Abstract
Asymmetric transition-metal catalysis has had a far-reaching impact on chemical synthesis. However, non-precious metal-catalysed strategies that provide direct entry to compounds with enantioenriched trisubstituted and fully substituted stereogenic centres are scarce. Here we show that a sterically encumbered chiral N-heterocyclic carbene-Ni(0) catalyst, in conjunction with an organotriflate and a metal alkoxide as hydride donor, promotes 1,2-hydroarylation and hydroalkenylation of diverse alkenes and 1,3-dienes. Replacing the metal alkoxide with an organometallic reagent allows installation of two different carbogenic motifs. These multicomponent reactions proceed through regio- and enantioselective carbonickelation followed by carbon–nickel bond transformation, providing a streamlined pathway towards enantioenriched carbon- or heteroatom-substituted tertiary or quaternary stereogenic centres. Through selective carbofunctionalizations, enantiodivergent access to opposite enantiomers may be achieved using the same catalyst antipode. The method enables practical access to complex bioactive molecules and other medicinally valuable but synthetically challenging building blocks, such as those that contain deuterated methyl groups.
Similar content being viewed by others
Data availability
All data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2128517 (8), 2149572 (95) and 2173668 (Ni-1). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
References
Lin, G.-Q., You, Q.-D. & Cheng, J.-F. Chiral Drugs: Chemistry and Biological Action (Wiley, 2011).
Mori, K. Bioactive natural products and chirality. Chirality 23, 449–462 (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).
Crossley, R. The relevance of chirality to the study of biological activity. Tetrahedron 48, 8155–8178 (1992).
Noyori, R. Asymmetric catalysis: science and opportunities (Nobel Lecture). Angew. Chem. Int. Ed. 41, 2008–2022 (2002).
Trost, B. M. Asymmetric catalysis: an enabling science. Proc. Natl Acad. Sci. USA 101, 5348–5355 (2004).
Liu, Y., Han, S.-J., Liu, W.-B. & Stoltz, B. M. Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules. Acc. Chem. Res. 48, 740–751 (2015).
Tombo, G. M. R. & Belluš, D. Chirality and crop protection. Angew. Chem. Int. Ed. 30, 1193–1215 (1991).
McDonald, R. I., Liu, G. & Stahl, S. S. Palladium(II)-catalysed alkene functionalization via nucleopalladation: stereochemical pathways and enantioselective catalytic applications. Chem. Rev. 111, 2981–3019 (2011).
Crisenza, G. E. M. & Bower, J. F. Branch selective Murai-type alkene hydroarylation reactions. Chem. Lett. 45, 2–9 (2016).
Chen, J. & Lu, Z. Asymmetric hydrofunctionalization of minimally functionalized alkenes via earth abundant transition metal catalysis. Org. Chem. Front. 5, 260–272 (2018).
Oxtoby, L. J., Gurak, J. A., Wisniewski, S. R., Eastgate, M. D. & Engle, K. M. Palladium-catalysed reductive Heck coupling of alkenes. Trends Chem. 1, 572–587 (2019).
Zweig, J. E., Kim, D. E. & Newhouse, R. T. Methods utilizing first-row transition metals in natural product total synthesis. Chem. Rev. 117, 11680–11752 (2017).
Zhang, M., Ji, Y. & Zhang, C. Transition metal catalysed enantioselective migratory functionalization reactions of alkenes through chain-walking. Chin. J. Chem. 40, 1608–1622 (2022).
Huang, X. et al. Enantioselective intermolecular Heck and reductive Heck reactions of aryl triflates, mesylates and tosylates catalysed by nickel. Angew. Chem. Int. Ed. 60, 2828–2832 (2021).
Chen, Y., Dang, L. & Ho, C.-Y. NHC–Ni catalysed enantioselective synthesis of 1,4-dienes by cross-hydroalkenylation of cyclic 1,3-dienes and heterosubstituted terminal olefins. Nat. Commun. 11, 2269 (2020).
Ho, C.-Y., Chan, C.-W. & He, L. Catalytic asymmetric hydroalkenylation of vinylarenes: electronic effects of substrates and chiral N-heterocyclic carbene ligands. Angew. Chem. Int. Ed. 54, 4512–4516 (2015).
Podhajsky, S. M., Iwai, Y., Cook-Sneathen, A. & Sigman, M. S. Asymmetric palladium-catalysed hydroarylation of styrenes and dienes. Tetrahedron 67, 4435–4441 (2011).
Chen, Y.-G. et al. Nickel-catalysed enantioselective hydroarylation and hydroalkenylation of styrenes. J. Am. Chem. Soc. 141, 3395–3399 (2019).
Lv, X.-Y., Fan, C., Xiao, L.-J., Xie, J.-H. & Zhou, Q.-L. Ligand-enabled Ni-catalysed enantioselective hydroarylation of styrenes and 1,3-dienes with arylboronic acids. CCS Chem. 1, 328–334 (2019).
Tran, H. N., Burgett, R. W. & Stanley, L. M. Nickel-catalysed asymmetric hydroarylation of vinylarenes: direct enantioselective synthesis of chiral 1,1-diarylethanes. J. Org. Chem. 86, 3836–3849 (2021).
Marcum, J. S., Taylor, T. R. & Meek, S. J. Enantioselective synthesis of functionalized arenes by nickel-catalysed site-selective hydroarylation of 1,3-dienes with aryl boronates. Angew. Chem. Int. Ed. 59, 14070–14075 (2020).
Friis, S. D., Pirnot, M. T. & Buchwald, S. L. Asymmetric hydroarylation of vinylarenes using a synergistic combination of CuH and Pd catalysis. J. Am. Chem. Soc. 138, 8372–8375 (2016).
Schuppe, A. W., Knippel, J. L., Borrajo-Calleja, G. M. & Buchwald, S. L. Enantioselective hydroalkenylation of olefins with enol sulfonates enabled by dual copper hydride and palladium catalysis. J. Am. Chem. Soc. 143, 5330–5335 (2021).
He, Y., Liu, C., Yu, L. & Zhu, S. Enantio- and regioselective NiH-catalysed reductive hydroarylation of vinylarenes with aryl iodides. Angew. Chem. Int. Ed. 59, 21530–21534 (2020).
He, Y., Song, H., Chen, J. & Zhu, S. NiH-catalysed asymmetric hydroarylation of N-acyl enamines to chiral benzylamines. Nat. Commun. 12, 638 (2021).
Cuesta-Galisteo, S., Schörgenhumer, J., Wei, X., Merino, J. & Nevado, C. Nickel-catalysed asymmetric synthesis of α-arylbenzamides. Angew. Chem. Int. Ed. 60, 1605–1609 (2021).
Anthony, D., Lin, Q., Baudet, J. & Diao, T. Nickel-catalysed asymmetric reductive diarylation of vinylarenes. Angew. Chem. Int. Ed. 58, 3198–3202 (2019).
Wei, X., Shu, W., García-Domínguez, A., Merino, E. & Nevado, C. Asymmetric Ni-catalysed radical relayed reductive coupling. J. Am. Chem. Soc. 142, 13515–13522 (2020).
Guo, L. et al. General method for enantioselective three-component carboarylation of alkenes enabled by visible-light dual photoredox/nickel catalysis. J. Am. Chem. Soc. 142, 20390–20399 (2020).
Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014).
Sardini, S. R. et al. Ni-catalysed arylboration of unactivated alkenes: scope and mechanistic studies. J. Am. Chem. Soc. 141, 9391–9400 (2019).
Thomas, S. P. & Aggarwal, V. K. Asymmetric hydroboration of 1,1-disubstituted alkenes. Angew. Chem. Int. Ed. 48, 1896–1898 (2009).
Mei, T.-S., Patel, H. H. & Sigman, M. S. Enantioselective construction of remote quaternary stereocentres. Nature 508, 340–344 (2014).
Zhang, C., Santiago, C. B., Crawford, J. M. & Sigman, M. S. Enantioselective dehydrogenative heck arylations of trisubstituted alkenes with indoles to construct quaternary stereocenters. J. Am. Chem. Soc. 137, 15668–15671 (2015).
Patel, H. H. & Sigman, M. S. Enantioselective palladium-catalysed alkenylation of trisubstituted alkenols to form allylic quaternary centers. J. Am. Chem. Soc. 138, 14226–14229 (2016).
Wang, Z., Yin, H. & Fu, G. C. Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563, 379–383 (2018).
Xiao, L.-J. et al. Nickel(0)-catalysed hydroarylation of styrenes and 1,3-dienes with organoboron compounds. Angew. Chem. Int. Ed. 57, 461–464 (2018).
Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns and frequency of nitrogen heterocycles among US FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).
Franz, A. K. & Wilson, S. O. Organosilicon molecules with medicinal applications. J. Med. Chem. 56, 388–405 (2013).
Yoshikai, N., Matsuda, H. & Nakamura, E. Hydroxyphosphine ligand for nickel-catalysed cross-coupling through nickel/magnesium bimetallic cooperation. J. Am. Chem. Soc. 131, 9590–9599 (2009).
Tasker, S. Z., Gutierrez, A. C. & Jamison, T. F. Nickel-catalysed Mizoroki–Heck reaction of aryl sulfonates and chlorides with electronically unbiased terminal olefins: high selectivity for branched products. Angew. Chem. Int. Ed. 53, 1858–1861 (2014).
Albright, A. et al. Design and synthesis of C2-symmetric N-heterocyclic carbene precursors and metal carbenoids. J. Org. Chem. 76, 7341–7351 (2011).
Liu, C.-F., Luo, X., Wang, H. & Koh, M. J. Catalytic regioselective olefin hydroarylation(alkenylation) by sequential carbonickelation-hydride transfer. J. Am. Chem. Soc. 143, 9498–9506 (2021).
Wang, H., Liu, C.-F., Martin, R. T., Gutierrez, O. & Koh, M. J. Directing-group-free catalytic dicarbofunctionalization of unactivated alkenes. Nat. Chem. 14, 188–195 (2022).
Würtz, S. & Glorius, F. Surveying sterically demanding N-heterocyclic carbene ligands with restricted flexibility for palladium-catalysed cross-coupling reactions. Acc. Chem. Res. 41, 1523–1533 (2008).
Harbeson, S. L. & Tung, R. D. Chapter 24 – Deuterium in drug discovery and development. Annu. Rep. Med. Chem. 46, 403–417 (2011).
Sun, Q. & Soulé, J.-F. Broadening of horizons in the synthesis of CD3-labeled molecules. Chem. Soc. Rev. 50, 10806–10835 (2021).
Atzrodt, J., Derdau, V., Fey, T. & Zimmermann, J. The renaissance of H/D exchange. Angew. Chem. Int. Ed. 46, 7744–7765 (2007).
Wang, Z.-C., Xie, P.-P., Xu, Y., Hong, X. & Shi, S.-L. Low-temperature nickel-catalysed C−N cross-coupling via kinetic resolution enabled by a bulky and flexible chiral N-heterocyclic carbene ligand. Angew. Chem. Int. Ed. 60, 16077–16084 (2021).
Green, S. A., Matos, J. L. M., Yagi, A. & Shenvi, R. A. Branch-selective hydroarylation: iodoarene–olefin cross-coupling. J. Am. Chem. Soc. 138, 12779–12782 (2016).
Cheltsov, A. V. et al. Vaccinia virus virulence factor N1L is a novel promising target for antiviral therapeutic intervention. J. Med. Chem. 53, 3899–3906 (2010).
Cai, Y. et al. Copper-catalysed enantioselective Markovnikov protoboration of α-olefins enabled by a buttressed N-heterocyclic carbene ligand. Angew. Chem. Int. Ed. 57, 1376–1380 (2018).
Xiang, J. N. et al. Method for preparing diphenyl propane lignan compound. Chinese patent CN102060640A (2011).
Weix, D. J. Methods and mechanisms for cross-electrophile coupling of Csp2 halides with alkyl electrophiles. Acc. Chem. Res. 48, 1767–1775 (2015).
Petruncio, G., Shellnutt, Z., Elahi-Mohassel, S., Alishetty, S. & Paige, M. Skipped dienes in natural product synthesis. Nat. Prod. Rep. 38, 2187–2213 (2021).
Hayashi, T., Konishi, M., Ito, H. & Kumada, M. Optically active allylsilanes. 1. Preparation by palladium-catalysed asymmetric Grignard cross-coupling and anti stereochemistry in electrophilic substitution reactions. J. Am. Chem. Soc. 104, 4962–4963 (1982).
Hayashi, T., Konishi, M., Ito, H. & Kumada, M. Optically active allylsilanes. 2. High stereoselectivity in asymmetric reaction with aldehydes producing homoallylic alcohols. J. Am. Chem. Soc. 104, 4963–4965 (1982).
Acknowledgements
This research was supported by the Ministry of Education of Singapore Academic Research Fund Tier 1 (A-0004139-00-00, M.J.K.) and by the National Key R&D Program of China (2021YFF0701600), the National Natural Science Foundation of China (91856111, 21871288, 21821002 and 22171280), the Science and Technology Commission of Shanghai Municipality (22XD1424900) and the CAS Youth Interdisciplinary Team (JCTD-2021-11, S.-L.S.). We thank G.K. Tan for X-ray crystallographic analysis.
Author information
Authors and Affiliations
Contributions
C.-F.L., Z.-C.W., X.L., J.L. and C.H.M.K. developed the catalytic method and conducted the mechanistic studies. M.J.K. and S.-L.S. directed the investigations. M.J.K. conceived the project and wrote the manuscript, with revisions provided by the other authors.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Catalysis thanks Chun Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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 Tables 1–8, Figs. 1–5, methods, note 1 and references.
Supplementary Data 1
Crystallographic data for compound 8.
Supplementary Data 2
Crystallographic data for compound 95.
Supplementary Data 3
Crystallographic data for compound Ni-1.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Liu, CF., Wang, ZC., Luo, X. et al. Synthesis of tri- and tetrasubstituted stereocentres by nickel-catalysed enantioselective olefin cross-couplings. Nat Catal 5, 934–942 (2022). https://doi.org/10.1038/s41929-022-00854-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41929-022-00854-8
- Springer Nature Limited
This article is cited by
-
Asymmetric paired oxidative and reductive catalysis enables enantioselective alkylarylation of olefins with C(sp3)−H bonds
Nature Communications (2024)
-
Enantioselective synthesis of multifunctional alkylboronates via N-heterocyclic carbene–nickel-catalysed carboboration of alkenes
Nature Synthesis (2024)
-
Enantioselective C–C cross-coupling of unactivated alkenes
Nature Catalysis (2023)
-
Pd-catalyzed diastereoselective 1,1-diarylation of 1,1-disubstituted alkenes enabling the modular synthesis of 1,1,2,2-tetraarylethanes
Science China Chemistry (2023)