Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry

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Science  14 Apr 2017:
Vol. 356, Issue 6334, eaaf7230
DOI: 10.1126/science.aaf7230

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Stitching one alkyl group to another

Chemical reactions such as Heck and Suzuki coupling facilitate access to an enormous range of relatively flat molecules. This geometrical constraint is associated with the comparative ease of linking together aryl and alkenyl carbons. Choi and Fu review recent developments in forming bonds between the more abundant alkyl carbon centers that underlie diverse molecules with complex three-dimensional structures. Nickel catalysis in particular has emerged as a powerful method to access individual mirror-image isomers selectively and thereby tune the biological properties of the targeted products.

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Structured Abstract


The development of useful new methods for the construction of carbon-carbon bonds has had an impact on the many scientific disciplines (including materials science, biology, and chemistry) that use organic compounds. Tremendous progress has been made in the past several decades in the creation of bonds between sp2-hybridized carbons (e.g., aryl-aryl bonds), particularly through the use of transition metal catalysis. In contrast, until recently, advances in the development of general methods that form bonds between sp3-hybridized carbons (alkyl-alkyl bonds) had been rather limited. A variety of approaches, such as classical SN2 reactions and transition metal catalysis, typically led to side reactions rather than the desired carbon-carbon bond formation. With transition metal catalysis, the unwanted but often facile β-hydride elimination of alkylmetal complexes presented a key impediment to efficient cross-coupling of alkyl electrophiles.

In the case of many alkyl-alkyl bonds, there is an additional challenge beyond construction of the carbon-carbon bond itself: controlling the stereochemistry at one or both carbons of the new bond. It is important to control the stereochemistry of organic molecules because of its influence on properties such as biological activity.

Each of these two challenges is difficult to solve individually; addressing them simultaneously is even more demanding. Until recently, the methods for achieving alkyl-alkyl bond formation were comparatively limited in scope, typically involving the use of unhindered (e.g., primary) electrophiles and unhindered, highly reactive nucleophiles (e.g., Grignard reagents, which have relatively poor functional group compatibility). With respect to enantioconvergent reactions, there were virtually no examples.


In recent years, it has been established that, through the action of an appropriate transition metal catalyst, it is possible to achieve a broad range of alkyl-alkyl bond-forming processes; nickel-based catalysts have proved to be especially effective. With respect to the electrophilic coupling partner, a wide range of secondary alkyl halides are now suitable. This has enabled the development of enantioconvergent reactions of readily available racemic secondary electrophiles. In view of the abundance of tertiary stereocenters in organic molecules, this is a noteworthy advance in synthesis.

With respect to the nucleophilic partner, alkylboron and alkylzinc reagents (Suzuki- and Negishi-type reactions, respectively) can now be used in a wide variety of alkyl-alkyl couplings, which greatly increases the utility of such processes, as these nucleophiles are more readily available and have much improved functional group compatibility relative to Grignard reagents. These new methods for alkyl-alkyl bond formation have been applied to the synthesis of natural products and other bioactive compounds.


A number of major challenges remain. For example, with regard to the electrophilic coupling partner, there is a need to develop general methods that are effective for tertiary alkyl halides, including enantioconvergent processes. With regard to the nucleophilic partner, there is a need to discover more versatile catalysts that can use a wide range of hindered (e.g., secondary and tertiary) alkylmetal reagents, as well as to achieve a broad spectrum of enantioconvergent couplings of racemic nucleophiles. These advances can enable the doubly stereoconvergent coupling of a racemic electrophile with a racemic nucleophile.

The synthesis of alkyl-alkyl bonds is arguably the most important bond construction in organic synthesis. The ability to achieve this bond formation at will, as well as to control the product stereochemistry, would transform organic synthesis and empower the many scientists who use organic molecules. Recent work has provided evidence that transition metal catalysis can address this exciting challenge.

Alkyl-alkyl bond formation, including control of stereochemistry: an ongoing challenge in organic synthesis.

From top to bottom: sp2- versus sp3-hybridized carbon-carbon bonds; the difficulty of stereochemical control; and enantioconvergent reactions of racemic secondary electrophiles and racemic nucleophiles. X, leaving group; M, metal.


Because the backbone of most organic molecules is composed primarily of carbon-carbon bonds, the development of efficient methods for their construction is one of the central challenges of organic synthesis. Transition metal–catalyzed cross-coupling reactions between organic electrophiles and nucleophiles serve as particularly powerful tools for achieving carbon-carbon bond formation. Until recently, the vast majority of cross-coupling processes had used either aryl or alkenyl electrophiles as one of the coupling partners. In the past 15 years, versatile new methods have been developed that effect cross-couplings of an array of alkyl electrophiles, thereby greatly expanding the diversity of target molecules that are readily accessible. The ability to couple alkyl electrophiles opens the door to a stereochemical dimension—specifically, enantioconvergent couplings of racemic electrophiles—that substantially enhances the already remarkable utility of cross-coupling processes.

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