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Organic synthesis provides opportunities to transform drug discovery

Nature Chemistry volume 10, pages 383–394 (2018)Cite this article

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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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Fig. 1: Molecule–value relationship in drug discovery and organic synthesis.
Fig. 2: Drug molecules typically feature a number of groups — often clustered — that present significant synthetic challenges.
Fig. 3: Syntheses involving nitrogen-containing compounds and late-stage functionalizations.
Fig. 4: Hypothetical transformations that would overcome some of the synthetic challenges outlined.
Fig. 5: Metal-catalysed C–C bond-forming reactions.
Fig. 6: In situ use of potentially unstable intermediates.
Fig. 7: Syntheses compatible with biomacromolecules are increasingly important.

References

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

  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).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  52. 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 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  64. 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 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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. 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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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. 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).

    Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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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

  1. Ian Churcher

    Present address: BenevolentBio, London, UK

  2. Anthony Wood

    Present address: GSK, Stevenage, UK

Authors and 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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Blakemore, D.C., Castro, L., Churcher, I. et al. Organic synthesis provides opportunities to transform drug discovery. Nature Chem 10, 383–394 (2018). https://doi.org/10.1038/s41557-018-0021-z

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