Glycosylations promoted by triflate-generating reagents are widespread synthetic methods for the construction of glycosidic scaffolds and glycoconjugates of biological and chemical interest. These processes are thought to proceed with the participation of a plethora of activated high energy intermediates such as the α- and β-glycosyl triflates, or even increasingly unstable glycosyl oxocarbenium-like species, among which only α-glycosyl triflates have been well characterized under representative reaction conditions. Interestingly, the remaining less accessible intermediates, yet to be experimentally described, seem to be particularly relevant in α-selective processes, involving weak acceptors. Herein, we report a detailed analysis of several paradigmatic and illustrative examples of such reactions, employing a combination of chemical, NMR, kinetic and theoretical approaches, culminating in the unprecedented detection and quantification of the true β-glycosyl triflate intermediates within activated donor mixtures. This achievement was further employed as a stepping-stone for the characterization of the triflate anomerization dynamics, which along with the acceptor substitutions, govern the stereochemical outcome of the reaction. The obtained data conclusively show that, even for highly dissociative reactions involving β-CIP species, the formation of the α-glycoside is necessarily preceded by a bimolecular α→β triflate interconversion, which under certain circumstances does become the rate-limiting step. Overall, our results rule out the prevalence of the Curtin-Hammett fast-exchange assumption for most glycosylations and highlight the distinct reactivity properties of α- and β- glycosyl triflates against neutral and anionic acceptors.

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剖析异头 β-三氟甲磺酸酯在糖基化反应中的重要作用

由三氟甲磺酸酯生成试剂促进的糖基化是构建具有生物学和化学意义的糖苷支架和糖缀合物的广泛合成方法。这些过程被认为是在大量活化的高能中间体的参与下进行的，例如 α- 和 β- 糖基三氟甲磺酸盐，甚至越来越不稳定的糖基氧代碳鎓类物质，其中只有 α-糖基三氟甲磺酸盐已被很好地表征代表性的反应条件。有趣的是，剩余的不易获得的中间体，尚未通过实验描述，似乎与 α 选择性过程特别相关，涉及弱受体。在此，我们报告了对此类反应的几个典型和说明性示例的详细分析，结合了化学、核磁共振、动力学和理论方法，最终实现了对活化供体混合物中真正的 β-糖基三氟甲磺酸酯中间体的前所未有的检测和定量。这一成就进一步被用作表征三氟甲磺酸酯异构化动力学的垫脚石，与受体取代一起控制反应的立体化学结果。获得的数据最终表明，即使对于涉及 β-CIP 物种的高度解离反应，α-糖苷的形成也必须先于双分子 α→β 三氟甲磺酸酯相互转化，这在某些情况下确实成为限速步骤。全面的，