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

Choi, Junwon and Fu, Gregory C. (2017) Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry. Science, 356 (6334). Art. No. eaaf7230. ISSN 0036-8075. PMCID PMC5611817. doi:10.1126/science.aaf7230.

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BACKGROUND: 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 sp^2-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 sp^3-hybridized carbons (alkyl-alkyl bonds) had been rather limited. A variety of approaches, such as classical S_N^2 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. ADVANCES: 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. OUTLOOK: 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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Choi, Junwon0000-0001-6004-5524
Fu, Gregory C.0000-0002-0927-680X
Alternate Title:Transition-Metal-Catalyzed Construction of Alkyl–Alkyl Bonds: Another Dimension in Cross-Coupling Chemistry
Additional Information:© 2017 American Association for the Advancement of Science. Supported by National Institute of General Medical Sciences grant R01-GM62871.
Funding AgencyGrant Number
Issue or Number:6334
PubMed Central ID:PMC5611817
Record Number:CaltechAUTHORS:20170413-145407242
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Official Citation:Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry BY JUNWON CHOI, GREGORY C. FU Science 14 Apr 2017: Vol. 356, Issue 6334, eaaf7230 DOI: 10.1126/science.aaf7230
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76559
Deposited By: Ruth Sustaita
Deposited On:13 Apr 2017 23:00
Last Modified:28 Mar 2022 22:16

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