Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
J Am Chem Soc. 2020 Sep 16;142(37):16039-16050. doi: 10.1021/jacs.0c07433. Epub 2020 Sep 4.
A next-generation total synthesis of vancomycin aglycon is detailed that was achieved in 17 steps (longest linear sequence, LLS) from the constituent amino acid subunits with kinetically controlled diastereoselective introduction of all three elements of atropisomerism. In addition to new syntheses of three of the seven amino acid subunits, highlights of the approach include a ligand-controlled atroposelective one-pot Miyaura borylation-Suzuki coupling sequence for introduction of the AB biaryl axis of chirality (>20:1 dr), an essentially instantaneous and scalable macrolactamization of the AB ring system nearly free of competitive epimerization (>30:1 dr), and two room-temperature atroposelective intramolecular SAr cyclizations for sequential CD (8:1 dr) and DE ring closures (14:1 dr) that benefit from both preorganization by the preformed AB ring system and subtle substituent effects. Combined with a protecting group free two-step enzymatic glycosylation of vancomycin aglycon, this provides a 19-step total synthesis of vancomycin. The approach paves the way for large-scale synthetic preparation of pocket-modified vancomycin analogues that directly address the underlying mechanism of resistance to vancomycin.
详细介绍了万古霉素糖基类似物的下一代全合成方法，该方法通过动力学控制的非对映选择性引入三个手性元素，从组成氨基酸亚基出发，经过 17 步（最长线性序列，LLS）完成。除了三种氨基酸亚基的新合成方法外，该方法的重点还包括配体控制的非对映选择性一锅法 Miyara 硼化-Suzuki 偶联序列，用于引入 AB 联芳基轴的手性（>20:1 dr），几乎没有竞争消旋化的 AB 环系统的瞬时和可扩展大环内酯化（>30:1 dr），以及两个室温非对映选择性分子内 SAr 环化反应，用于顺序 CD（8:1 dr）和 DE 环闭合（14:1 dr），这得益于预先形成的 AB 环系统的预组织和微妙的取代基效应。结合万古霉素糖基类似物的无保护基两步酶糖基化方法，这提供了万古霉素的 19 步全合成方法。该方法为大规模合成口袋修饰的万古霉素类似物铺平了道路，这些类似物直接针对万古霉素耐药的潜在机制。
