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  • Review Article
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Strategic application of C–H oxidation in natural product total synthesis

Nature Reviews Chemistry volume 7, pages 783–799 (2023)Cite this article

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Abstract

The oxidation of unactivated C–H bonds has emerged as an effective tactic in natural product synthesis and has altered how chemists approach the synthesis of complex molecules. The use of C–H oxidation methods has simplified the process of synthesis planning by expanding the choice of starting materials, limiting functional group interconversion and protecting group manipulations, and enabling late-stage diversification. In this Review, we propose classifications for C–H oxidations on the basis of their strategic purpose: type 1, which installs functionality that is used to establish the carbon skeleton of the target; type 2, which is used to construct a heterocyclic ring; and type 3, which installs peripheral functional groups. The reactions are further divided based on whether they are directed or undirected. For each classification, examples from recent literature are analysed. Finally, we provide two case studies of syntheses from our laboratory that were streamlined by the judicious use of C–H oxidation reactions.

Key points

  • C–H oxidation reactions of unactivated bonds have found increased application as key enabling steps in complex molecule synthesis.

  • Strategically, C–H oxidation reactions can serve the purpose of making, breaking or rearranging skeletal bonds (type 1), forming heterocyclic rings (type 2), and introducing peripheral functional groups (type 3).

  • From the many C–H bonds in a molecule, site-selectivity for oxidations can be guided by substrate sterics and electronics and/or supramolecular control (undirected) or by inherent functional groups (directed).

  • C–H oxidation reactions enable conversion of structurally complex, but readily available, starting materials to useful intermediates through introduction of remote functionalization.

  • Remote functionalization can be further leveraged to generate target-oriented complexity, that is, elimination, rearrangement, C–C bond formation and so on.

  • The logic of C–H oxidation reactions can be combined with traditional synthetic planning strategies to devise highly efficient and divergent syntheses.

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Fig. 1: Strategic use and cases of C–H oxidation.
Fig. 2: Syntheses of complex diterpenes featuring multiple C–H oxidations of terpene feedstocks by Renata and co-workers.
Fig. 3: Syntheses of spirochensilide A starting from lanosterol by Heretsch et al. and Deng et al.
Fig. 4: Synthesis of Illicium sesquiterpenes by Zhang et al.
Fig. 5: Synthesis of picrotoxinin by Shenvi et al.
Fig. 6: Synthesis of ent-trachylobane natural products by Magauer et al.
Fig. 7: Synthesis of dalesconol A by Luan et al.
Fig. 8: Synthesis of longiborneol sesquiterpenes by Sarpong and co-workers.
Fig. 9: Synthesis of cephalotane norditerpenoids by Sarpong and co-workers.

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References

  1. Yamaguchi, J., Yamaguchi, A. D. & Itami, K. C–H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals. Angew. Chem. Int. Ed. Engl. 51, 8960–9009 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Davies, H. M. L. & Morton, D. Recent advances in C–H functionalization. J. Org. Chem. 81, 343–350 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Rogge, T. et al. C–H activation. Nat. Rev. Methods Primers 1, 1–31 (2021).

    Article  Google Scholar 

  4. Davies, H. M. L., Bois, J. D. & Yu, J.-Q. C–H functionalization in organic synthesis. Chem. Soc. Rev. 40, 1855–1856 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Bellina, F. & Rossi, R. Transition metal-catalyzed direct arylation of substrates with activated sp3-hybridized C−H bonds and some of their synthetic equivalents with aryl halides and pseudohalides. Chem. Rev. 110, 1082–1146 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Che, C.-M., Lo, V. K.-Y., Zhou, C.-Y. & Huang, J.-S. Selective functionalisation of saturated C–H bonds with metalloporphyrin catalysts. Chem. Soc. Rev. 40, 1950–1975 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Zhou, M. & Crabtree, R. H. C–H oxidation by platinum group metal oxo or peroxo species. Chem. Soc. Rev. 40, 1875–1884 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Lu, H. & Zhang, X. P. Catalytic C–H functionalization by metalloporphyrins: recent developments and future directions. Chem. Soc. Rev. 40, 1899–1909 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Guo, X.-X., Gu, D.-W., Wu, Z. & Zhang, W. Copper-catalyzed C–H functionalization reactions: efficient synthesis of heterocycles. Chem. Rev. 115, 1622–1651 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Gensch, T., Hopkinson, M. N., Glorius, F. & Wencel-Delord, J. Mild metal-catalyzed C–H activation: examples and concepts. Chem. Soc. Rev. 45, 2900–2936 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Hartwig, J. F. Catalyst-controlled site-selective bond activation. Acc. Chem. Res. 50, 549–555 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gormisky, P. E. & White, M. C. Catalyst-controlled aliphatic C–H oxidations with a predictive model for site-selectivity. J. Am. Chem. Soc. 135, 14052–14055 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Zhang, Q. & Shi, B.-F. Site-selective functionalization of remote aliphatic C–H bonds via C–H metallation. Chem. Sci. 12, 841–852 (2021).

    Article  CAS  Google Scholar 

  14. Christmann, M. Selective oxidation of aliphatic C–H bonds in the synthesis of complex molecules. Angew. Chem. Int. Ed. Engl. 47, 2740–2742 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Gutekunst, W. R. & Baran, P. S. C–H functionalization logic in total synthesis. Chem. Soc. Rev. 40, 1976–1991 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. McMurray, L., O’Hara, F. & Gaunt, M. J. Recent developments in natural product synthesis using metal-catalysed C–H bond functionalisation. Chem. Soc. Rev. 40, 1885–1898 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Newhouse, T. & Baran, P. S. If C–H bonds could talk: selective C–H bond oxidation. Angew. Chem. Int. Ed. Engl. 50, 3362–3374 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen, D. Y.-K. & Youn, S. W. C–H activation: a complementary tool in the total synthesis of complex natural products. Chem. Eur. J. 18, 9452–9474 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Qiu, Y. & Gao, S. Trends in applying C–H oxidation to the total synthesis of natural products. Nat. Prod. Rep. 33, 562–581 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Karimov, R. R. & Hartwig, J. F. Transition-metal-catalyzed selective functionalization of C(sp3)−H bonds in natural products. Angew. Chem. Int. Ed. Engl. 57, 4234–4241 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Abrams, D. J., Provencher, P. A. & Sorensen, E. J. Recent applications of C–H functionalization in complex natural product synthesis. Chem. Soc. Rev. 47, 8925–8967 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Santana, V. C. S., Fernandes, M. C. V., Cappuccelli, I., Richieri, A. C. G. & de Lucca Jr, E. C. Metal-catalyzed C–H bond oxidation in the total synthesis of natural and unnatural products. Synthesis 54, 5337–5359 (2022).

    Article  CAS  Google Scholar 

  23. Trost, B. M. Selectivity: a key to synthetic efficiency. Science 219, 245–250 (1983).

    Article  CAS  PubMed  Google Scholar 

  24. King, S. M. & Herzon, S. B. Substrate-modified functional group reactivity: hasubanan and acutumine alkaloid syntheses. J. Org. Chem. 79, 8937–8947 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Green, S. A. et al. The high chemofidelity of metal-catalyzed hydrogen atom transfer. Acc. Chem. Res. 51, 2628–2640 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ishihara, Y. & Baran, P. S. Two-phase terpene total synthesis: historical perspective and application to the Taxol® problem. Synlett 2010, 1733–1745 (2010).

    Article  Google Scholar 

  27. Kanda, Y. et al. Two-phase synthesis of Taxol. J. Am. Chem. Soc. 142, 10526–10533 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kanda, Y., Ishihara, Y., Wilde, N. C. & Baran, P. S. Two-phase total synthesis of taxanes: tactics and strategies. J. Org. Chem. 85, 10293–10320 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Chen, K. & Baran, P. S. Total synthesis of eudesmane terpenes by site-selective C–H oxidations. Nature 459, 824–828 (2009). A landmark synthesis using C–H oxidations in a two-phase approach.

    Article  CAS  PubMed  Google Scholar 

  30. Hung, K. et al. Development of a terpene feedstock-based oxidative synthetic approach to the Illicium sesquiterpenes. J. Am. Chem. Soc. 141, 3083–3099 (2019). A synthesis featuring several enabling C–H oxidations expanding the possibilities of chiral pool strategies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. West, S. P., Bisai, A., Lim, A. D., Narayan, R. R. & Sarpong, R. Total synthesis of (+)-lyconadin A and related compounds via oxidative C−N bond formation. J. Am. Chem. Soc. 131, 11187–11194 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Fischer, D. F. & Sarpong, R. Total synthesis of (+)-complanadine A using an iridium-catalyzed pyridine C−H functionalization. J. Am. Chem. Soc. 132, 5926–5927 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Newton, J. N., Fischer, D. F. & Sarpong, R. Synthetic studies on pseudo-dimeric lycopodium alkaloids: total synthesis of complanadine B. Angew. Chem. Int. Ed. Engl. 52, 1726–1730 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Leal, R. A. et al. Application of a palladium-catalyzed C−H functionalization/indolization method to syntheses of cis-trikentrin A and herbindole B. Angew. Chem. Int. Ed. Engl. 55, 11824–11828 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Haider, M., Sennari, G., Eggert, A. & Sarpong, R. Total synthesis of the Cephalotaxus norditerpenoids (±)-cephanolides A–D. J. Am. Chem. Soc. 143, 2710–2715 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. Haley, H. M. S. et al. Bioinspired diversification approach toward the total synthesis of lycodine-type alkaloids. J. Am. Chem. Soc. 143, 4732–4740 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jones, K. E., Park, B., Doering, N. A., Baik, M.-H. & Sarpong, R. Rearrangements of the chrysanthenol core: application to a formal synthesis of xishacorene B. J. Am. Chem. Soc. 143, 20482–20490 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lusi, R. F., Sennari, G. & Sarpong, R. Total synthesis of nine longiborneol sesquiterpenoids using a functionalized camphor strategy. Nat. Chem. 14, 450–456 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lusi, R. F., Sennari, G. & Sarpong, R. Strategy evolution in a skeletal remodeling and C–H functionalization-based synthesis of the longiborneol sesquiterpenoids. J. Am. Chem. Soc. 144, 17277–17294 (2022). A synthesis that combines skeletal remodeling of the chiral pool feedstock, carvone and late-stage C–H oxidations to access several longiborneol sesquiterpenoids.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sennari, G. et al. Unified total syntheses of benzenoid cephalotane-type norditerpenoids: cephanolides and ceforalides. J. Am. Chem. Soc. 144, 19173–19185 (2022). A synthesis featuring a mix of aliphatic and aromatic C–H oxidations to access distinct natural product family members.

    Article  CAS  PubMed  Google Scholar 

  41. Perea, M. A. et al. General synthetic approach to diverse taxane cores. J. Am. Chem. Soc. 144, 21398–21407 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Breslow, R. Biomimetic control of chemical selectivity. Acc. Chem. Res. 13, 170–177 (1980). A classic example of directed C–H oxidation using a tethered benzophenone group.

    Article  CAS  Google Scholar 

  43. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C−H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mo, F., Tabor, J. R. & Dong, G. Alcohols or masked alcohols as directing groups for C–H bond functionalization. Chem. Lett. 43, 264–271 (2014).

    Article  CAS  Google Scholar 

  45. Gandeepan, P. & Ackermann, L. Transient directing groups for transformative C–H activation by synergistic metal catalysis. Chem 4, 199–222 (2018).

    Article  CAS  Google Scholar 

  46. Murali, K. et al. Decoding directing groups and their pivotal role in C−H activation. Chem. Eur. J. 27, 12453–12508 (2021).

    Article  CAS  PubMed  Google Scholar 

  47. Hartwig, J. F. & Larsen, M. A. Undirected, homogeneous C–H bond functionalization: challenges and opportunities. ACS Cent. Sci. 2, 281–292 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stout, C. N. & Renata, H. Reinvigorating the chiral pool: chemoenzymatic approaches to complex peptides and terpenoids. Acc. Chem. Res. 54, 1143–1156 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang, X. et al. Divergent synthesis of complex diterpenes through a hybrid oxidative approach. Science 369, 799–806 (2020). A chemoenzymatic synthesis featuring numerous strategically crucial C–H oxidations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hong, Y. J. & Tantillo, D. J. Formation of beyerene, kaurene, trachylobane, and atiserene diterpenes by rearrangements that avoid secondary carbocations. J. Am. Chem. Soc. 132, 5375–5386 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Li, C. et al. A hexacyclic ent-trachylobane diterpenoid possessing an oxetane ring from Mitrephora glabra. Org. Lett. 7, 5709–5712 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Groves, J. T., McClusky, G. A., White, R. E. & Coon, M. J. Aliphatic hydroxylation by highly purified liver microsomal cytochrome P-450. Evidence for a carbon radical intermediate. Biochem. Biophys. Res. Commun. 81, 154–160 (1978).

    Article  CAS  PubMed  Google Scholar 

  54. Loskot, S. A., Romney, D. K., Arnold, F. H. & Stoltz, B. M. Enantioselective total synthesis of nigelladine A via late-stage C–H oxidation enabled by an engineered P450 enzyme. J. Am. Chem. Soc. 139, 10196–10199 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sheldon, R. A., Brady, D. & Bode, M. L. The hitchhiker’s guide to biocatalysis: recent advances in the use of enzymes in organic synthesis. Chem. Sci. 11, 2587–2605 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Winkler, C. K., Schrittwieser, J. H. & Kroutil, W. Power of biocatalysis for organic synthesis. ACS Cent. Sci. 7, 55–71 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Arnold, F. H. Directed evolution: bringing new chemistry to life. Angew. Chem. Int. Ed. Engl. 57, 4143–4148 (2018).

    Article  CAS  PubMed  Google Scholar 

  58. Wang, Y. et al. Directed evolution: methodologies and applications. Chem. Rev. 121, 12384–12444 (2021).

    Article  CAS  PubMed  Google Scholar 

  59. Fasan, R. Tuning P450 enzymes as oxidation catalysts. ACS Catal. 2, 647–666 (2012).

    Article  CAS  Google Scholar 

  60. Rudolf, J. D., Dong, L.-B., Zhang, X., Renata, H. & Shen, B. Cytochrome P450-catalyzed hydroxylation initiating ether formation in platensimycin biosynthesis. J. Am. Chem. Soc. 140, 12349–12353 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Dong, L.-B. et al. Cryptic and stereospecific hydroxylation, oxidation, and reduction in platensimycin and platencin biosynthesis. J. Am. Chem. Soc. 141, 4043–4050 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Richter, M. J. R., Schneider, M., Brandstätter, M., Krautwald, S. & Carreira, E. M. Total synthesis of (−)-mitrephorone A. J. Am. Chem. Soc. 140, 16704–16710 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. Wein, L. A., Wurst, K., Angyal, P., Weisheit, L. & Magauer, T. Synthesis of (−)-mitrephorone A via a bioinspired late stage C–H oxidation of (−)-mitrephorone B. J. Am. Chem. Soc. 141, 19589–19593 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Alekseychuk, M., Adrian, S., Heinze, R. C. & Heretsch, P. Biogenesis-inspired, divergent synthesis of spirochensilide A, spirochensilide B, and abifarine B employing a radical-polar crossover rearrangement strategy. J. Am. Chem. Soc. 144, 11574–11579 (2022). A synthesis using C–H oxidation to access carbocationic intermediates akin to those in the biosynthesis.

    Article  CAS  PubMed  Google Scholar 

  65. Long, X., Li, J., Gao, F., Wu, H. & Deng, J. Bioinspired synthesis of spirochensilide A from lanosterol. J. Am. Chem. Soc. 144, 16292–16297 (2022). A synthesis published contemporaneously with the above reference, using a similar oxidation.

    Article  CAS  PubMed  Google Scholar 

  66. Zhao, Q.-Q. et al. Spirochensilides A and B, two new rearranged triterpenoids from Abies chensiensis. Org. Lett. 17, 2760–2763 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Wappes, E. A., Fosu, S. C., Chopko, T. C. & Nagib, D. A. Triiodide-mediated δ-amination of secondary C−H bonds. Angew. Chem. Int. Ed. Engl. 55, 9974–9978 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liang, X.-T., Chen, J.-H. & Yang, Z. Asymmetric total synthesis of (−)-spirochensilide A. J. Am. Chem. Soc. 142, 8116–8121 (2020).

    Article  CAS  PubMed  Google Scholar 

  69. Yang, D., Wong, M.-K., Wang, X.-C. & Tang, Y.-C. Regioselective intramolecular oxidation of unactivated C−H bonds by dioxiranes generated in situ. J. Am. Chem. Soc. 120, 6611–6612 (1998).

    Article  CAS  Google Scholar 

  70. Wong, M.-K. et al. Investigation on the regioselectivities of intramolecular oxidation of unactivated C−H bonds by dioxiranes generated in situ. J. Org. Chem. 68, 6321–6328 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Wong, M.-K., Chung, N.-W., He, L. & Yang, D. Substituent effects on regioselective intramolecular oxidation of unactivated C−H bonds: stereoselective synthesis of substituted tetrahydropyrans. J. Am. Chem. Soc. 125, 158–162 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Kasuya, S., Kamijo, S. & Inoue, M. Direct construction of 1,3-diaxial diol derivatives by C−H hydroxylation. Org. Lett. 11, 3630–3632 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Lane, J. F., Koch, W. T., Leeds, N. S. & Gorin, G. On the toxin of Illicium anisatum. I. The isolation and characterization of a convulsant principle: anisatin1. J. Am. Chem. Soc. 74, 3211–3215 (1952).

    Article  CAS  Google Scholar 

  74. Fukuyama, Y. & Huang, J.-M. in Studies in Natural Products Chemistry Vol. 32 (ed Atta-ur-Rahman) pp. 395–427 (Elsevier, 2005).

  75. Concepción, J. I., Francisco, C. G., Hernández, R., Salazar, J. A. & Suárez, E. Intramolecular hydrogen abstraction. Iodosobenzene diacetate, an efficient and convenient reagent for alkoxy radical generation. Tetrahedron Lett. 25, 1953–1956 (1984).

    Article  Google Scholar 

  76. Chen, M. S. & White, M. C. A predictably selective aliphatic C−H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Shen, Y. et al. Site-specific photochemical desaturation enables divergent syntheses of Illicium sesquiterpenes. J. Am. Chem. Soc. 143, 3256–3263 (2021). A synthesis that uses a versatile late-stage desaturation as a means of installing several different functional groups.

    Article  CAS  PubMed  Google Scholar 

  78. Condakes, M. L., Hung, K., Harwood, S. J. & Maimone, T. J. Total syntheses of (−)-majucin and (−)-jiadifenoxolane A, complex majucin-type Illicium sesquiterpenes. J. Am. Chem. Soc. 139, 17783–17786 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Condakes, M. L., Novaes, L. F. T. & Maimone, T. J. Contemporary synthetic strategies toward seco-prezizaane sesquiterpenes from Illicium species. J. Org. Chem. 83, 14843–14852 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Marco-Martínez, J., López-Carrillo, V., Buñuel, E., Simancas, R. & Cárdenas, D. J. Pd-catalyzed borylative cyclization of 1,6-enynes. J. Am. Chem. Soc. 129, 1874–1875 (2007).

    Article  PubMed  Google Scholar 

  81. Camelio, A. M., Barton, T., Guo, F., Shaw, T. & Siegel, D. Hydroxyl-directed cyclizations of 1,6-enynes. Org. Lett. 13, 1517–1519 (2011).

    Article  CAS  PubMed  Google Scholar 

  82. Berkessel, A., Adrio, J. A., Hüttenhain, D. & Neudörfl, J. M. Unveiling the “booster effect” of fluorinated alcohol solvents: aggregation-induced conformational changes and cooperatively enhanced H-bonding. J. Am. Chem. Soc. 128, 8421–8426 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Huang, J., Yokoyama, R., Yang, C. & Fukuyama, Y. Merrilactone A, a novel neurotrophic sesquiterpene dilactone from Illicium merrillianum. Tetrahedron Lett. 41, 6111–6114 (2000).

    Article  CAS  Google Scholar 

  84. Kouno, I., Mori, K., Okamoto, S. & Sato, S. Structures of anislactone A and B; novel type of sesquiterpene lactones from the pericarps of Illicium anisatum. Chem. Pharm. Bull. 38, 3060–3063 (1990).

    Article  CAS  Google Scholar 

  85. Inoue, M., Sato, T. & Hirama, M. Asymmetric total synthesis of (−)-merrilactone A: use of a bulky protecting group as long-range stereocontrolling element. Angew. Chem. Int. Ed. Engl. 45, 4843–4848 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Chen, J. et al. Total synthesis of (±)-merrilactone A. Angew. Chem. Int. Ed. Engl. 51, 5897–5899 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Crossley, S. W. M., Tong, G., Lambrecht, M. J., Burdge, H. E. & Shenvi, R. A. Synthesis of (−)-picrotoxinin by late-stage strong bond activation. J. Am. Chem. Soc. 142, 11376–11381 (2020). A synthesis that uses C–H oxidation not only to construct the heterocyclic core but also to excise an unwanted methyl group.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Porter, L. A. Picrotoxinin and related substances. Chem. Rev. 67, 441–464 (1967).

    Article  CAS  PubMed  Google Scholar 

  89. Corey, E. J. & Pearce, H. L. Total synthesis of picrotoxinin. J. Am. Chem. Soc. 101, 5841–5843 (1979).

    Article  CAS  Google Scholar 

  90. Corey, E. J. & Pearce, H. L. Total synthesis of picrotin. Tetrahedron Lett. 21, 1823–1824 (1980).

    Article  CAS  Google Scholar 

  91. Niwa, H. et al. Stereocontrolled total synthesis (−)-picrotoxinin and (+)-coriamyrtin via a common isotwistane intermediate. J. Am. Chem. Soc. 106, 4547–4552 (1984).

    Article  CAS  Google Scholar 

  92. Miyashita, M., Suzuki, T. & Yoshikoshi, A. Stereoselective total synthesis of (−)-picrotoxinin and (−)-picrotin. J. Am. Chem. Soc. 111, 3728–3734 (1989).

    Article  CAS  Google Scholar 

  93. Trost, B. M. & Krische, M. J. General strategy for the asymmetric synthesis of the picrotoxanes. J. Am. Chem. Soc. 118, 233–234 (1996).

    Article  CAS  Google Scholar 

  94. Trost, B. & Krische, M. J. Palladium-catalyzed enyne cycloisomerization reaction in an asymmetric approach to the picrotoxane sesquiterpenes. 2. Second-generation total syntheses of corianin, picrotoxinin, picrotin, and methyl picrotoxate. J. Am. Chem. Soc. 121, 6131–6141 (1999).

    Article  CAS  Google Scholar 

  95. Trost, B. M., Haffner, C. D., Jebaratnam, D. J., Krische, M. J. & Thomas, A. P. The palladium-catalyzed enyne cycloisomerization reaction in a general approach to the asymmetric syntheses of the picrotoxane sesquiterpenes. Part I. First-generation total synthesis of corianin and formal syntheses of picrotoxinin and picrotin. J. Am. Chem. Soc. 121, 6183–6192 (1999).

    Article  CAS  Google Scholar 

  96. Cao, J. et al. Synthesis of the tricyclic picrotoxane motif by an oxidative cascade cyclization. Org. Lett. 21, 4896–4899 (2019).

    Article  CAS  PubMed  Google Scholar 

  97. Hong, B., Luo, T. & Lei, X. Late-stage diversification of natural products. ACS Cent. Sci. 6, 622–635 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kim, K. E., Kim, A. N., McCormick, C. J. & Stoltz, B. M. Late-stage diversification: a motivating force in organic synthesis. J. Am. Chem. Soc. 143, 16890–16901 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Oeschger, R. et al. Diverse functionalization of strong alkyl C–H bonds by undirected borylation. Science 368, 736–741 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Carestia, A. M., Ravelli, D. & Alexanian, E. J. Reagent-dictated site selectivity in intermolecular aliphatic C–H functionalizations using nitrogen-centered radicals. Chem. Sci. 9, 5360–5365 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang, J. et al. A biocatalytic hydroxylation-enabled unified approach to C19-hydroxylated steroids. Nat. Commun. 10, 3378 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Fraga, B. M. The trachylobane diterpenes. Phytochem. Anal. 5, 49–56 (1994). A synthesis that takes advantage of the electron-releasing cyclopropane-containing skeleton of the natural product to enable site-selective C–H oxidation.

    Article  CAS  Google Scholar 

  103. Wein, L. A., Wurst, K. & Magauer, T. Total synthesis and late-stage C−H oxidations of ent-trachylobane natural products. Angew. Chem. Int. Ed. Engl. 61, e202113829 (2022).

    Article  CAS  PubMed  Google Scholar 

  104. Bovicelli, P., Lupattelli, P., Mincione, E., Prencipe, T. & Curci, R. Oxidation of natural targets by dioxiranes. 2. Direct hydroxylation at the side chain C-25 of cholestane derivatives and of vitamin D3 Windaus–Grundmann ketone. J. Org. Chem. 57, 5052–5054 (1992).

    Article  CAS  Google Scholar 

  105. Zou, L. et al. Enhanced reactivity in dioxirane C–H oxidations via strain release: a computational and experimental study. J. Org. Chem. 78, 4037–4048 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kawamata, Y. et al. Scalable, electrochemical oxidation of unactivated C–H bonds. J. Am. Chem. Soc. 139, 7448–7451 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wang, C., Shalyaev, K. V., Bonchio, M., Carofiglio, T. & Groves, J. T. Fast catalytic hydroxylation of hydrocarbons with ruthenium porphyrins. Inorg. Chem. 45, 4769–4782 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Vicens, L., Bietti, M. & Costas, M. General access to modified α-amino acids by bioinspired stereoselective γ-C−H bond lactonization. Angew. Chem. Int. Ed. Engl. 60, 4740–4746 (2021). A synthesis featuring a late-stage highly efficient, triply-operative aromatic C–H oxidation.

    Article  CAS  PubMed  Google Scholar 

  109. Zhao, P., Guo, Y. & Luan, X. Total synthesis of dalesconol A by Pd(0)/norbornene-catalyzed three-fold domino reaction and Pd(II)-catalyzed trihydroxylation. J. Am. Chem. Soc. 143, 21270–21274 (2021).

    Article  CAS  PubMed  Google Scholar 

  110. Zhang, Y. L. et al. Unprecedented immunosuppressive polyketides from Daldinia eschscholzii, a mantis-associated fungus. Angew. Chem. Int. Ed. Engl. 47, 5823–5826 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Neufeldt, S. R. & Sanford, M. S. O-Acetyl oximes as transformable directing groups for Pd-catalyzed C−H bond functionalization. Org. Lett. 12, 532–535 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Horwitz, M. A. Local desymmetrization as an engine of stereochemical elaboration in total synthesis. Tetrahedron Lett. 97, 153776 (2022).

    Article  CAS  Google Scholar 

  113. Bai, L. et al. Palladium/norbornene-catalyzed C−H alkylation/alkyne insertion/indole dearomatization domino reaction: assembly of spiroindolenine-containing pentacyclic frameworks. Angew. Chem. Int. Ed. Engl. 57, 5151–5155 (2018).

    Article  CAS  PubMed  Google Scholar 

  114. Nan, J., Yuan, Y., Bai, L., Liu, J. & Luan, X. Highly chemoselective construction of spiro[4,5]decane-embedded polycyclic scaffolds by a palladium/norbornene-catalyzed C–H activation/arene dearomatization reaction. Org. Lett. 20, 7731–7734 (2018).

    Article  CAS  PubMed  Google Scholar 

  115. Mo, F., Trzepkowski, L. J. & Dong, G. Synthesis of ortho-acylphenols through the palladium-catalyzed ketone-directed hydroxylation of arenes. Angew. Chem. Int. Ed. Engl. 51, 13075–13079 (2012).

    Article  CAS  PubMed  Google Scholar 

  116. Liang, Y.-F. et al. Ligand-promoted Pd-catalyzed oxime ether directed C–H hydroxylation of arenes. ACS Catal. 5, 6148–6152 (2015).

    Article  CAS  Google Scholar 

  117. Diao, T. & Stahl, S. S. Synthesis of cyclic enones via direct palladium-catalyzed aerobic dehydrogenation of ketones. J. Am. Chem. Soc. 133, 14566–14569 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kim, J. & Chang, S. Iridium-catalyzed direct CH amidation with weakly coordinating carbonyl directing groups under mild conditions. Angew. Chem. Int. Ed. Engl. 53, 2203–2207 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Ashley, J. N., Hobbs, B. C. & Raistrick, H. Studies in the biochemistry of micro-organisms: the crystalline colouring matters of Fusarium culmorum (W. G. Smith) Sacc. and related forms. Biochem. J. 31, 385–397 (1937).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Briggs, L. H. & Sutherland, M. D. The essential oil of Cupressus macrocarpa. J. Org. Chem. 07, 397–407 (1942).

    Article  CAS  Google Scholar 

  121. Akiyoshi, S., Erdtman, H. & Kubota, T. Chemistry of the natural order cupressales — XXVI: the identity of junipene, kuromatsuene and longifolene and of juniperol, kuromatsuol, macrocarpol and longiborneol. Tetrahedron 9, 237–239 (1960).

    Article  CAS  Google Scholar 

  122. Barton, D. H. R. & Werstiuk, N. H. Sesquiterpenoids. Part XIV. The constitution and stereochemistry of culmorin. J. Chem. Soc. C Org. https://doi.org/10.1039/J39680000148 (1968).

    Article  Google Scholar 

  123. Kasitu, G. C. et al. Isolation and characterization of culmorin derivatives produced by Fusarium culmorum CMI 14764. Can. J. Chem. 70, 1308–1316 (1992).

    Article  CAS  Google Scholar 

  124. Alam, M., Jones, E. B. G., Hossain, M. B. & van der Helm, D. Isolation and structure of isoculmorin from the marine fungus Kallichroma tethys. J. Nat. Prod. 59, 454–456 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Bahadoor, A. et al. Hydroxylation of longiborneol by a Clm2-encoded CYP450 monooxygenase to produce culmorin in Fusarium graminearum. J. Nat. Prod. 79, 81–88 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Masarwa, A., Weber, M. & Sarpong, R. Selective C–C and C–H bond activation/cleavage of pinene derivatives: synthesis of enantiopure cyclohexenone scaffolds and mechanistic insights. J. Am. Chem. Soc. 137, 6327–6334 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Lusi, R. F., Perea, M. A. & Sarpong, R. C–C bond cleavage of α-pinene derivatives prepared from carvone as a general strategy for complex molecule synthesis. Acc. Chem. Res. 55, 746–758 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Chen, M. S. & White, M. C. Combined effects on selectivity in Fe-catalyzed methylene oxidation. Science 327, 566–571 (2010). Codifies selectivity rules in undirected C–H oxidation using iron oxo complexes.

    Article  CAS  PubMed  Google Scholar 

  129. Simmons, E. M. & Hartwig, J. F. Catalytic functionalization of unactivated primary C–H bonds directed by an alcohol. Nature 483, 70–73 (2012).

    Article  CAS  PubMed  Google Scholar 

  130. Li, B., Driess, M. & Hartwig, J. F. Iridium-catalyzed regioselective silylation of secondary alkyl C–H bonds for the synthesis of 1,3-diols. J. Am. Chem. Soc. 136, 6586–6589 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Ma, X., Kucera, R., Goethe, O. F., Murphy, S. K. & Herzon, S. B. Directed C–H bond oxidation of (+)-pleuromutilin. J. Org. Chem. 83, 6843–6892 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Karmel, C., Li, B. & Hartwig, J. F. Rhodium-catalyzed regioselective silylation of alkyl C–H bonds for the synthesis of 1,4-diols. J. Am. Chem. Soc. 140, 1460–1470 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Nakazaki, M. & Naemura, K. Photolyses of isobornyl and bornyl nitrites. Bull. Chem. Soc. Jpn. 37, 532–535 (1964).

    Article  CAS  Google Scholar 

  134. Renata, H., Zhou, Q. & Baran, P. S. Strategic redox relay enables a scalable synthesis of ouabagenin, a bioactive cardenolide. Science 339, 59–63 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Berger, M., Knittl-Frank, C., Bauer, S., Winter, G. & Maulide, N. Application of relay C–H oxidation logic to polyhydroxylated oleanane triterpenoids. Chem 6, 1183–1189 (2020).

    Article  CAS  Google Scholar 

  136. Desai, L. V., Hull, K. L. & Sanford, M. S. Palladium-catalyzed oxygenation of unactivated sp3 C–H bonds. J. Am. Chem. Soc. 126, 9542–9543 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Trotta, A. H. Total synthesis of oridamycins A and B. Org. Lett. 17, 3358–3361 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Trotta, A. H. Toward a unified total synthesis of the xiamycin and oridamycin families of indolosesquiterpenes. J. Org. Chem. 82, 13500–13516 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Corey, E. J., Niimura, K., Konishi, Y., Hashimoto, S. & Hamada, Y. A new synthetic route to prostaglandins. Tetrahedron Lett. 27, 2199–2202 (1986).

    Article  CAS  Google Scholar 

  140. Siler, D. A., Mighion, J. D. & Sorensen, E. J. An enantiospecific synthesis of jiadifenolide. Angew. Chem. Int. Ed. Engl. 53, 5332–5335 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Fan, Y.-Y. et al. Cephanolides A–J, cephalotane-type diterpenoids from cephalotaxus sinensis. J. Nat. Prod. 80, 3159–3166 (2017).

    Article  CAS  PubMed  Google Scholar 

  142. Ge, Z.-P. et al. Cephalotane-type norditerpenoids from Cephalotaxus fortunei var. alpina. Chin. J. Chem. 40, 1177–1184 (2022).

    Article  CAS  Google Scholar 

  143. Xu, L., Wang, C., Gao, Z. & Zhao, Y.-M. Total synthesis of (±)-cephanolides B and C via a palladium-catalyzed cascade cyclization and late-stage sp3 C–H bond oxidation. J. Am. Chem. Soc. 140, 5653–5658 (2018).

    Article  CAS  PubMed  Google Scholar 

  144. Zhang, H., He, H. & Gao, S. Asymmetric total synthesis of cephanolide A. Angew. Chem. Int. Ed. Engl. 59, 20417–20422 (2020).

    Article  CAS  PubMed  Google Scholar 

  145. Zhang, H., He, H. & Gao, S. Asymmetric total synthesis of cephanolide B. Org. Chem. Front. 8, 555–559 (2021).

    Article  CAS  Google Scholar 

  146. Lu, Y., Xu, M.-M., Zhang, Z.-M., Zhang, J. & Cai, Q. Catalytic asymmetric inverse-electron-demand Diels–Alder reactions of 2-pyrones with indenes: total syntheses of cephanolides A and B. Angew. Chem. Int. Ed. Engl. 60, 26610–26615 (2021).

    Article  CAS  PubMed  Google Scholar 

  147. Li, A., He, Z., Liu, B., Yang, Z. & Zhang, Z. Stereoselective synthesis of (±)-cephanolide B. Org. Lett. 23, 9237–9240 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Qing, Z., Mao, P., Wang, T. & Zhai, H. Asymmetric total syntheses of cephalotane-type diterpenoids cephanolides A–D. J. Am. Chem. Soc. 144, 10640–10646 (2022).

    Article  CAS  PubMed  Google Scholar 

  149. Sun, Z. et al. Total synthesis of (−)-ceforalide B and (−)-cephanolides B–D. Org. Lett. 24, 7507–7511 (2022).

    Article  CAS  PubMed  Google Scholar 

  150. Marth, C. J. et al. Network-analysis-guided synthesis of weisaconitine D and liljestrandinine. Nature 528, 493–498 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Doering, N. A., Sarpong, R. & Hoffmann, R. W. A case for bond-network analysis in the synthesis of bridged polycyclic complex molecules: hetidine and hetisine diterpenoid alkaloids. Angew. Chem. Int. Ed. Engl. 59, 10722–10731 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Corey, E. J., Howe, W. J., Orf, H. W., Pensak, D. A. & Petersson, G. General methods of synthetic analysis. Strategic bond disconnections for bridged polycyclic structures. J. Am. Chem. Soc. 97, 6116–6124 (1975).

    Article  CAS  Google Scholar 

  153. Molander, G. A. & Sandrock, D. L. Utilization of potassium vinyltrifluoroborate in the development of a 1,2-dianion equivalent. Org. Lett. 11, 2369–2372 (2009).

    Article  CAS  PubMed  Google Scholar 

  154. Su, W. et al. Ligand-controlled regiodivergent copper-catalyzed alkylboration of alkenes. Angew. Chem. Int. Ed. Engl. 54, 12957–12961 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Liu, Z., Gao, Y., Zeng, T. & Engle, K. M. Transition-metal-catalyzed 1,2-carboboration of alkenes: strategies, mechanisms, and stereocontrol. Isr. J. Chem. 60, 219–229 (2020).

    Article  CAS  PubMed  Google Scholar 

  156. Clausen, F., Kischkewitz, M., Bergander, K. & Studer, A. Catalytic protodeboronation of pinacol boronic esters: formal anti-Markovnikov hydromethylation of alkenes. Chem. Sci. 10, 6210–6214 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Miyai, T., Ueba, M. & Baba, A. Novel synthetic usage of indium compounds as catalyst: reductive deoxygenation of aryl ketones and sec-benzylic alcohols. Synlett 1999, 182–184 (1999).

    Article  Google Scholar 

  158. Yasuda, M., Onishi, Y., Ueba, M., Miyai, T. & Baba, A. Direct reduction of alcohols: highly chemoselective reducing system for secondary or tertiary alcohols using chlorodiphenylsilane with a catalytic amount of indium trichloride. J. Org. Chem. 66, 7741–7744 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Yuan, C. et al. Metal-free oxidation of aromatic carbon–hydrogen bonds through a reverse-rebound mechanism. Nature 499, 192–196 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Berger, F. et al. Site-selective and versatile aromatic C–H functionalization by thianthrenation. Nature 567, 223–228 (2019).

    Article  CAS  PubMed  Google Scholar 

  161. Li, Z.-Y. & Wang, G.-W. Palladium-catalyzed decarboxylative ortho-ethoxycarbonylation of O-methyl ketoximes and 2-arylpyridines with potassium oxalate monoester. Org. Lett. 17, 4866–4869 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Weitz, D. J. & Bednarski, M. D. Synthesis of acyclic sugar aldehydes by ozonolysis of oximes. J. Org. Chem. 54, 4957–4959 (1989).

    Article  CAS  Google Scholar 

  163. Li, G.-X. et al. A unified photoredox-catalysis strategy for C(sp3)–H hydroxylation and amidation using hypervalent iodine. Chem. Sci. 8, 7180–7185 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. These authors contributed equally: Ian Bakanas, Robert F. Lusi.

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  1. Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA

    Ian Bakanas, Robert F. Lusi, Stefan Wiesler, Jack Hayward Cooke & Richmond Sarpong

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I.B. contributed to the discussion of content, researching, and writing and editing of this manuscript. R.F.L. helped in the manuscript conception, contributed to the discussion of content, researching, writing the case study and editing of the manuscript. S.W. contributed to the discussion of content, researching, writing the case study and editing of the manuscript. J.H.C. contributed to the discussion of content and editing of the manuscript. R.S. contributed to the conception and direction of the manuscript, discussion of content and editing of the manuscript.

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Bakanas, I., Lusi, R.F., Wiesler, S. et al. Strategic application of C–H oxidation in natural product total synthesis. Nat Rev Chem 7, 783–799 (2023). https://doi.org/10.1038/s41570-023-00534-6

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