Transformative Methods for the Solid Phase Synthesis of Oligosaccharides

低聚糖固相合成的转化方法 主要研究员：马修·布里查切克，缅因州大学化学系 摘要 与基因组学或蛋白质组学相比，对细胞中所有糖链结构的系统研究 (Glycomics)受到的关注要少得多。然而，这并不是由于缺乏生物 意义；碳水化合物在细胞信号、免疫反应、微生物 发病机制、肿瘤转移和蛋白质活性的调节。相反，知识差距是由于 糖糖的巨大复杂性，由大量的单糖组成，这些单糖是 以许多区域和立体化学组合的形式组装。因此，自然样品是复杂的。 防止大量纯聚糖分离的混合物。此外，目前合成的 获得低聚糖的方法比获得寡核苷酸(DNA和 RNA)和多肽，其存在自动固相协议。通常，低聚糖是 在溶液中通过结合适当的、预官能化的糖苷键一次一个构建 糖基供体和受体。这些糖基化反应对空间位阻和 碳水化合物上取代基和保护基团的电子属性。因此，这种化学物质 低聚糖的合成是繁琐的，通常只能由专门的合成碳水化合物来完成 化学家。 一种可以绕过与分子间糖基化相关的挑战的方法是 将糖基供体和受体的有效分子间偶联与随后的分子内偶联配对 重排以产生所需的天然糖苷键。第一步将解决以下方面的缺陷 通过利用快速、强劲的缩合反应来提高效率。当供体和受体连接时，一个 分子内重排以形成糖苷键将对保护的性质不那么敏感 碳水化合物的基团，并将具有高度立体选择性的潜力。通过应用这种方法 对于碳水化合物的固相合成，具有完整序列和立体化学控制的多糖将 容易接近。 基于分子间高效偶联和多聚糖固相合成的研究进展 立体选择性分子内重排可以提供大量定义明确的低聚糖。 所产生的碳水化合物将使对大量糖链结合蛋白的研究成为可能，这些蛋白将提供 对糖相关疾病的分子水平的了解，如炎症、病原体感染、 和癌症。此外，这项技术将使来自不同学科的科学家能够对 碳水化合物来获得所需的分子，而不需要像目前那样进行高度专业化的合成训练 对寡核苷酸和多肽来说是可能的。

Transformative Methods for the Solid Phase Synthesis of Oligosaccharides Principal Investigator: Matthew Brichacek, Department of Chemistry, University of Maine ABSTRACT When compared to genomics or proteomics, the systematic study of all glycan structures in a cell (glycomics) has received considerably less attention. However, this is not due to a lack of biological significance; where carbohydrates play an integral role in cell signaling, immune response, microbial pathogenesis, tumor metastasis, and modulation of protein activity. Instead, the knowledge gap is due to the immense complexity of the glycome, consisting of a large number of monosaccharide building blocks that are assembled in numerous regio- and stereochemical combinations. Consequently, natural samples are complex mixtures that prevent isolation of substantial quantities of pure glycans. Moreover, current synthetic methodology to obtain oligosaccharides is substantially less developed than those for oligonucleotides (DNA & RNA) and peptides, for which automated solid-phase protocols exist. Typically, oligosaccharides are constructed in solution one glycosidic linkage at a time by combination of the appropriate, prefunctionalized glycosyl donors and acceptors. These glycosylation reactions are extremely sensitive to the steric and electronic attributes of the substituents and protecting groups on the carbohydrates. Therefore, the chemical synthesis of oligosaccharides is tedious and generally performed only by specialized synthetic carbohydrate chemists. One approach that could circumvent the challenges associated with an intermolecular glycosylation is to pair an efficient intermolecular coupling of the glycosyl donor and acceptor with a subsequent intramolecular rearrangement to produce the desired natural glycosidic linkage. The first step will address the shortcomings in efficiency by utilizing rapid, robust condensation reactions. When the donor and acceptor are linked, an intramolecular rearrangement to form the glycosidic bond will be less sensitive to the nature of the protecting groups of the carbohydrates and will have the potential to be highly stereoselective. By applying this approach to carbohydrate synthesis on a solid phase, glycans with complete sequence and stereochemical control will be readily accessible. The development of a solid-phase synthesis of glycans based on an efficient intermolecular coupling and a stereoselective intramolecular rearrangement could provide ample quantities of well-defined oligosaccharides. The carbohydrates produced would enable investigations of numerous glycan-binding proteins that will provide a molecular level of understanding of glycan-associated disorders, such as inflammation, pathogen infection, and cancer. In addition, this technology would enable scientists from a wide variety of disciplines interested in carbohydrates to acquire the desired molecules without highly specialized synthetic training, as is currently possible for oligonucleotides and peptides.