Review

Enantioselective C(sp3)‒H bond activation by chiral transition metal catalysts

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Science  16 Feb 2018:
Vol. 359, Issue 6377, eaao4798
DOI: 10.1126/science.aao4798

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Left- or right-handed C–H bond activation

Although organic compounds consist mostly of carbon and hydrogen atoms, strategies for chemical synthesis have traditionally targeted the handful of more reactive interspersed oxygens, nitrogens, and halogens. Modifying C–H bonds directly is a more appealing approach, but selectivity remains a challenge. Saint-Denis et al. review recent progress in using transition metal catalysis to break just one of two mirror-image C–H bonds and then append a more complex substituent in its place. Ligand design has proven crucial to differentiate these otherwise similar bonds in a variety of molecular settings.

Science, this issue p. eaao4798

Structured Abstract

BACKGROUND

The ultimate goal of synthetic chemistry is the efficient assembly of molecules from readily available starting materials with minimal waste generation. The synthesis of organic molecules—compounds containing multiple carbon-hydrogen (C–H) and carbon-heteroatom (such as oxygen or nitrogen) bonds—has greatly improved our quality of life. Pharmaceuticals that can treat disease, agrochemicals that enhance crop yields, and materials used in computer engineering are but three illustrative examples. And yet more often than not, the syntheses of these substances have proved challenging because of restrictions on how molecules can be constructed.

Major advances in organic chemistry have relied on the discovery of reactions that dramatically altered chemists’ approach to building molecules. Canonical organic reactions typically rely on the high reactivity of functional groups (with respect to a C–H bond) in order to introduce new functionality in a target molecule. However, there are times when the accessibility of certain functional groups at particular carbon centers may be restricted; in these cases, the installation of functionality may require several steps and can lead to undesired side reactions, delaying the production of as well as decreasing the overall yield of a synthetic target.

Considering that organic molecules possess an abundance of C–H bonds, it should be unsurprising that C–H functionalization (the conversion of C–H bonds into C–X bonds, where X ≠ H) has garnered considerable attention as a technique that could alter synthetic organic chemistry by enabling relatively unreactive C–H bonds to be viewed as dormant functionality. And yet, to date applications of C–H functionalization logic are hindered by considerable limitations in terms of regioselectivity and stereoselectivity (the construction of chiral centers).

ADVANCES

Although numerous approaches to regioselective C–H functionalization have been extensively reported, only recently has attention been placed on addressing the issues of stereoselectivity. One such solution entails chiral transition metal catalysts in which a metal complexed to a chiral ligand reacts directly with a C–H bond, forming a chiral organometallic intermediate that is then diversely functionalized. A variety of transition metal catalysts have been shown to affect the asymmetric metallation 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 metals, creating a reactive chiral catalyst while also increasing the reactivity at the metal center, accelerating the rate of C–H activation.

OUTLOOK

In order for enantioselective C–H activation to become a standard disconnection in asymmetric syntheses, the efficiency of catalyses and breadth of transformations must be improved. Although the specific requirements to achieve these goals are unclear, 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 in high yields with high enantioselectivity. The impact of such progress will no doubt have rippling effects in seemingly disparate fields, such as medicine, by enabling the syntheses of previously inaccessible forms of matter.

Enantioselective C(sp3)–H activation.

Chiral transition metal catalysts can selectively func­tionalize both (Top) enantiotopic carbons and (Middle) enantiotopic protons through asymmetric metalation. (Bottom) Racemic mixtures (1:1 mixtures of enantiomers) may also be differen­tiated through kinetic resolution/C(sp3)–H activation.

Abstract

Organic molecules are rich in carbon-hydrogen bonds; consequently, the transformation of C–H bonds to new functionalities (such as C–C, C–N, and C–O bonds) has garnered much 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(sp3)–H bonds via transition metal catalysis, with an emphasis on key principles for both the development of chiral ligand scaffolds that can accelerate metalation of C(sp3)–H bonds and stereomodels for asymmetric metalation of prochiral C–H bonds by these catalysts.

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