The development of efficient methods, particularly catalytic and enantioselective processes, for the construction of all-carbon quaternary stereocentres is an important (and difficult) challenge in organic synthesis due to the occurrence of this motif in a range of bioactive molecules. One conceptually straightforward and potentially versatile approach is the catalytic enantioconvergent substitution reaction of a readily available racemic tertiary alkyl electrophile by an organometallic nucleophile; however, examples of such processes are rare. Here we demonstrate that a nickel-based chiral catalyst achieves enantioconvergent couplings of a variety of tertiary electrophiles (cyclic and acyclic α-halocarbonyl compounds) with alkenylmetal nucleophiles to form quaternary stereocentres with good yield and enantioselectivity under mild conditions in the presence of a range of functional groups. These couplings, which probably proceed via a radical pathway, provide access to an array of useful families of organic compounds, including intermediates in the total synthesis of two natural products, (–)-eburnamonine and madindoline A.
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The data that support the findings of this study are available in the Supplementary Information (experimental procedures and characterization data). Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 1958912 (13), 1958913 (81), and 1965146 (80). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
Christoffers, J. & Baro, A. Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis (Wiley–VCH, 2005).
Das, J. P. & Marek, I. Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. Chem. Commun. 47, 4593–4623 (2011).
Li, C., Ragab, S. S., Liu, G. & Tang, W. Enantioselective formation of quaternary carbon stereocenters in natural product synthesis: a recent update. Nat. Prod. Rep. 37, 276–292 (2020).
Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014).
Feng, J., Holmes, M. & Krische, M. J. Acyclic quaternary carbon stereocenters via enantioselective transition metal catalysis. Chem. Rev. 117, 12564–12580 (2017).
Braun, M. & Kotter, W. Titanium(iv)-catalyzed dynamic kinetic asymmetric transformation of alcohols, silyl ethers, and acetals under carbon allylation. Angew. Chem. Int. Ed. 43, 514–517 (2004).
Guo, C. et al. Core-structure-oriented asymmetric organocatalytic substitution of 3-hydroxyoxindoles: application in the enantioselective total synthesis of (+)-folicanthine. Angew. Chem. Int. Ed. 51, 1046–1050 (2012).
Zhao, W., Wang, Z., Chu, B. & Sun, J. Enantioselective formation of all-carbon quaternary stereocenters from indoles and tertiary alcohols bearing a directing group. Angew. Chem. Int. Ed. 54, 1910–1913 (2015).
Wendlandt, A. E., Vangal, P. & Jacobsen, E. N. Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. Nature 556, 447–451 (2018).
Trost, B. M. & Jiang, C. Atom economic asymmetric creation of quaternary carbon: regio- and enantioselective reactions of a vinylepoxide with a carbon nucleophile. J. Am. Chem. Soc. 123, 12907–12908 (2001).
Hou, X.-L. & Sun, N. Construction of chiral quaternary carbon centers by Pd-catalyzed asymmetric allylic substitution with P,N-1,1′-ferrocene ligands. Org. Lett. 6, 4399–4401 (2004).
Zhang, P., Le, H., Kyne, R. E. & Morken, J. P. Enantioselective construction of all-carbon quaternary centers by branch-selective Pd-catalyzed allyl-allyl cross-coupling. J. Am. Chem. Soc. 133, 9716–9719 (2011).
Khan, A., Yang, L., Xu, J., Jin, L. Y. & Zhang, Y. J. Palladium-catalyzed asymmetric decarboxylative cycloaddition of vinylethylene carbonates with Michael acceptors: construction of vicinal quaternary stereocenters. Angew. Chem. Int. Ed. 53, 11257–11260 (2014).
Tsuchida, K., Senda, Y., Nakajima, K. & Nishibayashi, Y. Construction of chiral tri- and tetra-arylmethanes bearing quaternary carbon centers: copper-catalyzed enantioselective propargylation of indoles with propargylic esters. Angew. Chem. Int. Ed. 55, 9728–9732 (2016).
Xu, Y.-W. & Hu, X.-P. Diastereo- and enantioselective copper-catalyzed decarboxylative ring-opening [3+2] annulation of tertiary propargylic carbamates through regioselective α-attack of γ-butenolides. Org. Lett. 21, 8091–8096 (2019).
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).
Zhang, H., Hong, L., Kang, H. & Wang, R. Construction of vicinal all-carbon quaternary stereocenters by catalytic asymmetric alkylation reaction of 3-bromooxindoles with 3-substituted indoles: total synthesis of (+)-perophoramidine. J. Am. Chem. Soc. 135, 14098–14101 (2013).
Zheng, J. et al. Nickel-catalyzed conjugate addition of silyl ketene imines to in situ generated indol-2-ones: highly enantioselective construction of vicinal all-carbon quaternary stereocenters. Angew. Chem. Int. Ed. 56, 13107–13111 (2017).
Liu, X. et al. Construction of vicinal all-carbon quaternary stereocenters enabled by a catalytic asymmetric dearomatization reaction of β-naphthols with 3-bromooxindoles. ACS Catal. 8, 10888–10894 (2018).
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).
Choi, J. & Fu, G. C. Transition metal-catalyzed alkyl–alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).
Iwasaki, T. & Kambe, N. Ni-catalyzed C–C couplings using alkyl electrophiles. Top. Curr. Chem. 374, 66 (2016).
Kaga, A. & Chiba, S. Engaging radicals in transition metal-catalyzed cross-coupling with alkyl electrophiles: recent advances. ACS Catal. 7, 4697–4706 (2017).
Wang, Z., Yin, H. & Fu, G. C. Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563, 379–383 (2018).
Li, J. et al. Formal enantioconvergent substitution of alkyl halides via catalytic asymmetric photoredox radical coupling. Nat. Commun. 9, 2445 (2018).
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).
Wu, L., Yang, G. & Zhang, W. Ni-catalyzed enantioconvergent coupling of epoxides with alkenylboronic acids: construction of oxindoles bearing quaternary carbons. CCS Chem 1, 623–631 (2019).
Korch, K. M., Loskot, S. A. & Stoltz, B. M. Asymmetric synthesis of quaternary stereocenters via metal enolates. In PATAI’S Chemistry of Functional Groups (ed Rappoport, Z.) https://doi.org/10.1002/9780470682531.pat0858 (2017).
Minko, Y. & Marek, I. Stereodefined acyclic trisubstituted metal enolates towards the asymmetric formation of quaternary carbon stereocentres. Chem. Commun. 50, 12597–12611 (2014).
Xu, S., Kamada, H., Kim, E. H., Oda, A. & Negishi, E.-I. Pd-catalyzed cross-coupling with organometals containing Zn, Al, Zr, and so on—the Negishi coupling and its recent advances. In Metal-Catalyzed Cross-Coupling Reactions and More Vol. 1 (eds De Meijere, A. & Brase, S., Oestreich, M.) 133–278 (Wiley–VCH, 2014).
Pandey, G., Mishra, A. & Khamrai, J. Generation of all-carbon quaternary stereocenters at the C-3 carbon of piperidinones and pyrrolidinones and its application in natural product total synthesis. Tetrahedron 74, 4903–4915 (2018).
Lou, S. & Fu, G. C. Enantioselective alkenylation via nickel-catalyzed cross-coupling with organozirconium reagents. J. Am. Chem. Soc. 132, 5010–5011 (2010).
Zhang, L. et al. Bakkenolide A inhibits leukemia by regulation of HDAC3 and PI3K/Akt-related signaling pathways. Biomedicine & Pharmacotherapy 83, 958–966 (2016).
Jennings, L. D. et al. Cyclobutane carboxamide inhibitors of fungal melanin: biosynthesis and their evaluation as fungicides. Bioorg. Med. Chem. 8, 897–907 (2000).
Saverino, D., Debbia, E. A., Pesce, A., Lepore, A. M. & Schito, G. C. Antibacterial profile of flurithromycin, a new macrolide. J. Antimicrob. Chemother. 30, 261–272 (1992).
Yang, X., Wu, T., Phipps, R. J. & Toste, F. D. Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev. 115, 826–870 (2015).
Bizet, V., Besset, T., Ma, J.-A. & Cahard, D. Recent progress in asymmetric fluorination and trifluoromethylation reactions. Curr. Top. Med. Chem. 14, 901–940 (2014).
Fujiwara, T. & Takeuchi, Y. Application of chiral α-monofluorocarbonyl compounds to analytical and medicinal chemistry. Curr. Org. Chem. 14, 950–961 (2010).
Zhu, Y. et al. Modern approaches for asymmetric construction of carbon−fluorine quaternary stereogenic centers: synthetic challenges and pharmaceutical needs. Chem. Rev. 118, 3887–3964 (2018).
Schley, N. D. & Fu, G. C. Nickel-catalyzed Negishi arylations of propargylic bromides: a mechanistic investigation. J. Am. Chem. Soc. 136, 16588–16593 (2014).
Yin, H. & Fu, G. C. A mechanistic investigation of enantioconvergent Kumada reactions of racemic α-bromoketones catalyzed by a nickel/bis(oxazoline) complex. J. Am. Chem. Soc. 141, 15433–15440 (2019).
Node, M., Nagasawa, H. & Fuji, K. Chiral total synthesis of indole alkaloids of the Aspidosperma and Hunteria types. J. Org. Chem. 55, 517–521 (1990).
Hosokawa, S. & Kobayashi, S. Total synthesis of madindoline A. J. Synth. Org. Chem Jpn. 59, 1103–1108 (2001).
This paper is dedicated to the memory of Professor Jonathan Williams (University of Bath). Support has been provided by the NIGMS (R37-GM62871) and the Dow Next Generation Educator Fund (grant to Caltech). We thank S.M. Batiste, L.M. Henling, H. Huo, F. Schneck, M.K. Takase, S.C. Virgil and W. Zhang for assistance and helpful discussions.
The authors declare no competing interests.
Peer review information Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.
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General information, preparation of ligands and electrophiles, catalytic enantioconvergent alkenylations, effect of reaction parameters, studies of functional group compatibility, derivatization of the coupling products, applications to the formal total synthesis of natural products, mechanistic studies, assignments of absolute configuration, references, NMR spectra and determination of stereoselectivity, Tables 1–5 and Figs. 1–3.
Supplementary Data 1
Crystallographic data for compound 13. CCDC reference 1958912.
Supplementary Data 2
Crystallographic data for compound 80. CCDC reference 1965146.
Supplementary Data 3
Crystallographic data for compound 81. CCDC reference 1958913.
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Wang, Z., Yang, ZP. & Fu, G.C. Quaternary stereocentres via catalytic enantioconvergent nucleophilic substitution reactions of tertiary alkyl halides. Nat. Chem. 13, 236–242 (2021). https://doi.org/10.1038/s41557-020-00609-7