Journal Article

Site-selective and stereoselective functionalization of non-activated tertiary C–H bonds

Liao, Kuangbiao, Musaev, Djamaladdin G., Boyarskikh, Vyacheslav, Pickel, Thomas C., Bacsa, John, Davies, Huw M. L.

2017

Overview

The functionalization of specific inert C–H bonds avoids the need for functional groups in organic synthesis and here the challenges of this approach are overcome using a dirhodium catalyst that is capable of C–H bond site-selectivity. Targeted tertiary C–H activation Carbon–hydrogen (C–H) bond functionalization has gained traction over recent years as a synthetically useful transformation, as it avoids the need for functional groups to do synthesis. These bonds are typically inert, and selectively reacting one in a molecule that is made up of mainly C–H bonds is a challenge. Here, Huw Davies and colleagues report that a dirhodium catalyst can selectively modify unactivated tertiary C–H bonds (that is, on a carbon with three carbon substituents) with generally high stereo- and site-selectivity. Moreover, several natural products were modified by this route, including steroids and a vitamin E derivative, indicating the use of this chemistry for the late-stage functionalization of complex molecules. 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 , 2 , 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 , 10 , 11 . 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 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 639/638/403/933 / 639/638/549/972 / 639/638/77/883 / Catalysis / Catalysts / Chemical bonds / Chemical synthesis / Functional groups / Haem / Humanities and Social Sciences / Hydrogen bonds / Iron / letter / multidisciplinary / Natural products / Organic compounds / Oxidation / Rhodium / Rhodium compounds / Science / Science (multidisciplinary) / Selectivity / Steroid hormones / Steroids / Substrates / Temperature / Tocopherol / Vitamin E