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| 化学酶法合成克级UDP-α-6-N3-glucose |
| Chemoenzymatic synthesis of UDP-α-6-N3-glucose in Gram Scale |
| 投稿时间：2025-03-25 修订日期：2025-04-22 |
| DOI： |
| 中文关键词: 硫杂冠醚 UDP-α-6-N3-glucose 克级制备 |
| 英文关键词:Thiocrown ether, UDP-α-6-N3-glucose, Gram scale |
| 基金项目: |
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| 摘要点击次数: 54 |
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| 中文摘要: |
| 尿苷二磷酸-6-脱氧-6-叠氮-α-D-吡喃葡萄糖（UDP-α-6-N3-glucose）作为糖基化修饰研究中的核心正交分子探针，在化学生物学领域发挥着极为重要的作用。本研究针对UDP-α-6-N3-glucose合成过程中存在的立体选择性控制困难及反应条件苛刻等关键技术瓶颈，通过对糖化学中经典的柯尼希斯－克诺尔反应（Koenigs-Knorr）反应进行创新性重建，创新性的引入对银离子有络合作用的硫杂冠醚，成功建立糖基磷酸化反应的立体化学控制新方法，实现了单一构型1-磷酸-α-6-脱氧-6-叠氮-吡喃葡萄糖的立体选择性合成。基于此关键中间体，经UDP糖焦磷酸化酶（AtUSP）催化的高效酶促反应，最终以36%的总收率获得高纯度目标产物UDP-α-6-N3-glucose（1.3 g，克级规模）。该研究不仅为糖基化研究提供了重要的化学工具分子，更通过新型催化剂介导的立体控制策略为糖基化反应提供了方法学参考。 |
| 英文摘要: |
| UDP-α-6-N3-glucose (uridine diphosphate-α-6-azido-glucose), a critical orthogonal probe for glycosylation studies, plays a key role in the field of chemical biology. The 1,2-cis stereoselectivity and labile phosphoester linkages present significant synthetic challenges in the synthesis of UDP-α-6-N?-glucose. This study addressed the critical technical challenges in the synthesis of uridine diphosphate-6-deoxy-6-azido-α-D-glucopyranose (UDP-α-6-N3-glucose), particularly the difficulties in stereoselective control and harsh reaction conditions. Through innovative restructuring of the classical Koenigs-Knorr glycosylation reaction in carbohydrate chemistry, we introduced a silver-ion-coordinating thia-crown ether ligand as a breakthrough strategy. This approach successfully established a novel stereochemical control method for the glycosyl phosphorylation reaction, achieving stereoselective synthesis of the mono-configurational intermediate 1-phospho-α-6-deoxy-6-azido-D-glucopyranose with exceptional α-selectivity (α/β > 20:1). Leveraging this key intermediate, a highly efficient enzymatic reaction catalyzed by UDP-sugar pyrophosphorylase (AtUSP) enabled gram-scale production of the target compound, yielding 1.3 g of UDP-α-6-N3-glucose with 98% HPLC purity and an overall yield of 36%. Beyond providing a crucial chemical tool for glycosylation studies, this work establishes a methodology framework through its ligand-mediated stereocontrol strategy, offering new mechanistic insights for glycosylation reaction engineering. |
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