Site-selective and stereoselective functionalization of non-activated tertiary C-H bonds
Site-selective and stereoselective functionalization of non-activated tertiary C-H bonds
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DOI：
10.1038/nature24641
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发表时间：
2017-11-30
期刊：
影响因子：
64.8
通讯作者：
Davies, Huw M. L.
中科院分区：
文献类型：
--
作者：
Liao, Kuangbiao;Pickel, Thomas C.;Davies, Huw M. L.
复杂有机化合物的合成通常依赖于控制官能团的反应。近年来，直接在C-H键上进行反应已经成为可能，以前被认为是不反应的（1-3）。其中一个主要的挑战是控制位点选择性，因为大多数有机化合物具有许多相似的C-H键。迄今为止，最完善的程序依赖于使用底物控制，其中底物具有一个固有的更具反应性的C-H键（4）或含有导向基团（5，6）或反应在分子内进行（7），以便有利于特定的C-H键。一种更通用但更具挑战性的方法是使用催化剂来控制基底中的哪个位点被官能化。p450酶表现出C-H氧化位点选择性，其中酶支架通过将其靠近铁-氧血红素复合物而使特定的C-H键官能化（8）。几项研究旨在用设计的过渡金属催化剂模拟这种酶的位点选择性，但很难达到非常高的位点选择性水平（9-11）。最近，我们报道了一种二铑催化剂，通过铑-卡宾诱导的C-H插入，对最易接近的非活化（即，不靠近官能团）二级C-H键进行位点选择性官能化（12）。在这里，我们描述了另一种具有非常不同的反应特性的铑催化剂。取代仲C-H键（12），新催化剂能够在最易接近的叔C-H键处具有精确的位点选择性。使用这种催化剂，我们修改了几种天然产物，包括类固醇和维生素E衍生物，表明这种合成方法的适用性后期功能化的复杂分子。这些研究表明，通过简单地选择合适的催化剂，可以在基底内的不同位置实现位点选择性。我们希望这项工作将激发设计更复杂的催化剂，使催化剂控制的C-H官能化成为合成复杂分子的广泛应用策略。
The synthesis of complex organic compounds usually relies on controlling the reactions of the functional groups. In recent years, it has become possible to carry out reactions directly on the C-H bonds, previously considered to be unreactive(1-3). One of the major challenges is to control the site-selectivity because most organic compounds have many similar C-H bonds. The most well developed procedures so far rely on the use of substrate control, in which the substrate has one inherently more reactive C-H bond(4) or contains a directing group(5,6) or the reaction is conducted intramolecularly(7) so that a specific C-H bond is favoured. A more versatile but more challenging approach is to use catalysts to control which site in the substrate is functionalized. p450 enzymes exhibit C-H oxidation site-selectivity, in which the enzyme scaffold causes a specific C-H bond to be functionalized by placing it close to the iron-oxo haem complex(8). Several studies have aimed to emulate this enzymatic site-selectivity with designed transition-metal catalysts but it is difficult to achieve exceptionally high levels of site-selectivity(9-11). Recently, we reported a dirhodium catalyst for the site-selective functionalization of the most accessible nonactivated (that is, not next to a functional group) secondary C-H bonds by means of rhodium-carbene-induced C-H insertion(12). Here we describe another dirhodium catalyst that has a very different reactivity profile. Instead of the secondary C-H bond(12), the new catalyst is capable of precise site-selectivity at the most accessible tertiary C-H bonds. Using this catalyst, we modify several natural products, including steroids and a vitamin E derivative, indicating the applicability of this method of synthesis to the late-stage functionalization of complex molecules. These studies show it is possible to achieve site-selectivity at different positions within a substrate simply by selecting the appropriate catalyst. We hope that this work will inspire the design of even more sophisticated catalysts, such that catalyst-controlled C-H functionalization becomes a broadly applied strategy for the synthesis of complex molecules.