SN2-type glycosylation using unprotected α-pyranose

<p>Chemical synthesis of structurally defined carbohydrates is indispensable for development of carbohydrate-related biology and therapeutics. While glycosylation reaction plays a pivotal role in carbohydrate synthesis, most of the chemical glycosylation have relied on protective-group strategy to construct properly protected and activated glycosyl donors.¹ On the other hand, we recently reported one-step β-selective glycosylation using unprotected glucose⁴under the optimized Mitsunobu conditions^2,3 (Scheme 1). Here we report that the β-selective glycosylation proceeds via S_N2 displacement of α-D-glucose, which was supported by the mechanistic experiments including ¹³C kinetic isotope effect. We were also successful to develop one-step synthesis of 1,2-cis-mannoside from α-D-mannose.</p><p>Considering the usual tendency for the Mitsunobu reaction to preferentially promote S_N2 displacement, the anomeric ratio of the starting pyranoses was checked. ¹H NMR of commercial D-glucose showed the existence of only α-anomer (Figure 1). The effects of the α/β ratio of D-glucose on the stereoselectivity of the glycosylation were examined using partially epimerized D-glucose (Table 1). A decrease in the α-anomer contents in the substrate resulted in a decrease in the β-anomer contents in the product. In addition to the above results, the experimental value of ¹³C kinetic isotope effect at the anomeric carbon (1.027, see Scheme 3)⁷ clearly showed that β-selective glycosylation of α-D-glucose would take place via loose S_N2 transition state (Scheme 4).</p><p>The mechanistic analysis suggested the stereochemistry of the glycosylation should depend only on the stereochemistry of the anomeric stereogenic center regardless of sugars. Based on the consideration, we applied the present glycosylation method to various unprotected α-pyranoses and obtained the corresponding β-glycosides with high selectivity (Scheme 5 and 6). Notably, one-step stereoselective synthesis of 1,2-cis-mannoside was successfully achieved using commercially available α-D-mannose, although stereoselective synthesis of 1,2-cis-mannosides is believed to be difficult due to both the anomeric effect and steric effect of the axial substitutent at the C2 position.</p><p>Scope of the glycosyl acceptors was investigated. Various nucleophiles with acidic proton including carboxylic acids⁵, phenols, and imides underwent glycosylation β-selectively (Figure 2). Since there are many natural products categorized as phenolic glycosides and aminoglycosides, the present method was expected to be applicable to efficient total synthesis of such natural products. The two-step synthesis of glucronide of anti-hypertensive medicine, gemefibrozil, was achieved through β-selective glycosylation and selective oxidation of the primary alcohol in the resulting β-glycoside (Scheme 7).¹²</p>