Abstract
Cyclic organic molecules are common among natural products and pharmaceuticals1,2. In fact, the overwhelming majority of small-molecule pharmaceuticals contain at least one ring system, as they provide control over molecular shape, often increasing oral bioavailability while providing enhanced control over the activity, specificity and physical properties of drug candidates3,4,5. Consequently, new methods for the direct site and diastereoselective synthesis of functionalized carbocycles are highly desirable. In principle, molecular editing by C–H activation offers an ideal route to these compounds. However, the site-selective C–H functionalization of cycloalkanes remains challenging because of the strain encountered in transannular C–H palladation. Here we report that two classes of ligands—quinuclidine-pyridones (L1, L2) and sulfonamide-pyridones (L3)—enable transannular γ-methylene C–H arylation of small- to medium-sized cycloalkane carboxylic acids, with ring sizes ranging from cyclobutane to cyclooctane. Excellent γ-regioselectivity was observed in the presence of multiple β-C–H bonds. This advance marks a major step towards achieving molecular editing of saturated carbocycles: a class of scaffolds that are important in synthetic and medicinal chemistry3,4,5. The utility of this protocol is demonstrated by two-step formal syntheses of a series of patented biologically active small molecules, prior syntheses of which required up to 11 steps6.
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 51 print issues and online access
$199.00 per year
only $3.90 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
The data supporting the findings of this study are available within the article and its Supplementary Information files.
References
Bemis, G. W. & Murcko, M. A. The properties of known drugs. 1. Molecular frameworks. J. Med. Chem. 39, 2887–2893 (1996).
Nicolaou, K. C. & Sorensen, E. J. Classics in Total Synthesis: Targets, Strategies, Methods (Wiley, 1996).
Veber, D. F. et al. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45, 2615–2623 (2002).
Fang, Z., Song, Y., Zhan, P., Zhang, Q. & Liu, X. Conformational restriction: an effective tactic in ‘follow-on’-based drug discovery. Future Med. Chem. 6, 885–901 (2014).
Shearer, J., Castro, J. L., Lawson, A. D. G., MacCoss, M. & Taylor, R. D. Rings in clinical trials and drugs: present and future. J. Med. Chem. 65, 8699–8712 (2022).
Dominguez, C. et al. Histone deacetylase inhibitors for treatment of neurodegenerative diseases. Patent WO 2014/159224 A1 (2 October 2014).
Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis (Wiley, 1989).
Ma, S. Handbook of Cyclization Reactions (Wiley, 2009).
Brill, Z. G., Condakes, M. L., Ting, C. P. & Maimone, T. J. Navigating the chiral pool in the total synthesis of complex terpene natural products. Chem. Rev. 117, 11753–11795 (2017).
Xia, G. et al. Reversing conventional site-selectivity in C(sp3)–H bond activation. Nat. Chem. 11, 571–577 (2019).
Fan, Z. et al. Molecular editing of aza-arene C–H bonds by distance, geometry and chirality. Nature 610, 87–93 (2022).
Meng, G. et al. Achieving site-selectivity for C–H activation processes based on distance and geometry: a carpenter’s approach. J. Am. Chem. Soc. 142, 10571–10591 (2020).
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).
Zaitsev, V. G., Shabashov, D. & Daugulis, O. Highly regioselective arylation of sp3 C–H bonds catalyzed by palladium acetate. J. Am. Chem. Soc. 127, 13154–13155 (2005).
Banerjee, A., Sarkar, S. & Patel, B. K. C–H functionalization of cycloalkanes. Org. Biomol. Chem. 15, 505–530 (2017).
Andra, M. S. et al. Enantio- and diastereoswitchable C–H arylation of methylene groups in cycloalkanes. Chem. Eur. J. 25, 8503–8507 (2019).
He, G. & Chen, G. A practical strategy for the structural diversification of aliphatic scaffolds through the palladium-catalyzed picolinamide-directed remote functionalization of unactivated C(sp3)–H bonds. Angew. Chem. Int. Edn 50, 5192–5196 (2011).
Cui, W. et al. Palladium-catalyzed remote C(sp3)−H arylation of 3-pinanamine. Org. Lett. 16, 4288–4291 (2014).
Seki, A., Takahashi, Y. & Miyake, T. Synthesis of cis-3-arylated cycloalkylamines through palladium-catalyzed methylene sp3 carbon–hydrogen-bond activation. Tetrahedron Lett. 55, 2838–2841 (2014).
Wu, Y., Chen, Y., Liu, T., Eastgate, M. D. & Yu, J. Q. Pd-catalyzed γ-C(sp3)−H arylation of free amines using a transient directing group. J. Am. Chem. Soc. 138, 14554–14557 (2016).
Topczewski, J. J., Cabrera, P. J., Saper, N. I. & Sanford, M. S. Palladium-catalysed transannular C–H functionalization of alicyclic amines. Nature 531, 220–224 (2016).
Xu, Y., Young, M. C., Wang, C., Magness, D. M. & Dong, G. Catalytic C(sp3)–H arylation of free primary amines with an exo directing group generated in situ. Angew. Chem. Int. Edn 55, 9084–9087 (2016).
Van Steijvoort, B. F., Kaval, N., Kulago, A. A. & Maes, B. U. W. Remote functionalization: palladium-catalyzed C5(sp3)–H arylation of 1-Boc-3-aminopiperidine through the use of a bidentate directing group. ACS Catal. 6, 4486–4490 (2016).
Zhao, J., Zhao, X., Cao, P., Liu, J. & Wu, B. Polycyclic azetidines and pyrrolidines via palladium-catalyzed intramolecular amination of unactivated C(sp3)−H bonds. Org. Lett. 19, 4880–4883 (2017).
Coomber, C. E. et al. Silver-free palladium-catalyzed C(sp3)−H arylation of saturated bicyclic amine scaffolds. J. Org. Chem. 83, 2495–2503 (2018).
Cabrera, P. J., Lee, M. & Sanford, M. S. Second-generation palladium catalyst system for transannular C−H functionalization of azabicycloalkanes. J. Am. Chem. Soc. 140, 5599–5606 (2018).
Chen, Y. Q. et al. Overcoming the limitations of γ- and δ-C−H arylation of amines through ligand development. J. Am. Chem. Soc. 140, 17884–17894 (2018).
Landge, V. G., Parveen, A., Nandakumar, A. & Balaraman, E. Pd(II)-catalyzed gamma-C(sp3)–H alkynylation of amides: selective functionalization of R chains of amides R1C(O)NHR. Chem. Commun. 54, 7483–7486 (2018).
Aguilera, E. Y. & Sanford, M. S. Model complexes for the palladium-catalyzed transannular C−H functionalization of alicyclic amines. Organometallics 38, 138–142 (2019).
Li, Z., Dechantsreiter, M. & Dandapani, S. Systematic investigation of the scope of transannular C−H heteroarylation of cyclic secondary amines for synthetic application in medicinal chemistry. J. Org. Chem. 85, 6747–6760 (2020).
Chan, H. S. S., Yang, J. & Yu, J.-Q. Catalyst-controlled site-selective methylene C–H lactonization of dicarboxylic acids. Science 376, 1481–1487 (2022).
Liu, B., Romine, A. M., Rubel, C. Z., Engle, K. M. & Shi, B.-F. Transition-metal-catalyzed, coordination-assisted functionalization of nonactivated C(sp3)−H bonds. Chem. Rev. 121, 14957–15074 (2021).
Stefane, B., Brozic, P., Vehovc, M., Rizner, T. L. & Gobec, S. New cyclopentane derivatives as inhibitors of steroid metabolizing enzymes AKR1C1 and AKR1C3. Eur. J. Med. Chem. 44, 2563–2571 (2009).
Haydar, S. N. et al. 5-membered heteroaryl carboxamide compounds for treatment of HBV. Patent WO 2020/086533 A1 (30 April 2020).
Chen, H. et al. Oxadiazole transient receptor potential channel inhibitors. Patent WO 2018/162607 A1 (13 September 2018).
Chobanian, H. et al. Antidiabetic compounds. Patent WO 2015/119899 A1 (13 August 2015).
McMinn, D. & Rao, M. Thiazole derivatives as protein secretion inhibitors. Patent WO 2020/176863 A1 (3 September 2020).
Li, L. & Zhong, M. Inhibitors of HCV NS5A. Patent WO 2010/065681 A1 (10 June 2010).
Wager, T. T. et al.Discovery of two clinical histamine H3receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)-phenyl]cyclobutanecarboxamide (PF-03654746) and trans−3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764). J. Med. Chem. 54, 7602–7620 (2011).
Shao, Q., Wu, K., Zhuang, Z., Qian, S. & Yu, J.-Q. From Pd(OAc)2 to chiral catalysts: the discovery and development of bifunctional mono-N-protected amino acid ligands for diverse C–H functionalization reactions. Acc. Chem. Res. 53, 833–851 (2020).
Wang, Z. et al. Ligand-controlled divergent dehydrogenative reactions of carboxylic acids via C−H activation. Science 374, 1281–1285 (2021).
Hamama, W. S., El-Magid, O. M. A. & Zoorob, H. H. Chemistry of quinuclidines as nitrogen bicyclic bridged-ring structures. J. Heterocyclic Chem. 43, 1397–1420 (2006).
Chen, G. et al. Ligand-accelerated enantioselective methylene C(sp3)–H bond activation. Science 353, 1023–1027 (2016).
Chen, G. et al. Ligand-enabled β-C–H arylation of α-amino acids without installing exogenous directing groups. Angew. Chem. Int. Edn 56, 1506–1509 (2017).
Zhuang, Z. et al. Ligand-enabled β-C(sp3)–H olefination of free carboxylic acids. J. Am. Chem. Soc. 140, 10363–10367 (2018).
Hu, L. et al. Pd(II)-catalyzed enantioselective C(sp3)−H activation/cross-coupling reactions of free carboxylic acids. Angew. Chem. Int. Edn 58, 2134–2138 (2019).
Strassfeld, D. A., Chen, C.-Y., Park, H. S., Phan, J. & Yu, J.-Q. δ-C(sp3)–H activation of free alcohols enabled by rationally designed H-bond-acceptor ligands. Preprint at https://doi.org/10.26434/chemrxiv-2023-19xhw (2023).
Li, C.-J. Cross-dehydrogenative coupling (CDC): exploring C–C bond formations beyond functional group transformations. Acc. Chem. Res. 42, 335–344 (2009).
Wang, P. et al. Ligand-accelerated non-directed C–H functionalization of arenes. Nature 551, 489–493 (2017).
Acknowledgements
We acknowledge The Scripps Research Institute and the National Institutes of Health (NIGMS grants 2R01GM084019 and F32GM143921) for their financial support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank S. Chan for proofreading and providing helpful suggestions in preparing the manuscript. We thank G. Meng, S. Chan and N. Lam for helpful discussions. We thank Y. Lin for the preparation of ligand. J. Chen, B. Sanchez and Q. N. Wong are acknowledged for their assistance with liquid chromatography–mass spectrometry analysis and for separation of some products. We thank M. Gembicky, J. Bailey and the University of California San Diego Crystallography Facility for X-ray crystallographic analysis.
Author information
Authors and Affiliations
Contributions
J.-Q.Y. conceived the concept. G.K. designed and prepared the quinuclidine-pyridone ligands. G.K. and T.S. discovered and developed the transannular γ-C–H arylation of cycloalkane carboxylic acids with ring sizes ranging from five to eight. D.A.S. and C.-Y.C. discovered and developed the transannular C–H arylation of cyclobutane carboxylic acids. G.K., D.A.S. and J.-Q.Y. wrote the manuscript. J.-Q.Y. directed the project.
Corresponding author
Ethics declarations
Competing interests
J.-Q.Y. and G.K. are inventors on a patent application related to the portion of this work covering 5- to 8-membered cycloalkane carboxylic acids and ligands L1 and L2 (US Patent application 63/483,314) filed by The Scripps Research Institute. The remaining authors declare no competing interests.
Peer review
Peer review information
Nature thanks Magnus Johansson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Sections 1–5
Including general information, an experimental section for transannular γ-methylene C–H activation, supplementary references, single crystal X-ray structures for compounds L1, 3c, 3s, 4ac, L2, 5b, 5k, 6a, 8a, C1 and C2, and 1H, 13C and 19F nuclear magnetic resonance (NMR) spectra data.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) 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
Kang, G., Strassfeld, D.A., Sheng, T. et al. Transannular C–H functionalization of cycloalkane carboxylic acids. Nature 618, 519–525 (2023). https://doi.org/10.1038/s41586-023-06000-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41586-023-06000-z
This article is cited by
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
