Background The ultimate goal of synthetic chemistry is the expedient and efficient assembly of molecules from readily available starting materials and reagents with minimal waste generation. The synthesis of organic molecules – i.e. compounds containing multiple carbon hydrogen bonds and as well as carbon heteroatom ( i.e. oxygen, nitrogen, sulfur, phosphorus, halogens, and boron) bonds – has greatly improved our quality of life: pharmaceuticals that can treat disease, agrochemicals that enhance crop yields, and organic materials used in computer engineering are but three illustrative examples. And yet, more often than not, the syntheses of these substances have proved challenging due to restrictions on how molecules can be constructed. Major advances in organic chemistry over the last century have relied on the discovery of novel disconnections, which has dramatically altered the approach chemists take to building molecules. These disconnections have been enabled by reaction discovery, including, but not limited to, the Grignard reaction, the Diels-Alder reaction, the Brown asymmetric allylation, the Wittig reaction, and more recently cross-coupling, olefin and alkyne metatheses, and asymmetric catalysis. Given that organic molecules possess an abundance of C–H bonds, it should be no surprise that C–H functionalization ( i.e. the select conversion of C–H bonds into C–X bonds, where X ≠ H) has, over the last few decades, garnered considerable attention as a technique that could dramatically alter synthetic disconnections, by enabling relatively unreactive C–H bonds to be viewed as dormant functionality. And yet, to date, application of C–H functionalization logic is dampened by considerable limitations in terms of chemoselectivity, regioselectivity, and stereoselectivity ( i.e. the construction of chiral centers). Advances Though numerous approaches to chemoselective and regioselective C–H functionalization have been extensively reported, only recently has attention been placed on addressing the issues of stereoselectivity. One such solution, entails the use of chiral transition metal catalysts for enantioselective C–H activation, in which a chiral transition metal catalyst directly reacts with a C–H bond, forming a chiral organometallic intermediate that may be diversified into various functionality. A variety of transition metal catalysts have been shown to affect the asymmetric metalation of C–H bonds of enantiotopic carbons (C–H bonds on different carbons) or enantiotopic protons (C–H bonds on the same carbon). The major driving force behind the development of enantioselective C–H activation has been the design of chiral ligands that bind to transition metal catalysts that both (A) create a steric environment that affords stereocontrol and (B) increase reactivity of a transition metal catalyst, thereby accelerating the rate of the C–H activation. Outlook Although enantioselective C–H activation is still in its infancy, preliminary data is promising and the recent progress of the field is reminiscent of the early stages of now mature sciences such as asymmetric hydrogenation which is now routinely used in synthesis. In order for enantioselective C–H activation to become a standard disconnection in asymmetric syntheses, the efficiency, catalytic turnovers, and breadth of transformations must be dramatically improved. Though the specific requirements to this end are unclear, given the tremendous impact of ligand design on the emergence of this field, we argue that improved ligand design will be instrumental to further progress, until any C–H bond of any molecule can be converted into any functionality with high efficiency and enantioselectivity. The impact of such progress will no doubt have rippling effect in seemingly dissonant fields such as biology, medicine, and materials science by enabling the synthesis of otherwise unimaginable forms of matter. Organic molecules are rich in carbon-hydrogen bonds; consequently, the transformation of C–H bonds to new functionalities ( e.g. C–C, C–N, and C–O, etc. ) has garnered a wealth of attention by the synthetic chemistry community. The utility of C–H activation in organic synthesis, however, cannot be fully realized until chemists achieve stereocontrol in the modification of C–H bonds. This review highlights recent efforts to enantioselectively functionalize C(sp 3 )–H bonds via transition metal catalysis, with an emphasis on both (A) the development of chiral ligand scaffolds that can accelerate metalation of C(sp 3 )–H bonds and (B) stereomodels for asymmetric metalation of prochiral C–H bonds by these catalysts. Several different approaches and the profound impact such reactions will have on the endeavors of organic chemists are herein discussed. Chiral transition metal catalysts can selectively functionalize both enantiotopic carbons ( top arrow ) and enantiotopic protons ( bottom arrow ) through asymmetric metalation.
