New strategies for the total synthesis of microbial glycans

微生物世界代表着取之不尽用之不竭的糖基分子来源，显示出惊人的结构多样性、生物功能和治疗特性。由于糖衍生的代谢物以复杂混合物的形式被发现，微生物多糖的化学合成是了解其生物学和治疗特性的诱人机会。沿着这些思路，我们研究计划的主要目标是开发创新的合成方法，使其能够制备具有治疗意义的微生物多糖。在接下来的五年期间，我们建议在四个不同的研究主题上开展工作，这些主题旨在朝着我们的长期目标取得重大进展。在第一个主题中，我们建议合成洋葱的重复单元(RU)，洋葱是洋葱伯克霍尔德菌复合体表面表达的一种多糖(PS)，洋葱伯克霍尔德菌复合体是一组导致严重医院感染的条件致病菌。洋葱的RU是由7个糖基组成的低聚物，其中一些在特定位置含酯取代基。在特定的“阿尔法”构型中存在高度支化的葡萄糖醛酸残基是一个重要的合成挑战，我们将试图利用分子内反应来解决这一问题。在第二个主题中，我们将合成能够模拟KDO的化合物，KDO是一种含有八碳羧酸的细菌糖，它是由致病性革兰氏阴性细菌产生的膜连接PSS的关键构建块。我们将用氮取代KDO的环内氧原子，以产生一个前所未有的化合物库，称为“KDO亚氨糖”。这些糖模拟物可以用来抑制或探测细菌PSS的生物合成。在第三个主题中，我们将调查Pantoea Ananatis的生物表面活性物质含量，这是一种非致病细菌，它产生具有大环特征的糖脂，我们称之为“Ananatoside”。我们将开发快速的化学酶方法来合成藻苷类生物表面活性剂及其更易溶于水的或二聚体的衍生物。在最后一个研究主题中，我们将调查被称为“吡喃糖苷”的稀有细菌糖如何反应形成稳定和可分离的“糖苷构象”，这是同一种化合物呈现两种不同的构象。我们将从实验数据和计算中收集全面的机械论见解。这一知识将被应用于空肠弯曲杆菌产生的PS的RU的合成，这种细菌是格林-巴利自身免疫综合征的主要触发因素。我们的研究计划的几个方面将导致合成化学的根本性进展。重要的是，在这项研究过程中将制备的糖基化合物可能会作为新的治疗方法、预防药物和生物材料对加拿大人的健康产生好处。

The microbial world represents an inexhaustible source of sugar-derived molecules, showing astonishing structural diversity, biological functions, and therapeutic properties. As sugar-derived metabolites are found in the form of complex mixtures, chemical synthesis of microbial glycans stands as a tantalizing opportunity to gain insight into their biological and therapeutic properties. Along these lines, the main objective of our research program is to develop innovative synthetic approaches enabling the preparation of therapeutically relevant microbial glycans. For the next five-year period, we propose to work on four different research themes, which have been designed to make significant progress toward our long-term goal. In a first theme, we propose to synthesize the repeating unit (RU) of cepacian, a polysaccharide (PS) expressed at the surface of Burkholderia cepacia complex, a group of opportunistic pathogens causing severe nosocomial infections. The RU of cepacian is an oligomer composed of seven sugar residues, some of them bearing ester substituents at specific positions. The presence of a highly branched glucuronic acid residue in a specific "alpha" configuration represents an important synthetic challenge, which we will try to solve capitalizing on intramolecular reactions. In a second theme, we will synthesize compounds that can mimic Kdo, an eight-carbon carboxylic acid-containing bacterial sugar, which stands as a crucial building block for the elaboration of membrane-linked PSs produced by pathogenic Gram-negative bacteria. We will replace the intracyclic oxygen atom of Kdo with a nitrogen to generate an unprecedented library of compounds called "Kdo iminosugars". These sugar mimics could be used to inhibit - or probe - the biosynthesis of bacterial PSs. In a third theme, we will investigate the biosurfactant content of Pantoea ananatis, a non-pathogenic bacterium, which produces glucolipid featuring macrocycles that we have called "ananatosides". We will develop expeditious chemo-enzymatic approaches for the synthesis of ananatoside-like biosurfactants and their more water soluble or dimeric derivatives. In a last research theme, we will investigate how rare bacterial sugars called "idopyranosides" can react to form stable and isolable "glycosidic conformers", which are the same compound presenting two different conformations. Thorough mechanistic insights will be gathered from experimental data and calculations. This knowledge will be applied to the synthesis of the RU of a PS produced by Campylobacter jejuni, a bacterium that is the main trigger of the Guillain-Barré auto-immune syndrome. Several aspects of our research program will lead to fundamental advances in synthetic chemistry. Importantly, the sugar-based compounds that will be prepared over the course of this research program could generate benefits for the health of Canadians as novel therapeutics, prophylactics, and biomaterials.