Novel reactions that can selectively functionalize carbon-hydrogen bonds are of intense interest to the chemical community because they offer new strategic approaches for synthesis. A very promising 'carbon-hydrogen functionalization' method involves the insertion of metal carbenes and nitrenes into C-H bonds. This area has experienced considerable growth in the past decade, particularly in the area of enantioselective intermolecular reactions. Here we discuss several facets of these kinds of C-H functionalization reactions and provide a perspective on how this methodology has affected the synthesis of complex natural products and potential pharmaceutical agents.I n 2006, 31 new chemical entities were introduced to the world pharmaceutical market and 2,075 molecules were in phase I or II of clinical development 1 . The majority of these were smallmolecule (relative molecular mass ,1,000) organic compounds 2 . As knowledge about the specific interactions of drugs in vivo increases, often so does the structural complexity of new drug targets. A major obstacle to the development of such drugs is the difficulty associated with synthesizing large quantities in an economical fashion, because complex multi-step syntheses are usually required. In the general media, it is often overlooked that the accessibility of the components required for these new treatments will often govern their eventual success or failure. Likewise, a design element of any pharmaceutical agent is the expectation that the target compounds can be made economically. Therefore, new strategies for synthesis can become enabling technologies, making available new targets and materials that would have been previously out of range. For example, new methodologies such as metal-catalysed crosscoupling 3 and olefin metathesis 4-6 have rapidly become central transformations in the synthesis of new pharmaceutical agents. Selective C-H functionalization is a class of reactions that could lead to a paradigm shift in organic synthesis, relying on selective modification of ubiquitous C-H bonds of organic compounds instead of the standard approach of conducting transformations on pre-existing functional groups. The reactive sites in each type of transformation are very different, as illustrated in Fig. 1.The many opportunities associated with C-H functionalization has made this field an active area of research. Organometallic chemists have focused much attention on developing 'C-H activation' strategies, whereby a highly reactive metal complex inserts into a C-H bond, activating the system for subsequent transformations 7-9 . One of the major challenges associated with this chemistry has been to render it catalytic in the metal complex 10 . A partial solution to this problem has been to use neighbouring functionality to direct less reactive metal complexes to the site for functionalization. Numerous reviews have been written about this method for C-H functionalization [11][12][13][14][15][16][17] . Here, however, we highlight another approach, in which a divalent c...

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The metal‐catalyzed decomposition of diazo compounds in the presence of alkenes is a well‐established reaction. Since the original Organic Reactions review on the reaction of ethyl diazoacetate with alkenes and aromatic compounds in 1970, several new developments have revolutionized this area of chemistry. Most notably, major advances have been made in catalyst design such that highly chemoselective, diastereoselective and enantioselective carbenoid transformations can now be achieved. Furthermore, it has been recognized that a wide array of carbenoid structures can be utilized in this chemistry, leading to a broad range of synthetic applications. This chapter comprises coverage of the metal‐catalyzed intermolecular cyclopropanations of diazo compounds containing at least one adjacent electron‐withdrawing group. The coverage of diazoacetate chemistry will be limited to material since 1970 because the previous Organic Reactions review covers the earlier literature. The alkene component is limited to alkenes, dienes, furans, and pyrroles because these are the systems that have resulted in the greatest developments since the 1970 review. Metal‐carbenoid intermediates derived from diazo compounds undergo a variety of useful reactions, including cyclopropanation, insertion, and ylide formation. In recent years several excellent reviews have appeared on various aspects of this chemistry. Three recent reviews have focused on asymmetric intermolecular cyclopropanations. Several books and reviews on carbenoid chemistry have major sections on intermolecular cyclopropanations. Because of the historical central prominence of carbenoids derived from diazoacetates, most reviews have tended to focus on this class of carbenoids. In this chapter, a comparison is presented of the chemical differences that exist among the major classes of carbenoids that contain adjacent electron‐withdrawing groups. The extensive nature of the topic precludes coverage of related reactions such as the metal‐catalyzed decomposition of diazoalkanes, phenyldiazoalkanes, or vinyldiazoalkanes that lack adjacent electron‐withdrawing functionality. Other cyclopropanation reactions such as the Simmons‐Smith reaction, photochemical or thermal decomposition of diazo compounds in the presence of alkenes, and cyclopropanation using stoichiometric metal carbenes are not covered.

The mechanism of rhodium-catalyzed cyclopropanation and C-H functionalization reactions with methyl phenyldiazoacetate and methyl diazoacetate has been studied computationally with DFT. In accordance with experimental data, it has been demonstrated that donor/acceptor rhodium carbenoids display potential energy activation barriers consistent with the much higher selectivity in cyclopropanation and C-H insertion chemistry compared to the traditionally used acceptor carbenoids derived from unsubstituted diazo esters. Significantly higher potential energy barriers were found for transformations of donor/acceptor carbenoids than for those of acceptor systems, primarily due to the inherent stability of the former. Analyses of transition state geometries have led to the development of a rational model for the prediction of the stereochemical outcome of intermolecular C-H insertions with donor/acceptor rhodium carbenoids.

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.