Abstract
Cross-coupling of two alkyl fragments is an efficient method to produce organic molecules rich in sp3-hybridized carbon centres, which are attractive candidate compounds in drug discovery. Enantioselective C(sp3)–C(sp3) coupling is challenging, especially of alkyl electrophiles without an activating group (aryl, vinyl, carbonyl). Here, we report a strategy based on nickel hydride addition to internal olefins followed by nickel-catalysed alkyl–alkyl coupling. This strategy enables the enantioselective cross-coupling of non-activated alkyl halides with alkenyl boronates to produce chiral alkyl boronates. Employing readily available and stable olefins as pro-chiral nucleophiles, the coupling proceeds under mild conditions and exhibits broad scope and high functional-group tolerance. Applications for the functionalization of natural products and drug molecules, as well as the synthesis of chiral building blocks and a key intermediate to (S)-(+)-pregabalin, are demonstrated.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
Crystallographic data for 3e′ and 4g′ have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2011678 (3e′) and CCDC 1971802 (4g′). Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk. All other data supporting the findings of this study, including experimental procedures and compound characterization, NMR, HPLC and X-ray analyses are available within the Article and its Supplementary Information.
Change history
01 March 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41557-021-00649-7
References
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).
Ritchie, T. J. & Macdonald, S. J. The impact of aromatic ring count on compound developability – are too many aromatic rings a liability in drug design? Drug Discov. Today 14, 1011–1020 (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).
Hu, X. Nickel-catalyzed cross coupling of non-activated alkyl halides: a mechanistic perspective. Chem. Sci. 2, 1867–1886 (2011).
Rudolph, A. & Lautens, M. Secondary alkyl halides in transition-metal-catalyzed cross-coupling reactions. Angew. Chem. Int. Ed. 48, 2656–2670 (2009).
Cherney, A. H., Kadunce, N. T. & Reisman, S. E. Enantioselective and enantiospecific transition-metal-catalyzed cross-coupling reactions of organometallic reagents to construct C–C bonds. Chem. Rev. 115, 9587–9652 (2015).
Glasspoole, B. W. & Crudden, C. M. The final frontier. Nat. Chem. 3, 912–913 (2011).
Owston, N. A. & Fu, G. C. Asymmetric alkyl–alkyl cross-couplings of unactivated secondary alkyl electrophiles: stereoconvergent Suzuki reactions of racemic acylated halohydrins. J. Am. Chem. Soc. 132, 11908–11909 (2010).
Wilsily, A., Tramutola, F., Owston, N. A. & Fu, G. C. New directing groups for metal-catalyzed asymmetric carbon–carbon bond-forming processes: stereoconvergent alkyl–alkyl Suzuki cross-couplings of unactivated electrophiles. J. Am. Chem. Soc. 134, 5794–5797 (2012).
Zultanski, S. L. & Fu, G. C. Catalytic asymmetric γ-alkylation of carbonyl compounds via stereoconvergent Suzuki cross-couplings. J. Am. Chem. Soc. 133, 15362–15364 (2011).
Arp, F. O. & Fu, G. C. Catalytic enantioselective Negishi reactions of racemic secondary benzylic halides. J. Am. Chem. Soc. 127, 10482–10483 (2005).
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).
Son, S. & Fu, G. C. Nickel-catalyzed asymmetric Negishi cross-couplings of secondary allylic chlorides with alkylzincs. J. Am. Chem. Soc. 130, 2756–2757 (2008).
Wang, Z., Yin, H. & Fu, G. C. Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563, 379–383 (2018).
Zhou, F., Zhang, Y., Xu, X. & Zhu, S. NiH-catalyzed remote asymmetric hydroalkylation of alkenes with racemic α-bromo amides. Angew. Chem. Int. Ed. 58, 1754–1758 (2019).
Cordier, C. J., Lundgren, R. J. & Fu, G. C. Enantioconvergent cross-couplings of racemic alkylmetal reagents with unactivated secondary alkyl electrophiles: catalytic asymmetric Negishi α-alkylations of N-Boc-pyrrolidine. J. Am. Chem. Soc. 135, 10946–10949 (2013).
Mu, X., Shibata, Y., Makida, Y. & Fu, G. C. Control of vicinal stereocenters through nickel-catalyzed alkyl–alkyl cross-coupling. Angew. Chem. Int. Ed. 56, 5821–5824 (2017).
Deutsch, C., Krause, N. & Lipshutz, B. H. CuH-catalyzed reactions. Chem. Rev. 108, 2916–2927 (2008).
Pirnot, M. T., Wang, Y. M. & Buchwald, S. L. Copper hydride catalyzed hydroamination of alkenes and alkynes. Angew. Chem. Int. Ed. 55, 48–57 (2016).
Zhu, S., Niljianskul, N. & Buchwald, S. L. Enantio- and regioselective CuH-catalyzed hydroamination of alkenes. J. Am. Chem. Soc. 135, 15746–15749 (2013).
Miki, Y., Hirano, K., Satoh, T. & Miura, M. Copper-catalyzed intermolecular regioselective hydroamination of styrenes with polymethylhydrosiloxane and hydroxylamines. Angew. Chem. Int. Ed. 52, 10830–10834 (2013).
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).
Yang, Y., Perry, I. B. & Buchwald, S. L. Copper-catalyzed enantioselective addition of styrene-derived nucleophiles to imines enabled by ligand-controlled chemoselective hydrocupration. J. Am. Chem. Soc. 138, 9787–9790 (2016).
Bandar, J. S., Ascic, E. & Buchwald, S. L. Enantioselective CuH-catalyzed reductive coupling of aryl alkenes and activated carboxylic acids. J. Am. Chem. Soc. 138, 5821–5824 (2016).
Lu, X. et al. Practical carbon–carbon bond formation from olefins through nickel-catalyzed reductive olefin hydrocarbonation. Nat. Commun. 7, 11129 (2016).
Bera, S. & Hu, X. Nickel-catalyzed regioselective hydroalkylation and hydroarylation of alkenyl boronic esters. Angew. Chem. Int. Ed. 58, 13854–13859 (2019).
Buslov, I., Becouse, J., Mazza, S., Montandon-Clerc, M. & Hu, X. Chemoselective alkene hydrosilylation catalyzed by nickel pincer complexes. Angew. Chem. Int. Ed. 54, 14523–14526 (2015).
Gaydou, M., Moragas, T., Juliá-Hernández, F. & Martin, R. Site-selective catalytic carboxylation of unsaturated hydrocarbons with CO2 and water. J. Am. Chem. Soc. 139, 12161–12164 (2017).
Zhou, F., Zhu, J., Zhang, Y. & Zhu, S. NiH-catalyzed reductive relay hydroalkylation: a strategy for the remote C(sp3)–H alkylation of alkenes. Angew. Chem. Int. Ed. 57, 4058–4062 (2018).
Sommer, H., Juliá-Hernández, F., Martin, R. & Marek, I. Walking metals for remote functionalization. ACS Cent. Sci. 4, 153–165 (2018).
Sun, S.-Z., Börjesson, M., Martin-Montero, R. & Martin, R. Site-selective Ni-catalyzed reductive coupling of α-haloboranes with unactivated olefins. J. Am. Chem. Soc. 140, 12765–12769 (2018).
Sun, S.-Z., Romano, C. & Martin, R. Site-selective catalytic deaminative alkylation of unactivated olefins. J. Am. Chem. Soc. 141, 16197–16201 (2019).
He, Y., Cai, Y. & Zhu, S. Mild and regioselective benzylic C–H functionalization: Ni-catalyzed reductive arylation of remote and proximal olefins. J. Am. Chem. Soc. 139, 1061–1064 (2017).
Vasseur, A., Bruffaerts, J. & Marek, I. Remote functionalization through alkene isomerization. Nat. Chem. 8, 209–219 (2016).
Zhang, Y., Han, B. & Zhu, S. Rapid access to highly functionalized alkyl boronates by NiH-catalyzed remote hydroarylation of boron-containing alkenes. Angew. Chem. Int. Ed. 58, 13860–13864 (2019).
Davidson, M., Hughes, A. K., Marder, T. B. & Wade, K. Contemporary Boron Chemistry (Royal Society of Chemistry, 2000).
Liu, S.-Y. & Stephan, D. W. Contemporary research in boron chemistry. Chem. Soc. Rev. 48, 3434–3435 (2019).
Leonori, D. & Aggarwal, V. K. Stereospecific couplings of secondary and tertiary boronic esters. Angew. Chem. Int. Ed. 54, 1082–1096 (2015).
Sandford, C. & Aggarwal, V. K. Stereospecific functionalizations and transformations of secondary and tertiary boronic esters. Chem. Commun. 53, 5481–5494 (2017).
Collins, B. S. L., Wilson, C. M., Myers, E. L. & Aggarwal, V. K. Asymmetric synthesis of secondary and tertiary boronic esters. Angew. Chem. Int. Ed. 56, 11700–11733 (2017).
Brown, H. C. & Zweifel, G. Hydroboration as a convenient procedure for the asymmetric synthesis of alcohols of high optical purity. J. Am. Chem. Soc. 83, 486–487 (1961).
Hall, D. G. (ed.) Boronic Acids: Preparation, Applications in Organic Synthesis and Medicine (Wiley–VCH, 2006).
Burns, M. et al. Assembly-line synthesis of organic molecules with tailored shapes. Nature 513, 183–188 (2014).
Ganić, A. & Pfaltz, A. Iridium-catalyzed enantioselective hydrogenation of alkenylboronic esters. Chem. Eur. J. 18, 6724–6728 (2012).
Xi, Y. & Hartwig, J. F. Diverse asymmetric hydrofunctionalization of aliphatic internal alkenes through catalytic regioselective hydroboration. J. Am. Chem. Soc. 138, 6703–6706 (2016).
Zhang, L. et al. Catalytic conjunctive cross-coupling enabled by metal-induced metallate rearrangement. Science 351, 70–74 (2016).
Schmidt, J., Choi, J., Liu, A. T., Slusarczyk, M. & Fu, G. C. A general, modular method for the catalytic asymmetric synthesis of alkylboronate esters. Science 354, 1265–1269 (2016).
Stoltz, B. M. et al. Potassium tert-butoxide-catalyzed dehydrogenative C–H silylation of heteroaromatics: a combined experimental and computational mechanistic study. J. Am. Chem. Soc. 139, 6867–6879 (2017).
Wynn, D. A., Roth, M. M. & Pollard, B. D. The solubility of alkali-metal fluorides in non-aqueous solvents with and without crown ethers, as determined by flame emission spectrometry. Talanta 31, 1036–1040 (1984).
Chen, Z.-M., Hilton, M. J. & Sigman, M. S. Palladium-catalyzed enantioselective redox-relay Heck arylation of 1,1-disubstituted homoallylic alcohols. J. Am. Chem. Soc. 138, 11461–11464 (2016).
Sawamura, M. & Ito, Y. Catalytic asymmetric synthesis by means of secondary interaction between chiral ligands and substrates. Chem. Rev. 92, 857–871 (1992).
Corriu, R. J. P., Guerin, C., Henner, B. & Wang, Q. Pentacoordinate hydridosilicates: synthesis and some aspects of their reactivity. Organometallics 10, 2297–2303 (1991).
Bandar, J. S., Pirnot, M. T. & Buchwald, S. L. Mechanistic studies lead to dramatically improved reaction conditions for the Cu-catalyzed asymmetric hydroamination of olefins. J. Am. Chem. Soc. 137, 14812–14818 (2015).
Huo, H., Gorsline, B. J. & Fu, G. C. Catalyst-controlled doubly enantioconvergent coupling of racemic alkyl nucleophiles and electrophiles. Science 367, 559–564 (2020).
Frampton, J. E. Pregabalin: a review of its use in adults with generalized anxiety disorder. CNS Drugs 28, 835–854 (2014).
Mujahid, M. & Muthukrishnan, M. A new enantioselective synthesis of the anticonvulsant drug pregabalin (Lyrica) based on a hydrolytic kinetic resolution method. Chirality 25, 965–969 (2013).
Zheng, B. & Srebnik, M. Preparation and selective cleavage reactions of boron-zirconium 1,1-bimetalloalkanes. Tetrahedron Lett. 34, 4133–4136 (1993).
Gutierrez, O., Tellis, J. C., Primer, D. N., Molander, G. A. & Kozlowski, M. C. Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. J. Am. Chem. Soc. 137, 4896–4899 (2015).
Author information
Authors and Affiliations
Contributions
S.B. and X.H. conceived the project. S.B. designed and optimized the synthetic method. S.B. and R.M. studied the scope, application and mechanism. All authors analysed the data and co-wrote the manuscript. X.H. directed the research.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information
Supplementary information including optimization of reaction conditions (Supplementary Tables 1–6), general procedures, functional group transformations, mechanistic investigations, crystallography details, NMR spectra of compounds, references.
Supplementary Data 1
Compound 3e′.
Supplementary Data 2
Compound 4g′.
Rights and permissions
About this article
Cite this article
Bera, S., Mao, R. & Hu, X. Enantioselective C(sp3)–C(sp3) cross-coupling of non-activated alkyl electrophiles via nickel hydride catalysis. Nat. Chem. 13, 270–277 (2021). https://doi.org/10.1038/s41557-020-00576-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41557-020-00576-z
This article is cited by
-
Ligand-controlled NiH-catalyzed regiodivergent hydroalkylation of 2-alkenylazaarenes
Science China Chemistry (2024)
-
Ligand-modulated nickel-catalyzed regioselective silylalkylation of alkenes
Nature Communications (2023)
-
Ligand-enabled Ni-catalysed enantioconvergent intermolecular Alkyl-Alkyl cross-coupling between distinct Alkyl halides
Nature Communications (2023)
-
Nickel-catalysed hydrodimerization of unactivated terminal alkenes
Nature Synthesis (2023)
-
Electrochemical halogen-atom transfer alkylation via α-aminoalkyl radical activation of alkyl iodides
Nature Communications (2023)