A 3,4-trans-Fused Cyclic Protecting Group Facilitates a-Selective Catalytic Synthesis of 2-Deoxyglycosides**

A practical approach has been developed to convert glucals and rhamnals into disaccharides or glycoconjugates with high a-selectivity and yields (77–97%) using a trans-fused cyclic 3,4-O-disiloxane protecting group and TsOH·H2O (1 mol%) as a catalyst. Control of the anomeric selectivity arises from conformational locking of the intermediate oxacarbenium cation. Glucals outperform rhamnals because the C6 side-chain conformation augments the selectivity. Chiral acetals are ubiquitous in many natural products ranging from spiroketal polyketides to complex oligosaccharides with a wide range of biological activities. Deoxyhexoses are an important class of glycans which occur widely in natural products such as antibiotics and anticancer agents. Thus, it is not surprising that much research has been devoted to the development of efficient and stereoselective methodologies which can give access to this important class of chiral acetals. Herein we report a direct, practical, and stereoselective synthesis of 2-deoxyglucosides and l-rhamnosides using catalytic amounts of 4-toluenesulfonic acid monohydrate (TsOH·H2O). We show that conformational constraints induced by careful choice of protecting groups can help bias the outcome of the reaction and thus achieve high astereocontrol. Moreover, the importance of side-chain conformation is highlighted by increased selectivities with glucal as compared to rhamnal substrates. The stereoselective formation of glycosidic linkages is one of the most challenging aspects of modern oligosaccharide chemistry. With 2-deoxyglycosides, the lack of a C2 substituent, which can direct the coupling, further complicates matters and mixtures of anomers tend to be produced. Despite the development of many indirect and direct methods, the stereoselective synthesis of deoxyglucosides remains particularly difficult. As part of our ongoing interest in developing stereoselective glycosylation methods, we decided to focus our attention on the synthesis of deoxyglycosides. Recently, our team reported a mild organocatalytic method for the synthesis of 2-deoxygalactosides in excellent yields and aselectivity (Scheme 1a). Although the thiourea 1 worked well with galactals, reactions with glucals such as 5 were slower, less stereoselective, and Ferrier rearrangement sideproducts (7) were observed (Scheme 1b). These results were not completely unexpected as glycosylation reactions with glucal derivatives tend to furnish poor selectivity and reactivity, which is normally attributed to the lack of the axial C4 OH substituent on the ring, thus leading to the attack of the nucleophile from both faces of the ring. It is generally agreed that acid-catalyzed direct nucleophilic substitution on a glycal is likely to proceed via oxacarbenium ion intermediates. It has been shown that substituted tetrahydropyran oxacarbenium ions generally adopt half-chair conformations (Scheme 2). Two half-chair Scheme 1. Thiourea-catalyzed synthesis of deoxyglycosides. a) Galactal series. b) Glucal series. [*] Dr. E. I. Balmond, Dr. D. Benito-Alifonso, Prof. R. W. Alder,