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. 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 or contains a directing group or the reaction is conducted intramolecularly 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. 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. Recently, we reported a dirhodium catalyst for the site-selective functionalization of the most accessible non-activated (that is, not next to a functional group) secondary C–H bonds by means of rhodium-carbene-induced C–H insertion. Here we describe another dirhodium catalyst that has a very different reactivity profile. Instead of the secondary C–H bond, 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.

中文翻译：

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非活化叔 C-H 键的位点选择性和立体选择性功能化

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，可以直接在 C-H 键上进行反应，以前被认为是非反应性的。主要挑战之一是控制位点选择性，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底物控制的使用，其中底物具有一个固有的更具反应性的 C-H 键或包含一个导向基团，或者反应在分子内进行，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底物中的哪个位点被功能化。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导致特定的 C-H 键被功能化。几项研究旨在通过设计的过渡金属催化剂来模拟这种酶促位点选择性，但很难实现极高水平的位点选择性。最近，我们报道了一种用于通过铑-卡宾诱导的 C-H 插入对最容易获得的未活化（即，不在官能团旁边）二级 C-H 键进行位点选择性官能化的二铑催化剂。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。代替二级 C-H 键，新催化剂能够在最容易接近的三级 C-H 键上进行精确的位点选择性。使用这种催化剂，我们修改了几种天然产品，包括类固醇和维生素 E 衍生物，表明这种合成方法适用于复杂分子的后期功能化。这些研究表明，只需选择合适的催化剂，就可以在基材内的不同位置实现位点选择性。我们希望这项工作能够激发更复杂催化剂的设计，使催化剂控制的 C-H 功能化成为合成复杂分子的广泛应用策略。