DataSheet1_Versatile approach towards fully desymmetrized trehalose with a novel set of orthogonal protecting groups.pdf

Trehalose-containing glycans play an essential role in bacterial pathogenesis, host-pathogen interaction, and cell signaling. The investigation of trehalose uptake and metabolism in Mycobacteria using synthetic desymmetrized trehalose probes is an important approach for the development of diagnostic tools and potential therapeutics for tuberculosis. Trehalose-derived mycobacterial glycolipids activate the innate immune response through recognition by the C-type lectin Mincle, justifying efforts to develop novel trehalose-based Mincle-dependent adjuvants. The chemical synthesis of trehalose-based glycoconjugates, glycolipids, and small-molecule trehalose probes requires the challenging chemical desymmetrization of eight hydroxyl groups in a C2-symmetric disaccharide αGlc(1↔1)αGlc. Using a novel set of orthogonal protecting groups, we developed a flexible multiscale synthetic approach to a collection of differently and variably protected fully desymmetrized trehalose derivatives, ready for final chemical modification with relevant functional or reporter groups. Using a regioselective and site-specific protecting group strategy, we performed multiple symmetry-breaking operations, resulting in a library of trehalose-derived orthogonally protected building blocks as a versatile source for the synthesis of complex trehalose-containing glycans.

含海藻糖（trehalose）的聚糖在细菌致病机制、宿主-病原体互作以及细胞信号通路中发挥至关重要的作用。利用合成去对称化海藻糖探针研究分枝杆菌属（Mycobacteria）内的海藻糖摄取与代谢过程，是开发结核病诊断工具与潜在治疗手段的重要途径。海藻糖衍生的分枝杆菌糖脂可通过C型凝集素Mincle识别激活固有免疫应答，为此类基于海藻糖的Mincle依赖性新型佐剂的开发提供了理论依据。基于海藻糖的糖缀合物、糖脂以及小分子海藻糖探针的化学合成，需要对C2对称二糖αGlc(1↔1)αGlc中的八个羟基进行极具挑战性的化学去对称化修饰。本研究依托一套新型正交保护基体系，开发了一种灵活的多尺度合成策略，可获得一系列经不同模式、不同程度保护的完全去对称化海藻糖衍生物，可直接用于后续相关功能基团或报告基团的最终化学修饰。本研究采用区域选择性与位点特异性的保护基策略，完成多轮破对称操作，最终得到一系列正交保护的海藻糖衍生结构砌块库，可作为合成复杂含海藻糖聚糖的通用合成原料。