Department of Chemistry, University of California, Davis , One Shields Avenue, Davis, California 95616, United States.
J Org Chem. 2014 Feb 21;79(4):1736-48. doi: 10.1021/jo402736g. Epub 2014 Feb 7.
Carbohydrates mediate a wide range of biological processes, and understanding these events and how they might be influenced is a complex undertaking that requires access to pure glycoconjugates. The isolation of sufficient quantities of carbohydrates and glycolipids from biological samples remains a significant challenge that has redirected efforts toward chemical synthesis. However, progress toward complex glycoconjugate total synthesis has been slowed by the need for multiple protection and deprotection steps owing to the large number of similarly reactive hydroxyls in carbohydrates. Two methodologies, regioselective silyl exchange technology (ReSET) and glycosyl iodide glycosylation have now been integrated to streamline the synthesis of the globo series trisaccharides (globotriaose and isoglobotriaose) and α-lactosylceramide (α-LacCer). These glycoconjugates include tumor-associated carbohydrate antigens (TACAs) and immunostimulatory glycolipids that hold promise as immunotherapeutics. Beyond the utility of the step-economy syntheses afforded by this synthetic platform, the studies also reveal a unique electronic interplay between acetate and silyl ether protecting groups. Incorporation of acetates proximal to silyl ethers attenuates their reactivity while reducing undesirable side reactions. This phenomenon can be used to fine-tune the reactivity of silylated/acetylated sugar building blocks.
碳水化合物介导了广泛的生物过程，理解这些事件以及它们可能受到的影响是一项复杂的任务，需要获得纯糖缀合物。从生物样本中分离足够数量的碳水化合物和糖脂仍然是一个重大挑战，这促使人们转向化学合成。然而，由于碳水化合物中大量类似反应性的羟基，需要进行多次保护和脱保护步骤，因此复杂糖缀合物全合成的进展一直受到阻碍。两种方法，即区域选择性硅醚交换技术（ReSET）和糖苷碘糖苷化，现已整合在一起，以简化 globo 系列三糖（globotriaose 和 isoglobotriaose）和α-乳糖基神经酰胺（α-LacCer）的合成。这些糖缀合物包括肿瘤相关的碳水化合物抗原（TACAs）和免疫刺激性糖脂，它们有望成为免疫疗法。除了该合成平台提供的分步经济性合成的实用性之外，这些研究还揭示了醋酸盐和硅醚保护基之间独特的电子相互作用。在靠近硅醚的位置引入醋酸盐会降低其反应性，同时减少不必要的副反应。这种现象可用于微调硅烷化/乙酰化糖砌块的反应性。
