Synthesis of (+)-ribostamycin by catalytic, enantioselective hydroamination of benzene.
Synthesis of (+)-ribostamycin by catalytic, enantioselective hydroamination of benzene.
复制标题
苯催化氢胺化合成（+）-核糖霉素。
DOI：
10.1038/s44160-022-00080-x
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
Sarlah, David
中科院分区：
文献类型：
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作者：
Ungarean, Chad N;Galer, Petra;Zhang, Yu;Lee, Ken S;Ngai, Justin M;Lee, Sungjong;Liu, Peng;Sarlah, David
氨基糖苷类化合物是一类天然产物，其中几个不同的糖部分被结合到氨基环醇核心上。AGs是一类主要的抗生素，靶向许多有问题的病原体的原核核糖体。迄今为止，已经分离出数百种AG，其中1，3-二氨基环己烷三醇（称为2-脱氧链霉胺（2-DOS））是最丰富的糖苷配基核心。然而，由于其多样性和复杂的结构，所有基于AG的药物要么是天然物质，要么是通过后期修饰制备的类似物。AG的合成方法是罕见的和漫长的;大多数研究涉及半合成的重组修饰片段。在这里，我们报告了基于2-DOS的AG抗生素核糖霉素的自下而上的化学合成，该合成从苯开始经过十次线性操作。一个关键的转化涉及铜催化的，对映选择性的，脱芳氢胺化，这为快速和选择性地引入剩余的2-DOS杂原子官能团奠定了基础。这项工作证明了定制的脱芳逻辑和后续烯烃官能化的策略性使用的组合如何可以提供对AG类化合物的实用和简洁的访问。
Aminoglycosides (AGs) represent a large group of pseudoglycoside natural products, in which several different sugar moieties are harnessed to an aminocyclitol core. AGs constitute a major class of antibiotics that target the prokaryotic ribosome of many problematic pathogens. Hundreds of AGs have been isolated to date, with 1,3-diaminocyclohexanetriol, known as 2-deoxystreptamine (2-DOS), being the most abundant aglycon core. However, owning to their diverse and complex architecture, all AG-based drugs are either natural substances or analogues prepared by late-stage modifications. Synthetic approaches to AGs are rare and lengthy; most studies involve semi-synthetic reunion of modified fragments. Here we report a bottom-up chemical synthesis of the 2-DOS-based AG antibiotic ribostamycin, which proceeds in ten linear operations from benzene. A key enabling transformation involves a Cu-catalyzed, enantioselective, dearomative hydroamination, which set the stage for the rapid and selective introduction of the remaining 2-DOS heteroatom functionality. This work demonstrates how the combination of a tailored, dearomative logic and strategic use of subsequent olefin functionalizations can provide practical and concise access to the AG class of compounds.