Carbon–carbon bonds, including those between sp3-hybridized carbon atoms (alkyl–alkyl bonds), typically comprise much of the framework of organic molecules. In the case of sp3-hybridized carbon, the carbon can be stereogenic and the particular stereochemistry can have implications for structure and function1,2,3. As a consequence, the development of methods that simultaneously construct alkyl–alkyl bonds and control stereochemistry is important, although challenging. Here we describe a strategy for enantioselective alkyl–alkyl bond formation, in which a racemic alkyl electrophile is coupled with an olefin in the presence of a hydrosilane, rather than via a traditional electrophile–nucleophile cross-coupling, through the action of a chiral nickel catalyst. We demonstrate that families of racemic alkyl halides—including secondary and tertiary electrophiles, which have not previously been shown to be suitable for enantioconvergent coupling with alkyl metal nucleophiles—cross-couple with olefins with good enantioselectivity and yield under very mild reaction conditions. Given the ready availability of olefins, our approach opens the door to developing more general methods for enantioconvergent alkyl–alkyl coupling.
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The data that support the findings of this study are available within the paper, its Supplementary Information (experimental procedures and characterization data) and from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/structures; crystallographic data are available free of charge under CCDC reference numbers 1822790–1822793, 1839344–1839346 and 1861568).
Carreira, E. M. & Yamamoto, H. (eds) Comprehensive Chirality (Academic, Amsterdam, 2012).
Lin, G.-Q., You, Q.-D. & Cheng, J.-F. (eds) Chiral Drugs: Chemistry and Biological Action (Wiley, New York, 2011).
Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).
Choi, J. & Fu, G. C. Transition metal-catalyzed alkyl–alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).
Fu, G. C. Transition-metal catalysis of nucleophilic substitution reactions: a radical alternative to SN1 and SN2 processes. ACS Cent. Sci. 3, 692–700 (2017).
Iwasaki, T. & Kambe, N. in Comprehensive Organic Synthesis 2nd edn, Vol. 3 (eds Knochel, P. et. al.) 337–391 (Elsevier, Amsterdam, 2014).
Geist, E., Kirschning, A. & Schmidt, T. sp 3–sp 3 coupling reactions in the synthesis of natural products and biologically active molecules. Nat. Prod. Rep. 31, 441–448 (2014).
Lu, X. et al. Practical carbon–carbon bond formation from olefins through nickel-catalysed reductive olefin hydrocarbonation. Nat. Commun. 7, 11129 (2016).
Wang, Y.-M., Bruno, N. C., Placeres, A. L., Zhu, S. & Buchwald, S. L. Enantioselective synthesis of carbo- and heterocycles through a CuH-catalyzed hydroalkylation approach. J. Am. Chem. Soc. 137, 10524–10527 (2015).
Tobert, J. A. Lovastatin and beyond: the history of the HMG–CoA reductase inhibitors. Nat. Rev. Drug Discov. 2, 517–526 (2003).
Ganellin, C. R. in Introduction to Biological and Small Molecule Drug Research and Development (eds Ganellin, C. R. et al.) 339–416 (Elsevier, Amsterdam, 2013).
Stoltz, B. M. et al. in Comprehensive Organic Synthesis 2nd edn, Vol. 3 (eds Knochel, P. et. al.) 1–55 (Elsevier, Amsterdam, 2014).
MacMillan, D. W. C. & Watson, A. J. B. in Science of Synthesis: Stereoselective Synthesis Vol. 3 (ed. Evans, P. A.) 675–745 (Thieme, New York, 2011).
Fischer, C. & Fu, G. C. Asymmetric nickel-catalyzed Negishi cross-couplings of secondary α-bromo amides with organozinc reagents. J. Am. Chem. Soc. 127, 4594–4595 (2005).
Gouverneur, V. & Müller, K. Fluorine in Pharmaceutical and Medicinal Chemistry (Imperial College Press, London, 2012).
Juliá-Hernández, F., Moragas, T., Cornella, J. & Martin, R. Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide. Nature 545, 84–88 (2017).
Zhou, F., Zhu, J., Zhang, Y. & Zhu, S. NiH-catalyzed reductive relay hydroalkylation: a strategy for the remote C(sp 3)–H alkylation of alkenes. Angew. Chem. Int. Ed. 57, 4058–4062 (2018).
Hoveyda, A. H., Evans, D. A. & Fu, G. C. Substrate-directable chemical reactions. Chem. Rev. 93, 1307–1370 (1993).
Derosa, J., Tran, V. T., Boulous, M. N., Chen, J. S. & Engle, K. M. Nickel-catalyzed β,γ-dicarbofunctionalization of alkenyl carbonyl compounds via conjunctive cross-coupling. J. Am. Chem. Soc. 139, 10657–10660 (2017).
Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014).
Ding, C.-H. & Hou, X.-L. in Comprehensive Organic Synthesis 2nd edn, Vol. 4 (eds Knochel, P. et. al.) 648–698 (Elsevier, Amsterdam, 2014).
Murakata, M., Jono, T., Mizuno, Y. & Hoshino, O. Construction of chiral quaternary carbon centers by catalytic enantioselective radical-mediated allylation of α-iodolactones using allyltributyltin in the presence of a chiral Lewis acid. J. Am. Chem. Soc. 119, 11713–11714 (1997).
Ma, S., Han, X., Krishnan, S., Virgil, S. C. & Stoltz, B. M. Catalytic enantioselective stereoablative alkylation of 3-halooxindoles: facile access to oxindoles with C3 all-carbon quaternary stereocenters. Angew. Chem. Int. Ed. 48, 8037–8041 (2009).
Banik, B. K. (ed.) β-Lactams: Unique Structures of Distinction for Novel Molecules (Springer, Berlin, 2013).
Decuyper, L. et al. Antibacterial and β-lactamase inhibitory activity of monocyclic β-lactams. Med. Res. Rev. 38, 426–503 (2018).
Galletti, P. & Giacomini, D. Monocyclic β-lactams: new structures for new biological activities. Curr. Med. Chem. 18, 4265–4283 (2011).
Chrusciel, R. A. et al. Therapeutic compounds and compositions. WO patent 2015/120062 A2 (2015).
Ojima, I., Zuniga, E. S. & Seitz, J. D. in β-Lactams: Unique Structures of Distinction for Novel Molecules (ed. Banik, B. K.) 1–64 (Springer, Berlin, 2013).
Du, X. & Huang, Z. Advances in base-metal-catalyzed alkene hydrosilylation. ACS Catal. 7, 1227–1243 (2017).
Schley, N. D. & Fu, G. C. Nickel-catalyzed Negishi arylations of propargylic bromides: a mechanistic investigation. J. Am. Chem. Soc. 136, 16588–16593 (2014).
Henry-Riyad, H. et al. in Handbook of Reagents for Organic Synthesis (ed. Fuchs, P. L.) 620–626 (Wiley, New York, 2013).
Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences, R01–GM62871) and the Gordon and Betty Moore Foundation (Caltech Center for Catalysis and Chemical Synthesis). We thank L. M. Henling, D. G. VanderVelde and S. C. Virgil for assistance and discussions.
Nature thanks C. Gosmini and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
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This file contains: I. General Information; II. Catalytic Enantioconvergent Couplings; III. Effect of Reaction Parameters; IV. Functional-Group Compatibility; V. Derivatization of the Coupling Products; VI. Mechanistic Studies; VII. Assignment of Absolute Configuration; VIII. References; and IX. 1H NMR and 13C NMR Spectra; ee Analysis.
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Wang, Z., Yin, H. & Fu, G.C. Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563, 379–383 (2018). https://doi.org/10.1038/s41586-018-0669-y
- Alkyl Electrophiles
- Racemic Alkyl
- Nucleophile Electrophile
- Enantiomeric Excess
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