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).
More News
Daily briefing: Why exercise is good for us
Daily briefing: Orangutan is first wild animal seen using medicinal plant
Old electric-vehicle batteries can find new purpose — on the grid