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Organic synthesis provides opportunities to transform drug discovery

Nature Chemistryvolume 10pages383394 (2018) | Download Citation

Abstract

Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C–H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C–X or C–C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

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References

  1. 1.

    Zhang, X. & MacMillan, D. W. C. Alcohols as latent coupling fragments for metallaphotoredox catalysis: sp 3sp 2 cross-coupling of oxalates with aryl halides. J. Am. Chem. Soc. 138, 13862–13865 (2016).

  2. 2.

    Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

  3. 3.

    Romero, N. A. & Nicewicz, D. A. Organic photoredox catalysis. Chem. Rev. 116, 10075–10166 (2016).

  4. 4.

    Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).

  5. 5.

    Eastgate, M. D., Schmidt, M. A. & Fandrick, K. R. On the design of complex drug candidate syntheses in the pharmaceutical industry. Nat. Rev. Chem 1, 0016 (2017).

  6. 6.

    Flick, A. C. et al. Synthetic Approaches to the new drugs approved during 2015. J. Med. Chem. 60, 6480–6515 (2017).

  7. 7.

    Michaudel, Q., Ishihara, Y. & Baran, P. S. Academia–industry symbiosis in organic chemistry. Acc. Chem. Res. 48, 712–721 (2015).

  8. 8.

    Kilpin, K. J. & Whitby, R. J. Chemistry central journal themed issue: dial-a-molecule. Chem. Central J. https://doi.org/10.1186/s13065-015-0122-3(2015).

  9. 9.

    Allen, D. Where will we get the next generation of medicinal chemists? Drug Discov. Today 21, 704–706 (2016).

  10. 10.

    http://www.roche.com/careers/country/switzerland/ch-your-job/students_and_graduates/ch_internships/rich_program.htm.

  11. 11.

    Foley, D. J., Nelson, A. & Marsden, S. P. Evaluating new chemistry to drive molecular discovery: fit for purpose? Ang. Chem. Int. Ed. 55, 13650–13657 (2016).

  12. 12.

    Kutchukian, P. S. et al. Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods. Chem. Sci. 7, 2604–2613 (2016).

  13. 13.

    Kemmitt, P. D. et al. Synthesis of 3-(hetero)aryl tetrahydropyrazolo[3,4-c]pyridines by Suzuki–Miyaura cross-coupling methodology. J. Org. Chem. 79, 7682–7688 (2014).

  14. 14.

    Noonan, G. M., Dishington, A. P., Pink, J. & Campbell, A. D. Studies on the coupling of substituted 2-amino-1,3-oxazoles with chloro-heterocycles. Tetrahedron Lett. 53, 3038–3043 (2012).

  15. 15.

    Olsen, E. P. K., Arrechea, P. L. & Buchwald, S. L. Mechanistic insight leads to a ligand which facilitates the palladium-catalyzed formation of 2-(hetero)arylaminooxazoles and 4-(hetero)arylaminothiazoles. Ang. Chem. Int. Ed. 56, 10569–10572 (2017).

  16. 16.

    Buitrago Santanilla, A. et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347, 49–53 (2015).

  17. 17.

    Nadin, A., Hattotuwagama, C. & Churcher, I. Lead-oriented synthesis: a new opportunity for synthetic chemistry. Ang. Chem. Int. Ed. 51, 1114–1122 (2012).

  18. 18.

    Blakemore, D. C., Doyle, P. M. & Fobian, Y. M. (eds) Synthetic Methods in Drug Discovery: Volume 2 (Royal Society of Chemistry, 2016).

  19. 19.

    Goldberg, F. W., Kettle, J. G., Kogej, T., Perry, M. W. D. & Tomkinson, N. P. Designing novel building blocks is an overlooked strategy to improve compound quality. Drug Discov. Today 20, 11–17 (2015).

  20. 20.

    Gensch, T., Teders, M. & Glorius, F. Approach to comparing the functional group tolerance of reactions. J. Org. Chem. 82, 9154–9159 (2017).

  21. 21.

    Collins, K. D. & Glorius, F. A robustness screen for the rapid assessment of chemical reactions. Nat. Chem. 5, 597–601 (2013).

  22. 22.

    Shevlin, M. Practical high-throughput experimentation for chemists. ACS Med. Chem. Lett 8, 601–607 (2017).

  23. 23.

    Durak, L. J., Payne, J. T. & Lewis, J. C. Late-stage diversification of biologically active molecules via chemoenzymatic C–H functionalization. ACS Catal. 6, 1451–1454 (2016).

  24. 24.

    Fox, J. C., Gilligan, R. E., Pitts, A. K., Bennett, H. R. & Gaunt, M. J. The total synthesis of K-252c (staurosporinone) via a sequential C-H functionalisation strategy. Chem. Sci. 7, 2706–2710 (2016).

  25. 25.

    Kim, Y., Park, J. & Chang, S. A direct access to 7-aminoindoles via iridium-catalyzed mild C–H amidation of N-pivaloylindoles with organic azides. Org. Lett. 18, 1892–1895 (2016).

  26. 26.

    Calleja, J. et al. A steric tethering approach enables palladium-catalysed C–H activation of primary amino alcohols. Nat. Chem. 7, 1009–1016 (2015).

  27. 27.

    Pryde, D. C. et al. Selection of a novel anti-nicotine vaccine: influence of antigen design on antibody function in mice. PLoS ONE 8, e76557 (2013).

  28. 28.

    Sadler, S. A. et al. Multidirectional synthesis of substituted indazoles via iridium-catalyzed C–H borylation. J. Org. Chem. 80, 5308–5314 (2015).

  29. 29.

    O’Hara, F., Blackmond, D. G. & Baran, P. S. Radical-based regioselective C–H functionalization of electron-deficient heteroarenes: scope, tunability, and predictability. J. Am. Chem. Soc. 135, 12122–12134 (2013).

  30. 30.

    White, M. C. Adding aliphatic C–H bond oxidations to synthesis. Science 335, 807–809 (2012).

  31. 31.

    Liao, K., Negretti, S., Musaev, D. G., Bacsa, J. & Davies, H. M. L. Site-selective and stereoselective functionalization of unactivated C–H bonds. Nature 533, 230–234 (2016).

  32. 32.

    Osberger, T. J., Rogness, D. C., Kohrt, J. T., Stepan, A. F. & White, M. C. Oxidative diversification of amino acids and peptides by small-molecule iron catalysis. Nature 537, 214–219 (2016).

  33. 33.

    Zhang, Z., Tanaka, K. & Yu, J.-Q. Remote site-selective C–H activation directed by a catalytic bifunctional template. Nature 543, 538–542 (2017).

  34. 34.

    Wu, Q.-F. et al. Formation of α-chiral centers by asymmetric β-C(sp 3–H arylation, alkenylation, and alkynylation. Science 355, 499–503 (2017).

  35. 35.

    Nielsen, M. K., Ugaz, C. R., Li, W. & Doyle, A. G. PyFluor: a low-cost, stable, and selective deoxyfluorination reagent. J. Am. Chem. Soc. 137, 9571–9574 (2015).

  36. 36.

    Yamada, S., Gavryushin, A. & Knochel, P. Convenient electrophilic fluorination of functionalized aryl and heteroaryl magnesium reagents. Ang. Chem. Int. Ed. 49, 2215–2218 (2010).

  37. 37.

    Fier, P. S. & Hartwig, J. F. Selective C–H fluorination of pyridines and diazines inspired by a classic amination reaction. Science 342, 956–960 (2013).

  38. 38.

    Meanwell, M., Nodwell, M. B., Martin, R. E. & Britton, R. A Convenient late-stage fluorination of pyridylic C−H bonds with N-fluorobenzenesulfonimide. Ang. Chem. Int. Ed. 55, 13244–13248 (2016).

  39. 39.

    Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

  40. 40.

    Campbell, M. G. & Ritter, T. Late-stage fluorination: from fundamentals to application. Org. Process Res. Dev. 18, 474–480 (2014).

  41. 41.

    Brooks, A. F., Topczewski, J. J., Ichiishi, N., Sanford, M. S. & Scott, P. J. H. Late-stage [18F]fluorination: new solutions to old problems. Chem. Sci. 5, 4545–4553 (2014).

  42. 42.

    Shiozaki, M. et al. Discovery of (1S, 2R, 3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: novel and highly selective aggrecanase inhibitors. J. Med. Chem. 54, 2839–2863 (2011).

  43. 43.

    Liu, W. & Groves, J. T. Manganese catalyzed C–H halogenation. Acc Chem. Res. 48, 1727–1735 (2015).

  44. 44.

    Cheng, C. & Hartwig, J. F. Iridium-catalyzed silylation of aryl C–H bonds. J. Am. Chem. Soc. 137, 592–595 (2015).

  45. 45.

    Morstein, J., Hou, H., Cheng, C. & Hartwig, J. F. Trifluoromethylation of arylsilanes with [(phen)CuCF3]. Ang. Chem. 128, 8186–8189 (2016).

  46. 46.

    Genovino, J., Sames, D., Hamann, L. G. & Touré, B. B. Accessing drug metabolites via transition-metal catalyzed C−H oxidation: the liver as synthetic inspiration. Ang. Chem. Int. Ed. 55, 14218–14238 (2016).

  47. 47.

    Huff, C. A. et al. Photoredox-catalyzed hydroxymethylation of heteroaromatic bases. J. Org. Chem. 81, 6980–6987 (2016).

  48. 48.

    Chessari, G. et al. Fragment-based drug discovery targeting inhibitor of apoptosis proteins: discovery of a non-alanine lead series with dual activity against cIAP1 and XIAP. J. Med. Chem. 58, 6574–6588 (2015).

  49. 49.

    Palmer, N., Peakman, T. M., Norton, D. & Rees, D. C. Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD). Org. Biomol. Chem. 14, 1599–1610 (2016).

  50. 50.

    Johnson, C. N., Erlanson, D. A., Murray, C. W. & Rees, D. C. Fragment-to-lead medicinal chemistry publications in 2015. J. Med. Chem. 60, 89–99 (2017).

  51. 51.

    Chen, M. S. & White, M. C. Combined effects on selectivity in Fe-catalyzed methylene oxidation. Science 327, 566–571 (2010).

  52. 52.

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

  53. 53.

    Bigi, M. A., Reed, S. A. & White, M. C. Diverting non-haem iron catalysed aliphatic C–H hydroxylations towards desaturations. Nat. Chem. 3, 216–222 (2011).

  54. 54.

    Paradine, S. M. & White, M. C. Iron-catalyzed intramolecular allylic C–H amination. J. Am. Chem. Soc. 134, 2036–2039 (2012).

  55. 55.

    Bigi, M. A., Reed, S. A. & White, M. C. Directed metal (oxo) aliphatic C–H hydroxylations: overriding substrate bias. J. Am. Chem. Soc. 134, 9721–9726 (2012).

  56. 56.

    Bigi, M. A. & White, M. C. Terminal olefins to linear α,β-unsaturated ketones: Pd(II)/hypervalent iodine co-catalyzed Wacker oxidation–dehydrogenation. J. Am. Chem. Soc. 135, 7831–7834 (2013).

  57. 57.

    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).

  58. 58.

    Paradine, S. M. et al. A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp 3)–H amination. Nat. Chem. 7, 987–994 (2015).

  59. 59.

    Howell, J. M., Feng, K., Clark, J. R., Trzepkowski, L. J. & White, M. C. Remote oxidation of aliphatic C–H bonds in nitrogen-containing molecules. J. Am. Chem. Soc. 137, 14590–14593 (2015).

  60. 60.

    Liu, W. & Groves, J. T. Manganese porphyrins catalyze selective C−H bond halogenations. J. Am. Chem. Soc. 12847–12849 (2010).

  61. 61.

    Liu, W. et al. Oxidative Aliphatic C–H fluorination with fluoride ion catalyzed by a manganese porphyrin. Science 337, 1322–1325 (2012).

  62. 62.

    Liu, W. & Groves, J. T. Manganese-catalyzed oxidative benzylic C–H fluorination by gluoride ions. Ang. Chem. Int. Ed. 52, 6024–6027 (2013).

  63. 63.

    Liu, W. & Groves, J. T. Manganese catalyzed C–H halogenation. Acc. Chem. Res. 48, 1727–1735 (2015).

  64. 64.

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

  65. 65.

    Le, C., Liang, Y., Evans, R. W., Li, X. & MacMillan, D. W. C. Selective sp 3 C–H alkylation via polarity-match-based cross-coupling. Nature 547, 79–83 (2017).

  66. 66.

    Foley, D. J., Doveston, R. G., Churcher, I., Nelson, A. & Marsden, S. P. A systematic approach to diverse, lead-like scaffolds from α,α-disubstituted amino acids. Chem. Commun. 51, 11174–11177 (2015).

  67. 67.

    Wang, Y.-M., Bruno, N. C., Placeres, Á. L., Zhu, S. & Buchwald, S. L. Enantioselective synthesis of carbo- and heterocycles through a CuH-catalyzed hydroalkylation approach. J. Am. Chem. Soc. 137, 10524–10527 (2015).

  68. 68.

    Gotoh, H., Okamura, D., Ishikawa, H. & Hayashi, Y. diphenylprolinol silyl ether as a catalyst in an asymmetric, catalytic, and direct michael reaction of nitroethanol with α,β-unsaturated aldehydes. Org. Lett. 11, 4056–4059 (2009).

  69. 69.

    Barber, D. M., Ďuriš, A., Thompson, A. L., Sanganee, H. J. & Dixon, D. J. One-pot asymmetric nitro-mannich/hydroamination cascades for the synthesis of pyrrolidine derivatives: combining organocatalysis and gold catalysis. ACS Catal. 4, 634–638 (2014).

  70. 70.

    Jain, P., Verma, P., Xia, G. & Yu, J.-Q. Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides. Nat. Chem. 9, 140–144 (2017).

  71. 71.

    Liskey, C. W. & Hartwig, J. F. Iridium-catalyzed C–H borylation of cyclopropanes. J. Am. Chem. Soc. 135, 3375–3378 (2013).

  72. 72.

    Schneider, N., Lowe, D. M., Sayle, R. A., Tarselli, M. A. & Landrum, G. A. Big data from pharmaceutical patents: a computational analysis of medicinal chemists’ bread and butter. J. Med. Chem. 59, 4385–4402 (2016).

  73. 73.

    Roughley, S. D. & Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451–3479 (2011).

  74. 74.

    Beletskaya, I. P. & Cheprakov, A. V. The complementary competitors: palladium and copper in C–N cross-coupling reactions. Organometallics 31, 7753–7808 (2012).

  75. 75.

    Surry, D. S. & Buchwald, S. L. Dialkylbiaryl phosphines in Pd-catalyzed amination: a user’s guide. Chem. Sci 2, 27–50 (2011).

  76. 76.

    Surry, D. S. & Buchwald, S. L. Diamine ligands in copper-catalyzed reactions. Chem. Sci. 1, 13–31 (2010).

  77. 77.

    Surry, D. S. & Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination. Ang. Chem. Int. Ed. 47, 6338–6361 (2008).

  78. 78.

    Sambiagio, C., Marsden, S. P., Blacker, A. J. & McGowan, P. C. Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development. Chem. Soc. Rev. 43, 3525–3550 (2014).

  79. 79.

    Kataoka, N., Shelby, Q., Stambuli, J. P. & Hartwig, J. F. Air stable, sterically hindered ferrocenyl dialkylphosphines for palladium-catalyzed C−C, C−N and C−O bond-forming cross-couplings. J. Org. Chem. 67, 5553–5566 (2002).

  80. 80.

    Fu, G. C. The development of versatile methods for palladium-catalyzed coupling reactions of aryl electrophiles through the use of P(t-Bu)3 and PCy3 as ligands. Acc. Chem. Res. 41, 1555–1564 (2008).

  81. 81.

    Zapf, A. et al. Practical synthesis of new and highly efficient ligands for the Suzuki reaction of aryl chlorides. Chem. Commun. 38–39 (2004).

  82. 82.

    Troshin, K. & Hartwig, J. F. Snap deconvolution: An informatics approach to high-throughput discovery of catalytic reactions. Science 357, 175–181 (2017).

  83. 83.

    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).

  84. 84.

    Akai, Y., Konnert, L., Yamamoto, T. & Suginome, M. Asymmetric Suzuki-Miyaura cross-coupling of 1-bromo-2-naphthoates using the helically chiral polymer ligand PQXphos. Chemical Commun. 51, 7211–7214 (2015).

  85. 85.

    Bhimireddy, E. & Corey, E. J. Method for highly enantioselective ligation of two chiral C(sp 3) stereocenters. J. Am. Chem. Soc. 139, 11044–11047 (2017).

  86. 86.

    Schäfer, P., Palacin, T., Sidera, M. & Fletcher, S. P. Asymmetric Suzuki-Miyaura coupling of heterocycles via rhodium-catalysed allylic arylation of racemates. 8, 15762 (2017).

  87. 87.

    Handa, S., Wang, Y., Gallou, F. & Lipshutz, B. H. Sustainable Fe–ppm Pd nanoparticle catalysis of Suzuki–Miyaura cross-couplings in water. Science 349, 1087–1091 (2015).

  88. 88.

    Isley, N. A., Gallou, F. & Lipshutz, B. H. Transforming Suzuki–Miyaura cross-couplings of mida boronates into a green technology: no organic solvents. J. Am. Chem. Soc. 135, 17707–17710 (2013).

  89. 89.

    Handa, S., Smith, J. D., Hageman, M. S., Gonzalez, M. & Lipshutz, B. H. Synergistic and selective copper/ppm Pd-catalyzed Suzuki–Miyaura couplings: in water, mild conditions, with recycling. ACS Catal. 6, 8179–8183 (2016).

  90. 90.

    Bhonde, V. R., O’Neill, B. T. & Buchwald, S. L. An improved system for the aqueous Lipshutz–Negishi cross-coupling of alkyl halides with aryl electrophiles. Ang. Chem. Int. Ed. 55, 1849–1853 (2016).

  91. 91.

    Lee, N. R., Gallou, F. & Lipshutz, B. H. SNAr reactions in aqueous nanomicelles: from milligrams to grams with no dipolar aprotic solvents needed. Org. Process Res. Dev. 21, 218–221 (2017).

  92. 92.

    Sheldon, I., Arends & Hanefeld, U. Green Chemistry and Catalysis (Wiley-VCH, 2007).

  93. 93.

    Magano, J. & Monfette, S. Development of an air-stable, broadly applicable nickel source for nickel-catalyzed cross-coupling. ACS Catal. 5, 3120–3123 (2015).

  94. 94.

    Egorova, K. S. & Ananikov, V. P. Which metals are green for catalysis? Comparison of the toxicities of Ni, Cu, Fe, Pd, Pt, Rh, and Au salts. Ang. Chem. Int. Ed. 55, 12150–12162 (2016).

  95. 95.

    Quasdorf, K. W., Riener, M., Petrova, K. V. & Garg, N. K. Suzuki−Miyaura coupling of aryl carbamates, carbonates, and sulfamates. J. Am. Chem. Soc. 131, 17748–17749 (2009).

  96. 96.

    Qin, T. et al. Nickel-catalyzed barton decarboxylation and giese reactions: a practical take on classic transforms. Ang. Chem. 129, 266–271 (2017).

  97. 97.

    Johnston, C. P., Smith, R. T., Allmendinger, S. & MacMillan, D. W. C. Metallaphotoredox-catalysed sp 3sp 3 cross-coupling of carboxylic acids with alkyl halides. Nature 536, 322–325 (2016).

  98. 98.

    Lou, S. & Fu, G. C. Nickel/bis(oxazoline)-catalyzed asymmetric Kumada reactions of alkyl electrophiles: cross-couplings of racemic α-bromoketones. J. Am. Chem. Soc. 132, 1264–1266 (2010).

  99. 99.

    Lu, Z. & Fu, G. C. Alkyl–alkyl Suzuki cross-coupling of unactivated secondary alkyl chlorides. Ang. Chem. Int. Ed. (2010).

  100. 100.

    Owston, N. A. & Fu, G. C. Asymmetric alkyl−alkyl cross-couplings of unactivated secondary alkyl electrophiles: stereoconvergent Suzuki reactions of racemic acylated halohydrins. J. Am. Chem. Soc. 132, 11908–11909 (2010).

  101. 101.

    Lu, Z., Wilsily, A. & Fu, G. C. Stereoconvergent amine-directed alkyl–alkyl Suzuki reactions of unactivated secondary alkyl chlorides. J. Am. Chem. Soc. 133, 8154–8157 (2011).

  102. 102.

    Zultanski, S. L. & Fu, G. C. Catalytic asymmetric γ-alkylation of carbonyl compounds via stereoconvergent Suzuki cross-couplings. J. Am. Chem. Soc. 133, 15362–15364 (2011).

  103. 103.

    Oelke, A. J., Sun, J. & Fu, G. C. Nickel-catalyzed enantioselective cross-couplings of racemic secondary electrophiles that bear an oxygen leaving group. J. Am. Chem. Soc. 134, 2966–2969 (2012).

  104. 104.

    Binder, J. T., Cordier, C. J. & Fu, G. C. Catalytic enantioselective cross-couplings of secondary alkyl electrophiles with secondary alkylmetal nucleophiles: Negishi reactions of racemic benzylic bromides with achiral alkylzinc reagents. J. Am. Chem. Soc. 134, 17003–17006 (2012).

  105. 105.

    Zultanski, S. L. & Fu, G. C. Nickel-catalyzed carbon–carbon bond-forming reactions of unactivated tertiary alkyl halides: Suzuki arylations. J. Am. Chem. Soc. 135, 624–627 (2013).

  106. 106.

    Cordier, C. J., Lundgren, R. J. & Fu, G. C. Enantioconvergent cross-couplings of racemic alkylmetal reagents with unactivated secondary alkyl electrophiles: catalytic asymmetric Negishi α-alkylations of N-Boc-pyrrolidine. J. Am. Chem. Soc. 135, 10946–10949 (2013).

  107. 107.

    Liang, Y. & Fu, G. C. Nickel-catalyzed alkyl–alkyl cross-couplings of fluorinated secondary electrophiles: a general approach to the synthesis of compounds having a perfluoroalkyl substituent. Ang. Chem. Int. Ed. 54, 9047–9051 (2015).

  108. 108.

    Liang, Y. & Fu, G. C. Stereoconvergent Negishi arylations of racemic secondary alkyl electrophiles: differentiating between a CF3 and an alkyl group. J. Am. Chem. Soc. 137, 9523–9526 (2015).

  109. 109.

    Molander, G. A. & Argintaru, O. A. Stereospecific Ni-catalyzed cross-coupling of potassium alkenyltrifluoroborates with alkyl halides. Org. Lett. 16, 1904–1907 (2014).

  110. 110.

    Tellis, J. C., Primer, D. N. & Molander, G. A. Single-electron transmetalation in organoboron cross-coupling by photoredox/nickel dual catalysis. Science 345, 433–436 (2014).

  111. 111.

    Primer, D. N., Karakaya, I., Tellis, J. C. & Molander, G. A. Single-electron transmetalation: an enabling technology for secondary alkylboron cross-coupling. J. Am. Chem. Soc. 137, 2195–2198 (2015).

  112. 112.

    Gutierrez, O., Tellis, J. C., Primer, D. N., Molander, G. A. & Kozlowski, M. C. Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. J. Am. Chem. Soc. 137, 4896–4899 (2015).

  113. 113.

    Molander, G. A., Traister, K. M. & O’Neill, B. T. Engaging nonaromatic, heterocyclic tosylates in reductive cross-coupling with aryl and heteroaryl bromides. J. Org. Chem. 80, 2907–2911 (2015).

  114. 114.

    Tellis, J. C. et al. Single-electron transmetalation via photoredox/nickel dual catalysis: unlocking a new paradigm for sp 3sp 2 cross-coupling. Acc. Chem. Res. 49, 1429–1439 (2016).

  115. 115.

    Karimi-Nami, R., Tellis, J. C. & Molander, G. A. Single-electron transmetalation: protecting-group-independent synthesis of secondary benzylic alcohol derivatives via photoredox/nickel dual catalysis. Org. Lett. 8, 2572–2575 (2016).

  116. 116.

    El Khatib, M., Serafim, R. A. M. & Molander, G. A. α-Arylation/heteroarylation of chiral α-aminomethyltrifluoroborates by synergistic iridium photoredox/nickel cross-coupling catalysis. Ang. Chem. Int. Ed. 55, 254–258 (2016).

  117. 117.

    Heitz, D. R., Tellis, J. C. & Molander, G. A. Photochemical nickel-catalyzed C–H arylation: synthetic scope and mechanistic investigations. J. Am. Chem. Soc. 138, 12715–12718 (2016).

  118. 118.

    Vara, B. A., Jouffroy, M. & Molander, G. A. C. sp 3)–C(sp 2) cross-coupling of alkylsilicates with borylated aryl bromides — an iterative platform to alkylated aryl- and heteroaryl boronates. Chem. Sci. 8, 530–535 (2017).

  119. 119.

    Choi, J. & Fu, G. C. Transition metal–catalyzed alkyl-alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, aaf7230 (2017).

  120. 120.

    Zhang, P., Le, C. C. & MacMillan, D. W. C. Silyl radical activation of alkyl halides in metallaphotoredox catalysis: a unique pathway for cross-electrophile coupling. J. Am. Chem. Soc. 138, 8084–8087 (2016).

  121. 121.

    Jin, J. & MacMillan, D. W. C. Direct α-arylation of ethers through the combination of photoredox-mediated C–H functionalization and the minisci reaction. Ang. Chem. Int. Ed. 54, 1565–1569 (2015).

  122. 122.

    Huihui, K. M. M. et al. Decarboxylative cross-electrophile coupling of N-hydroxyphthalimide esters with aryl iodides. J. Am. Chem. Soc. 138, 5016–5019 (2016).

  123. 123.

    Cornella, J. et al. Practical Ni-catalyzed aryl–alkyl cross-coupling of secondary redox-active esters. J. Am. Chem. Soc. 138, 2174–2177 (2016).

  124. 124.

    Wang, J. et al. Nickel-catalyzed cross-coupling of redox-active esters with boronic acids. Ang. Chem. Int. Ed. 55, 9676–9679 (2016).

  125. 125.

    Sandfort, F., O’Neill, M. J., Cornella, J., Wimmer, L. & Baran, P. S. Alkyl−(hetero)aryl bond formation via decarboxylative cross-coupling: a systematic analysis. Ang. Chem. Int. Ed. 56, 3319–3323 (2017).

  126. 126.

    Molander, G. A., Traister, K. M. & O’Neill, B. T. Reductive cross-coupling of nonaromatic, heterocyclic bromides with aryl and heteroaryl bromides. J. Org. Chem. 79, 5771–5780 (2014).

  127. 127.

    Anka-Lufford, L. L., Huihui, K. M. M., Gower, N. J., Ackerman, L. K. G. & Weix, D. J. Nickel-catalyzed cross-electrophile coupling with organic reductants in non-amide solvents. Chem. Euro. J. 22, 11564–11567 (2016).

  128. 128.

    Weix, D. J. Methods and mechanisms for cross-electrophile coupling of Csp 2 halides with alkyl electrophiles. Acc. Chem. Res. 48, 1767–1775 (2015).

  129. 129.

    Perkins, R. J., Pedro, D. J. & Hansen, E. C. Electrochemical nickel catalysis for sp 2sp 3 cross-electrophile coupling reactions of unactivated alkyl jalides. Org. Lett. 19, 3755–3758 (2017).

  130. 130.

    Yan, M., Kawamata, Y. & Baran, P. S. Synthetic organic electrochemistry: calling all engineers. Ang. Chem. Int. Ed. https://doi.org/10.1002/anie.201707584 (2017).

  131. 131.

    Liu, Y. & Ge, H. Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group. Nat. Chem. 9, 26–32 (2017).

  132. 132.

    Shavnya, A., Coffey, S. B., Smith, A. C. & Mascitti, V. Palladium-catalyzed sulfination of aryl and heteroaryl halides: direct access to sulfones and sulfonamides. Org. Lett. 15, 6226–6229 (2013).

  133. 133.

    Leonard, J. et al. A survey of the borrowing hydrogen approach to the synthesis of some pharmaceutically relevant intermediates. Org. Process Res. Dev. 19, 1400–1410 (2015).

  134. 134.

    Mutti, F. G., Knaus, T., Scrutton, N. S., Breuer, M. & Turner, N. J. Conversion of alcohols to enantiopure amines through dual-enzyme hydrogen-borrowing cascades. Science 349, 1525–1529 (2015).

  135. 135.

    Roda, N. M. et al. Cyclopropanation using flow-generated diazo compounds. Org. Biomol. Chem. 13, 2550–2554 (2015).

  136. 136.

    Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 79, 629–661 (2016).

  137. 137.

    Harvey, A. L., Edrada-Ebel, R. & Quinn, R. J. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug. Discov. 14, 111–129 (2015).

  138. 138.

    Shen, B. A new golden age of natural products drug discovery. Cell 163, 1297–1300 (2015).

  139. 139.

    Ross, S. P. & Hoye, T. R. Reactions of hexadehydro-Diels-Alder benzynes with structurally complex multifunctional natural products. Nat. Chem. 9, 523–530 (2017).

  140. 140.

    Seiple, I. B. et al. A platform for the discovery of new macrolide antibiotics. Nature 533, 338–345 (2016).

  141. 141.

    Baumann, M. et al. A modular flow reactor for performing Curtius rearrangements as a continuous flow process. Org. Biomol. Chem. 6, 1577–1586 (2008).

  142. 142.

    Luk, K.-C. & Satz, A. L. in A Handbook for DNA-Encoded Chemistry 67–98 (John Wiley & Sons, Hoboken, 2014).

  143. 143.

    Franzini, R. M. & Randolph, C. Chemical space of DNA-encoded libraries. J. Medicinal Chem. 59, 6629–6644 (2016).

  144. 144.

    Zhou, Q. et al. Bioconjugation by native chemical tagging of C–H bonds. J. Am. Chem. Soc. 135, 12994–12997 (2013).

  145. 145.

    Vinogradova, E. V., Zhang, C., Spokoyny, A. M., Pentelute, B. L. & Buchwald, S. L. Organometallic palladium reagents for cysteine bioconjugation. Nature 526, 687–691 (2015).

  146. 146.

    Fitzpatrick, D. E., Battilocchio, C. & Ley, S. V. Enabling technologies for the future of chemical synthesis. ACS Central Sci. 2, 131–138 (2016).

  147. 147.

    Lin, H., Dai, C., Jamison, T. F. & Jensen, K. F. A rapid total synthesis of ciprofloxacin hydrochloride in continuous flow. Ang. Chem. Int. Ed. 56, 8870–8873 (2017).

  148. 148.

    Woerly, E. M., Roy, J. & Burke, M. D. Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nat. Chem. 6, 484–491 (2014).

  149. 149.

    Szymkuć, S. et al. Computer-assisted synthetic planning: the end of the beginning. Ang. Chem. Int. Ed. 55, 5904–5937 (2016).

  150. 150.

    Wei, J. N., Duvenaud, D. & Aspuru-Guzik, A. Neural networks for the prediction of organic chemistry reactions. ACS Central Sci. 2, 725–732 (2016).

  151. 151.

    Schneider, N., Lowe, D. M., Sayle, R. A. & Landrum, G. A. Development of a novel fingerprint for chemical reactions and its application to large-scale reaction classification and similarity. J. Chem. Inform. Model. 55, 39–53 (2015).

  152. 152.

    Segler, M. H. S. & Waller, M. P. Neural-symbolic machine learning for retrosynthesis and reaction prediction. Chem. Euro. J. 23, 5966–5971 (2017).

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Acknowledgements

We thank D. Dixon (University of Oxford) and S. Marsden (University of Leeds) for commenting on the manuscript. We also thank T. McGuire and F. Goldberg (AstraZeneca), C. Johnson (Astex) and N. Fadeyi (Pfizer) for help in preparing the manuscript, and A. Davey for assistance with the graphical abstract.

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Author notes

    • Ian Churcher

    Present address: BenevolentBio, London, UK

    • Anthony Wood

    Present address: GSK, Stevenage, UK

Affiliations

  1. Medicinal Sciences, Pfizer, Inc. Eastern Point Road, Groton, CT, USA

    • David C. Blakemore
  2. UCB, Slough, Berkshire, UK

    • Luis Castro
  3. GSK Medicines Research Centre, Stevenage, UK

    • Ian Churcher
  4. Astex Pharmaceuticals, Cambridge, UK

    • David C. Rees
  5. Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland

    • Andrew W. Thomas
  6. Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK

    • David M. Wilson
  7. Medicinal Sciences, Pfizer, Inc., Cambridge, MA, USA

    • Anthony Wood

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The authors contributed jointly to the writing of this paper.

Corresponding author

Correspondence to David C. Rees.

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https://doi.org/10.1038/s41557-018-0021-z

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