 July 2005; accepted 25 July 2005 Available online 15 August 2005 Abstract—The unique reactivity of glycosyl iodides and the fact that they react under neutral conditions makes them the donors of choice in our glycosylation strategies. Glycosyl iodides are generated in situ from either the anomeric acetate or the anomeric sily- lated derivative yielding the a-iodide. In the reported glycosylation reactions, protected glucosyl, galactosyl, and mannosyl iodides were reacted with trimethylene oxide as the acceptor, yielding the b-anomer as the major product. In the absence of neighboring group participation, b-selectivity is thought to arise from nucleophilic displacement of the a-iodide in an S N 2-like mechanism, while the a-product is the result of nucleophilic attack on the b-iodide. In this study, increased b-selectivity using an inverse thermal effect is demonstrated. Ó 2005 Elsevier Ltd. All rights reserved. Recent studies in our laboratory have shown the unique reactivity and selectivity of oxacyclic ethers as acceptors in glycosylation reactions with glycosyl iodides. 1 Highly strained cyclic ethers 2 such as trimethylene oxide proved especially useful due to symmetrical ring opening upon exposure to the iodide. b-Selectivity is believed to arise from an S N 2-like displacement of the a-iodide (1) by acceptor (2) leading to the formation of the b-oxonium ion (3), which is susceptible to ring opening by the iodide to yield the b-glycoside (4)(Fig. 1). While we were able to achieve as high as 8:1 b-selectiv- ity, a-glycoside (7) formation could not be avoided. Our current hypothesis is that a-glycosidation occurs from a combination of ring opening of the a-oxonium ion (6) resulting from addition to oxonium intermediate (5) and from nucleophilic displacement of the b-glycosyl iodide (8) generated from in situ anomerization (Fig. 2). We reasoned that lower reaction temperatures would suppress the formation of 5, 3 and since at the onset of the reaction the concentration of iodide anion is low, the combination of these two factors would lead to increased b-selectivity. Thus we initiated the current study on the thermal effect of b-glycosidation using glycosyl iodides. Glycosyl iodides 4 are quantitatively generated from either the anomeric acetate or the anomeric silylated derivative by treatment with TMSI. 5 The side product of the acetate reaction is TMSOAc, which is capable of reforming the glycosyl acetate. This problem may be overcome by azeotroping the iodide with toluene 6 or by introducing MgO as an effective trap. 1 A typical experimental example is the galactosylation of 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.07.129 Keywords: Glycosyl iodide; b-Selective glycosidation. * Corresponding author. Tel.: +1 5307549577; fax: +1 5307528995; e-mail: gervay@chem.ucdavis.edu O n(RO) I O .. O n(RO) O + O n(RO) 1 2 3 4 I _ O I RO RO RO 3 Figure 1. Mechanism of b-glycoside formation. O n(RO) I O .. O n(RO) O + I _ O n(RO) O I 8 6 7 5 O n(RO) I 1 .. I _ O RO O + I _ .. RO RO RO 6 RO RO Figure 2. Mechanism of a-glycoside formation. Tetrahedron Letters 46 (2005) 6727–6728 Tetrahedron Letters