Next-Generation Total Synthesis of Vancomycin,Journal of the American Chemical Society

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Next-Generation Total Synthesis of Vancomycin
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-09-04 , DOI: 10.1021/jacs.0c07433
Maxwell J Moore ₁ , Shiwei Qu ₁ , Ceheng Tan ₁ , Yu Cai ₁ , Yuzo Mogi ₁ , D Jamin Keith ₁ , Dale L Boger ₁

Affiliation

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 SNAr 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.

中文翻译：

新一代万古霉素全合成

详细介绍了万古霉素苷元的下一代全合成，该合成通过 17 个步骤（最长线性序列，LLS）从组成氨基酸亚基实现，并通过动力学控制的非对映选择性引入所有三个阻转异构元素。除了七个氨基酸亚基中三个的新合成外，该方法的亮点还包括配体控制的atroposelective一锅Miyaura硼化-Suzuki偶联序列，用于引入AB联芳基手性轴(>20:1 dr)， AB 环系统基本上是瞬时且可扩展的大内酰胺化，几乎没有竞争性差向异构化 (>30:1 dr)，以及用于连续 CD (8:1 dr) 和 DE 环闭合 (14:1 dr) 受益于预先形成的 AB 环系统的预组织和微妙的取代基效应。与万古霉素苷元的无保护基团两步酶促糖基化相结合，这提供了万古霉素的 19 步全合成。该方法为大规模合成制备口袋修饰的万古霉素类似物铺平了道路，直接解决了万古霉素耐药的潜在机制。

更新日期：2020-09-04

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