Zucchetta Daniele, Zamyatina Alla
Department of Natural Sciences and Sustainable Resources, Institute of Organic Chemistry, BOKU University, 1190 Vienna, Austria.
Beilstein J Org Chem. 2025 Aug 27;21:1700-1718. doi: 10.3762/bjoc.21.133. eCollection 2025.
Nonreducing disaccharides are prevalent in non-mammalian glycans and glycolipids, serving as pivotal structural components in mycobacterial glycans, microbial oligosaccharide and nucleoside antibiotics, as well as biologically active mimetics of bacterial pathogen-associated molecular patterns (PAMPs). As integral components of PAMPs, 1,1'-linked disaccharide-containing biomolecules play important roles in host-pathogen interactions, cellular signaling, and pathogenesis. Accessing complex biomolecules containing nonreducing disaccharides is often hindered by difficulties in isolating them from natural sources, which can result in impure or degraded products, particularly when sensitive functional groups are involved. Consequently, approaches to 1,1'-glycosylation for the synthesis of nonreducing disaccharides with defined anomeric configurations are essential for the development of 1,1'-disaccharide-containing biomolecules used in vaccine research, as well as for therapeutic and diagnostic applications. The assembly of nonreducing 1,1'-linked disaccharides presents greater challenges than conventional chemical glycosylation due to the need for simultaneous control of stereochemistry at two anomeric centers. The structural complexity of natural biomolecules entailing 1,1'-disaccharides, which feature asymmetrically distributed functional groups across their two pyranose rings, emphasizes the importance of robust, stereoselective synthetic strategies capable of producing fully orthogonally protected 1,1'-linked sugars suitable for selective chemical modification. This review highlights recent advances in 1,1'-glycosylation and provides an overview of selected glycosylation strategies, including those aimed at forming α,β-, β,β-, and α,α-1,1'-glycosidic linkages. Particular emphasis is placed on the challenges of achieving stereoselectivity with lactol glycosyl acceptors, which commonly exist as mixtures of anomers and are therefore problematic to use in chemical glycosylation reactions.
非还原性二糖在非哺乳动物聚糖和糖脂中普遍存在，是分枝杆菌聚糖、微生物寡糖和核苷抗生素中的关键结构成分，也是细菌病原体相关分子模式（PAMP）的生物活性模拟物。作为PAMP的组成部分，含1,1'-连接二糖的生物分子在宿主-病原体相互作用、细胞信号传导和发病机制中发挥重要作用。从天然来源分离含非还原性二糖的复杂生物分子往往存在困难，这可能导致产物不纯或降解，尤其是涉及敏感官能团时。因此，用于合成具有明确异头构型的非还原性二糖的1,1'-糖基化方法对于开发用于疫苗研究以及治疗和诊断应用的含1,1'-二糖生物分子至关重要。由于需要同时控制两个异头中心的立体化学，非还原性1,1'-连接二糖的组装比传统化学糖基化面临更大挑战。含有1,1'-二糖的天然生物分子结构复杂，其两个吡喃糖环上的官能团不对称分布，这凸显了强大的立体选择性合成策略的重要性，该策略能够生产出适合选择性化学修饰的完全正交保护的1,1'-连接糖。本综述重点介绍了1,1'-糖基化的最新进展，并概述了选定的糖基化策略，包括旨在形成α,β-、β,β-和α,α-1,1'-糖苷键的策略。特别强调了使用乳醇糖基受体实现立体选择性所面临的挑战，乳醇糖基受体通常以异头物混合物的形式存在，因此在化学糖基化反应中使用存在问题。
