Stereospecific Csp 3 Suzuki–Miyaura Cross-Coupling That Evades β-Oxygen Elimination
Stereospecific Csp 3 Suzuki–Miyaura Cross-Coupling That Evades β-Oxygen Elimination
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避免β-氧消除的立体特异性 Csp 3 Suzuki–Miyaura 交叉偶联
DOI：
10.1021/acscatal.2c03245
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发表时间：
2022
期刊：
影响因子：
12.9
通讯作者：
Burke, Martin D.
中科院分区：
文献类型：
--
作者：
LaPorte, Antonio J.;Shi, Yao;Hein, Jason E.;Burke, Martin D.
立体特异的Csp3Suzuki-Miyaura交叉偶联可以将立体化学中复杂的小分子合成转变为一种简单且可广泛使用的过程。然而，大多数目前的方法不兼容复杂的构建块，这些构建块代表了天然产品和其他复杂靶标中常见的密集排列的多立体中心包含基序。在这里，我们报告了一种方法，它使α-甲基-β-羟基基序能够嵌入到立体化学定义的仲烷基硼酸酯构建块中，这些构建块很容易以立体特异性的方式交叉偶联。该基序存在于>；18 000天然产物以及其他富含CSP3的有机片段中。同时使用β-芳氧基硅基作为双重用途的易位反应促进基和稳定的β-氧替代物来解决空间效应引起的转金属反应活性降低和与β-含氧Csp3硼酸酯的交叉偶联相关的有害副反应。包括实时高效液相分析在内的机理研究表明，原位生成的五元频那醇硅氧硼酸酯随后被水解为二羟基硅氧硼酸酯，在立体专一性过程中充当激活的转位伙伴，从而保持构型。
Stereospecific Csp3Suzuki–Miyaura cross-coupling could transform stereochemically complex small molecule synthesis into a simple and broadly accessible process. However, most current methods are not compatible with complex building blocks that represent densely packed, multistereogenic center-containing motifs commonly found in natural products and other complex targets. Here, we report a method that enables the α-methyl-β-hydroxyl motif, which is found in >18 000 natural products as well as other Csp3-rich organic fragments, to be embedded within stereochemically defined secondary alkyl boronic ester building blocks that are readily cross-coupled in a stereospecific manner. The steric effect-mediated decrease in reactivity toward transmetalation and deleterious side reactions associated with the cross-coupling of β-oxygen-containing Csp3boronic esters are concomitantly addressed using β-aryloxysilyl groups as dual-purpose transmetalation-promoting groups and stable β-oxygen surrogates. Mechanistic studies including real-time HPLC analysis show that a five-membered pinacol siloxaborolate generated in situ is then hydrolyzed to a dihydroxysiloxaborolate that acts as an activated transmetalation partner in a stereospecific process that proceeds with retention of configuration.