New strategies for the total synthesis of microbial glycans

微生物界是取之不尽、用之不竭的糖源分子，具有惊人的结构多样性、生物功能和治疗特性。由于糖衍生代谢物以复杂混合物的形式被发现，微生物聚糖的化学合成为深入了解其生物学和治疗特性提供了一个诱人的机会。沿着这些路线，我们研究计划的主要目标是开发创新的合成方法，使制备治疗相关的微生物聚糖成为可能。在接下来的五年里，我们建议在四个不同的研究主题上工作，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，我们提出合成洋葱菌的重复单位（RU），这是一种表达于洋葱伯克霍尔德菌复合体表面的多糖（PS），这是一组导致严重医院感染的机会致病菌。乙酸的RU是由七个糖残基组成的低聚物，其中一些在特定位置上带有酯取代基。高支化葡萄糖醛酸残基在特定“α”构型中的存在是一个重要的合成挑战，我们将尝试利用分子内反应来解决这个问题。在第二个主题中，我们将合成可以模仿Kdo的化合物，Kdo是一种含八碳羧酸的细菌糖，它是致病性革兰氏阴性菌产生的膜连接ps的重要组成部分。我们将用一个氮取代Kdo的环内氧原子，生成一个前所未有的化合物库，称为“Kdo亚糖”。这些糖模拟物可以用来抑制或探测细菌ps的生物合成。在第三个主题中，我们将研究Pantoea ananatis的生物表面活性剂含量，Pantoea ananatis是一种非致病性细菌，它产生具有大环的糖脂，我们称之为“ananatosides”。我们将开发快速的化学-酶方法来合成安纳托苷类生物表面活性剂及其更水溶性或二聚体衍生物。在最后一个研究主题中，我们将研究罕见的细菌糖“异吡喃苷”如何反应形成稳定且可分离的“糖苷构象”，即相同的化合物呈现两种不同的构象。将从实验数据和计算中收集透彻的机理见解。这一知识将应用于由空肠弯曲杆菌产生的一种PS的RU的合成，这种细菌是格林-巴罗自身免疫综合征的主要触发因素。我们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，在这个研究项目的过程中制备的糖基化合物可以作为新的治疗药物、预防药物和生物材料为加拿大人的健康带来好处。

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.