Total Synthesis of Legionaminic Acid as Basis for Serological Studies

Legionaminic acid is a nine-carbon diamino monosaccharide that is found coating the surface of various bacterial human pathogens. Its unique structure makes it a valuable biological probe, but access via isolation is difficult and no practical synthesis has been reported. We describe a stereoselective synthesis that yields a legionaminic acid building block as well as linker-equipped conjugation-ready legionaminic acid starting from cheap d-threonine. To set the desired amino and hydroxyl group pattern of the target, we designed a concise sequence of stereoselective reactions. The key transformations rely on chelation-controlled organometallic additions and a Petasis multicomponent reaction. The legionaminic acid was synthesized in a form that enables attachment to surfaces. Glycan microarray containing legionaminic acid revealed that human antibodies bind the synthetic glycoside. The synthetic bacterial monosaccharide is a valuable probe to detect an immune response to bacterial pathogens such as Legionella pneumophila, the causative agent of Legionnaire’s disease.军团胺酸（legionaminic acid）是一种九碳二氨基单糖，常覆盖于多种可感染人类的细菌病原体表面。其独特的分子结构使其成为极具价值的生物探针，但通过分离提取获取该物质难度极大，目前尚无实用的合成路线被报道。本文报道了一种立体选择性合成策略，以廉价的d-苏氨酸（d-threonine）为起始原料，成功制备了军团胺酸结构砌块，以及带有连接臂、可直接用于偶联反应的军团胺酸衍生物。为精准构建目标分子所需的氨基与羟基立体排布模式，我们设计了简洁的立体选择性反应序列，关键转化步骤依赖于螯合控制的有机金属加成反应与Petasis多组分反应。所合成的军团胺酸具备可用于表面修饰的活性形式。搭载军团胺酸的聚糖微阵列（glycan microarray）实验结果显示，人类抗体可特异性结合该合成糖苷。这种人工合成的细菌源单糖可作为极具价值的生物探针，用于检测机体针对嗜肺军团菌（Legionella pneumophila，军团病（Legionnaire’s disease）的致病菌）等致病细菌的免疫应答。