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REVIEW (Open Access)
Contents Vol 74(5)

The Future of Retrosynthesis and Synthetic Planning: Algorithmic, Humanistic or the Interplay?

Craig M. Williams https://orcid.org/0000-0002-3834-7398 A B and Madeleine A. Dallaston https://orcid.org/0000-0002-9247-9682 A
+ Author Affiliations
- Author Affiliations

A School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Qld 4072, Australia.

B Corresponding author. Email: c.williams3@uq.edu.au




Craig M. Williams (C.M.W.) was born in Adelaide, Australia. He received his B.Sc. (Hons) degree in chemistry in 1994 from Flinders University. In 1997, he was awarded his Ph.D. in organic chemistry from the same institution under the supervision of Professor Rolf H. Prager. He undertook post-doctoral studies as an Alexander von Humboldt Fellow working with Professor Armin de Meijere at the Georg-August-Universität, Göttingen, Germany, from 1997 to 1999. In early 1999, he accepted a second post-doctoral fellowship at the Australian National University with Professor Lewis N. Mander. Professor Williams has held an academic position at the University of Queensland since 2000, and during this time has won a number of awards including a Thieme Chemistry Journals Award in 2007, an Australian Research Council Future Fellowship award in 2011, and the Award for Outstanding Contribution to Research (SCMB, UQ, 2019). The Williams research group explores numerous interests within the discipline of organic chemistry (e.g. medicinal chemistry, fundamental molecules, natural product isolation, microelectronics, drug and agrichemical development, impact sensitive molecules) enabled by organic synthesis refined through the construction of biologically active complex natural products (diterpenes, polyketides, alkaloids), and designs synthetic methodology to assist in this endeavour (synthetic transformations and reagents). Professor Williams especially enjoys teaching whole molecule retrosynthesis to undergraduate and post-graduate students.


Madeleine A. Dallaston (M.A.D.) was born in Leicester, England, and grew up in Brisbane, Australia. In 2016, she received her B.Sc. from Griffith University, earning the RACI Queensland Branch Prize for that year. In 2017, she undertook a B.Sc. (Hons) at the University of Queensland in collaboration with Defense Science and Technology, working on energetic materials for countermeasures development. She then commenced her Ph.D. in organic chemistry at the University of Queensland under the supervision of Professor Williams and G. Paul Savage in 2018, focusing on the synthesis of novel heterocycles for application as bioisosteres.

Australian Journal of Chemistry 74(5) 291-326 https://doi.org/10.1071/CH20371
Submitted: 21 December 2020  Accepted: 25 March 2021   Published: 12 May 2021

Journal Compilation © CSIRO 2021 Open Access CC BY

Abstract

The practice of deploying and teaching retrosynthesis is on the cusp of considerable change, which in turn forces practitioners and educators to contemplate whether this impending change will advance or erode the efficiency and elegance of organic synthesis in the future. A short treatise is presented herein that covers the concept of retrosynthesis, along with exemplified methods and theories, and an attempt to comprehend the impact of artificial intelligence in an era when freely and commercially available retrosynthetic and forward synthesis planning programs are increasingly prevalent. Will the computer ever compete with human retrosynthetic design and the art of organic synthesis?

Keywords: retrosynthesis, biomimetic synthesis, natural products, computer assisted synthesis, total synthesis, computer assisted retrosynthesis, artificial intelligence, antithetic analysis.


References

[1]     (a) E. J. Corey, X.-M. Cheng, The Logic of Chemical Synthesis 1995 (Wiley: New York, NY).
      (b) E. J. Corey, Chem. Soc. Rev. 1988, 17, 111.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) E. J. Corey, Pure Appl. Chem. 1967, 14, 19.
         | Crossref | GoogleScholarGoogle Scholar |

[2]     (a) The Nobel Prize, The Nobel Prize in Chemistry 1990. Nobel Media AB 2020. Available at: https://www.nobelprize.org/prizes/chemistry/1990/summary (accessed 11 Jun 2020)
      (b) E. J. Corey, Angew. Chem. Int. Ed. Engl. 1991, 30, 455.
         | Crossref | GoogleScholarGoogle Scholar |

[3]     (a) S. Warren, Designing Organic Syntheses: A Programmed Introduction to the Synthon Approach 1982 (Wiley: New York, NY).
         (b) S. Warren, P. Wyatt, Organic Synthesis: The Disconnection Approach, 2nd Edn 2008 (John Wiley & Sons: New York, NY).

[4]  M. B. Smith, J. Chem. Educ. 1990, 67, 848.
         | Crossref | GoogleScholarGoogle Scholar |

[5]     (a) J. Saunders, Top Drugs: Top Synthetic Routes 2000 (Oxford University Press: Oxford).
      (b) T. P. Stockdale, C. M. Williams, Chem. Soc. Rev. 2015, 44, 7737.
         | Crossref | GoogleScholarGoogle Scholar |

[6]  K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis: Targets, Strategies, Methods 1996 (Wiley-VCH: Weinheim).

[7]  K. C. Nicolaou, S. A. Snyder, Classics in Total Synthesis II: More Targets, Strategies, Methods 2003 (Wiley-VCH: Weinheim).

[8]  K. C. Nicolaou, J. S. Chen, Classics in Total Synthesis III: Further Targets, Strategies, Methods 2011 (Wiley-VCH: Weinheim).

[9]  (a) D. G. Brown, J. Boström, J. Med. Chem. 2016, 59, 4443.
         | Crossref | GoogleScholarGoogle Scholar | 26571338PubMed |
      (b) S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451.
         | Crossref | GoogleScholarGoogle Scholar |

[10]  (a) H. M. L. Davies, K. Liao, Nat. Rev. Chem. 2019, 3, 347.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) Y. Wei, P. Hu, M. Zhang, W. Su, Chem. Rev. 2017, 117, 8864.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) J. He, M. Wasa, K. S. L. Chan, Q. Shao, J.-Q. Yu, Chem. Rev. 2017, 117, 8754.
         | Crossref | GoogleScholarGoogle Scholar |

[11]  D. Petzold, M. Giedyk, A. Chatterjee, B. König, Eur. J. Org. Chem. 2020, 1193.
         | Crossref | GoogleScholarGoogle Scholar |

[12]  (a) E. J. Corey, W. T. Wipke, Science 1969, 166, 178.
         | Crossref | GoogleScholarGoogle Scholar | 17731475PubMed |
      (b) E. J. Corey, W. J. Howe, H. W. Orf, D. A. Pensak, G. Petersson, J. Am. Chem. Soc. 1975, 97, 6116.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) E. J. Corey, W. L. Jorgensen, J. Am. Chem. Soc. 1976, 98, 189.
         | Crossref | GoogleScholarGoogle Scholar |
      (d) E. J. Corey, A. K. Long, S. D. Rubenstein, Science 1985, 228, 408.
         | Crossref | GoogleScholarGoogle Scholar |
      (e) K. Lin, Y. Xu, J. Pei, L. Lai, Chem. Sci. 2020, 11, 3355.
         | Crossref | GoogleScholarGoogle Scholar |
      (f) P. Schwaller, R. Petraglia, V. Zullo, V. H. Nair, R. A. Haeuselmann, R. Pisoni, C. Bekas, A. Iuliano, T. Laino, Chem. Sci. 2020, 11, 3316.
         | Crossref | GoogleScholarGoogle Scholar |

[13]  (a) H. L. Gelernter, A. F. Sanders, D. L. Larsen, K. K. Agarwal, R. H. Boivie, G. A. Spritzer, J. E. Searleman, Science 1977, 197, 1041.
         | Crossref | GoogleScholarGoogle Scholar | 17836062PubMed |
      (b) W. T. Wipke, G. I. Ouchi, S Krishnan, Artif. Intell. 1978, 11, 173.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) S. Szymkuć, E. P. Gajewska, T. Klucznik, K. Molga, P. Dittwald, M. Startek, M. Bajczyk, B. A. Grzybowski, Angew. Chem. Int. Ed. 2016, 55, 5904.
         | Crossref | GoogleScholarGoogle Scholar |

[14]  J. W. Cornforth, R. H. Cornforth, K. K. Mathew, J. Chem. Soc. 1959, 2539.
         | Crossref | GoogleScholarGoogle Scholar |

[15]  The carbon unit equation approach has been recently deployed to construct an all-trans-polyprenol with 100 carbons; see: Y. Totsuka, Y. Yasuno, T. Shinada, Chem. Lett. 2019, 48, 491.
         | Crossref | GoogleScholarGoogle Scholar |

[16]  The non-traditional version of the retrosynthesis arrow (i.e. a closed in forward arrow) is frowned on by the authors and is never utilised. The authors believe that this arrow has introduced confusion to the discipline because it indicates a forward direction rather than reverse. The authors surmise that the introduction of the non-traditional arrow arose in the first Classics in Total Synthesis book series.[6]

[17]     (a) For a detailed overview of retrosynthesis, see: M. B. Smith, Organic Synthesis 4th Edn 2016 (Academic Press) and preceding Edns 1–3.
      (b) K. C. Nicolaou, C. R. H. Hale, Natl. Sci. Rev. 2014, 1, 233.
         | Crossref | GoogleScholarGoogle Scholar |

[18]  (a) M. C. de la Torre, M. A. Sierra, Angew. Chem. Int. Ed. Engl. 2004, 43, 160.
         | Crossref | GoogleScholarGoogle Scholar | 14695603PubMed |
      (b) M. Razzak, J. K. De Brabander, Nat. Chem. Biol. 2011, 7, 865.
         | Crossref | GoogleScholarGoogle Scholar |

[19]  L. F. Tietze, Chem. Rev. 1996, 96, 115.
         | Crossref | GoogleScholarGoogle Scholar | 11848746PubMed |

[20]  J. C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan, Chem. Rev. 2005, 105, 1001.
         | Crossref | GoogleScholarGoogle Scholar | 15755083PubMed |

[21]  (a) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. Int. Ed. 2006, 45, 7134.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38, 2993.
         | Crossref | GoogleScholarGoogle Scholar |

[22]  J. Y. W. Mak, C. M. Williams, Nat. Prod. Rep. 2012, 29, 440.
         | Crossref | GoogleScholarGoogle Scholar |

[23]  K. Kawazu, Agric. Biol. Chem. 1980, 44, 1367.
         | Crossref | GoogleScholarGoogle Scholar |

[24]  M. Kubo, M. Nakai, K. Harada, Y. Fukuyama, Tetrahedron 2019, 75, 2379.and references therein.
         | Crossref | GoogleScholarGoogle Scholar |

[25]  Y. Fukuyama, M. Kubo, H. Minami, H. Yuasa, A. Matsuo, T. Fujii, M. Morisaki, K. Harada, Chem. Pharm. Bull. 2005, 53, 72.
         | Crossref | GoogleScholarGoogle Scholar |

[26]  M. G. Constantino, V. L. Júnior, G. V. José Da Silva, Molecules 2002, 7, 456.
         | Crossref | GoogleScholarGoogle Scholar |

[27]  B. D. Schwartz, D. P. Tilly, R. Heim, S. Wiedemann, C. M. Williams, P. V. Bernhardt, Eur. J. Org. Chem. 2006, 3181.
         | Crossref | GoogleScholarGoogle Scholar |

[28]  M. J. Gallen, R. Goumont, T. Clark, F. Terrier, C. M. Williams, Angew. Chem. Int. Ed. 2006, 45, 2929.
         | Crossref | GoogleScholarGoogle Scholar |

[29]  (a) A. Porzelle, C. M. Williams, B. D. Schwartz, I. R. Gentle, Synlett 2005, 2923.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) B. D. Schwartz, A. Porzelle, K. S. Jack, J. M. Faber, I. R. Gentle, C. M. Williams, Adv. Synth. Catal. 2009, 351, 1148.
         | Crossref | GoogleScholarGoogle Scholar |

[30]  W. A. Eger, R. L. Grange, H. Schill, R. Goumont, T. Clark, C. M. Williams, Eur. J. Org. Chem. 2011, 2548.
         | Crossref | GoogleScholarGoogle Scholar |

[31]  E. Winterfeldt, H. Bauermeister, H. Riechers, D. Schomburg, P. Washausen, Angew. Chem. Int. Ed. Engl. 1991, 30, 191.
         | Crossref | GoogleScholarGoogle Scholar |

[32]  A. P.-J. Chen, C. M. Williams, Org. Lett. 2008, 10, 3441.
         | Crossref | GoogleScholarGoogle Scholar |

[33]  (a) Considering that the natural product isolation procedure used methanol as the extracting solvent (often for weeks), there existed the potential that the methylated systems were artefacts of isolation; see for example: R. J. Capon, Nat. Prod. Rep. 2020, 37, 55.
         | Crossref | GoogleScholarGoogle Scholar | 31046051PubMed |
      (b) L. A. Maslovskaya, A. I. Savchenko, V. A. Gordon, P. W. Reddell, C. J. Pierce, P. G. Parsons, C. M. Williams, Chem. – Eur. J. 2017, 23, 537.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) J. B. McAlpine, S.-N. Chen, A. Kutateladze, J. B. MacMillan, G. Appendino, A. Barison, M. A. Beniddir, M. W. Biavatti, S. Bluml, A. Boufridi, M. S. Butler, R. J. Capon, Y. H. Choi, D. Coppage, P. Crews, M. T. Crimmins, M. Csete, P. Dewapriya, J. M. Egan, M. J. Garson, G. Genta-Jouve, W. H. Gerwick, H. Gross, M. K. Harper, P. Hermanto, J. M. Hook, L. Hunter, D. Jeannerat, N.-Y. Ji, T. A. Johnson, D. G. I. Kingston, H. Koshino, H.-W. Lee, G. Lewin, J. Li, R. G. Linington, M. Liu, K. L. McPhail, T. F. Molinski, B. S. Moore, J.-W. Nam, R. P. Neupane, M. Niemitz, J.-M. Nuzillard, N. H. Oberlies, F. M. M. Ocampos, G. Pan, R. J. Quinn, D. S. Reddy, J.-H. Renault, J. Rivera-Chávez, W. Robien, C. M. Saunders, T. J. Schmidt, C. Seger, B. Shen, C. Steinbeck, H. Stuppner, S. Sturm, O. Taglialatela-Scafati, D. J. Tantillo, R. Verpoorte, B.-G. Wang, C. M. Williams, P. G. Williams, J. Wist, J.-M. Yue, C. Zhang, Z. Xu, C. Simmler, D. C. Lankin, J. Bisson, G. F. Pauli, Nat. Prod. Rep. 2019, 36, 35.
         | Crossref | GoogleScholarGoogle Scholar |

[34]  (a) J. Y. W. Mak, C. M. Williams, Chem. Commun. 2012, 287.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) J. Y. W. Mak, C. M. Williams, Eur. J. Org. Chem. 2012, 2001.
         | Crossref | GoogleScholarGoogle Scholar |

[35]  (a) A. P.-J. Chen, C. C. Müller, H. M. Cooper, C. M. Williams, Org. Lett. 2009, 11, 3758.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) A. P.-J. Chen, C. C. Müller, H. M. Cooper, C. M. Williams, Tetrahedron 2010, 66, 6842.
         | Crossref | GoogleScholarGoogle Scholar |

[36]  (a) M. J. Gallen, C. M. Williams, Org. Lett. 2008, 10, 713.
         | Crossref | GoogleScholarGoogle Scholar | 18247495PubMed |
      (b) M. J. Gallen, C. M. Williams, Eur. J. Org. Chem. 2008, 4697.
         | Crossref | GoogleScholarGoogle Scholar |

[37]  (a) G. A. Strohmeier, H. Pichler, O. May, M. Gruber-Khadjawi, Chem. Rev. 2011, 111, 4141.
         | Crossref | GoogleScholarGoogle Scholar | 21553913PubMed |
      (b) H.-P. Meyer, E. Eichhorn, S. Hanlon, S. Lütz, M. Schürmann, R. Wohlgemuthf, R. Coppolecchiag, Catal. Sci. Technol. 2013, 3, 29.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) M. Winkler, M. Geier, S. P. Hanlon, B. Nidetzky, A. Glieder, Angew. Chem. Int. Ed. 2018, 57, 13406.
         | Crossref | GoogleScholarGoogle Scholar |

[38]  L. A. Baker, C. M. Williams, P. V. Bernhardt, G. W. Yanik, Tetrahedron 2006, 62, 7355.
         | Crossref | GoogleScholarGoogle Scholar |

[39]  P. A. Wender, Nat. Prod. Rep. 2014, 31, 433.
         | Crossref | GoogleScholarGoogle Scholar | 24589860PubMed |

[40]  P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res. 2008, 41, 40.
         | Crossref | GoogleScholarGoogle Scholar | 18159936PubMed |

[41]  P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 962.
         | Crossref | GoogleScholarGoogle Scholar |

[42]  P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 3157.
         | Crossref | GoogleScholarGoogle Scholar |

[43]  M. A. Ogliaruso, M. G. Romanelli, E. I. Becker, Chem. Rev. 1965, 65, 261.
         | Crossref | GoogleScholarGoogle Scholar |

[44]  K. Hafner, K. Goliasch, Chem. Ber. 1961, 94, 2909.
         | Crossref | GoogleScholarGoogle Scholar |

[45]  E. T. McBee, R. K. Meyers, J. Am. Chem. Soc. 1955, 77, 88.
         | Crossref | GoogleScholarGoogle Scholar |

[46]  S. D. Houston, B. A. Chalmers, G. P. Savage, C. M. Williams, Org. Biomol. Chem. 2019, 17, 1067.
         | Crossref | GoogleScholarGoogle Scholar | 30644962PubMed |

[47]  (a) E. J. Ko, G. P. Savage, C. M. Williams, J. Tsanaktsidis, Org. Lett. 2011, 13, 1944.
         | Crossref | GoogleScholarGoogle Scholar | 21438514PubMed |
      (b) J. Ho, J. Zheng, R. Meana-Pañeda, D. G. Truhlar, E. J. Ko, G. P. Savage, C. M. Williams, M. L. Coote, J. Tsanaktsidis, J. Org. Chem. 2013, 78, 6677.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) E. J. Ko, C. M. Williams, G. P. Savage, J. Tsanaktsidis, Org. Synth. 2012, 89, 471.
         | Crossref | GoogleScholarGoogle Scholar |

[48]  (a) P. E. Eaton, Angew. Chem., Int. Ed. Engl. 1992, 31, 1421.[Angew. Chem. 1992, 104, 1447.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) K. F. Biegasiewicz, J. R. Griffiths, G. P. Savage, J. Tsanaktsidis, R. Priefer, Chem. Rev. 2015, 115, 6719.
         | Crossref | GoogleScholarGoogle Scholar |

[49]  (a) M. J. Falkiner, S. W. Littler, K. J. McRae, G. P. Savage, J. Tsanaktsidis, Org. Process Res. Dev. 2013, 17, 1503.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) D. E. Collin, E. H. Jackman, N. Jouandon, W. Sun, M. E. Light, D. C. Harrowven, B. Linclau, Synthesis 2021, 53, 1307.
         | Crossref | GoogleScholarGoogle Scholar |

[50]  (a) M. A. Dallaston, J. S. Brusnahan, C. Wall, C. M. Williams, Chem. – Eur. J. 2019, 25, 8344.
         | Crossref | GoogleScholarGoogle Scholar | 31124182PubMed |
      (b) M. A. Dallaston, S. D. Houston, C. M. Williams, Chem. – Eur. J. 2020, 26, 11966.
         | Crossref | GoogleScholarGoogle Scholar |

[51]  (a) B. A. Chalmers, H. Xing, S. D. Houston, C. Clark, S. Ghassabian, A. Kuo, B. Cao, A. Reitsma, C.-E. P. Murray, J. E. Stok, G. M. Boyle, C. J. Pierce, S. W. Littler, D. A. Winkler, P. V. Bernhardt, C. Pasay, J. J. De Voss, J. McCarthy, P. G. Parsons, G. H. Walter, M. T. Smith, H. M. Cooper, S. K. Nilsson, J. Tsanaktsidis, G. P. Savage, C. M. Williams, Angew. Chem. Int. Ed. 2016, 55, 3580.[Angew. Chem. 2016, 128, 3644]
         | Crossref | GoogleScholarGoogle Scholar |
      (b) T. A. Reekie, C. M. Williams, L. M. Rendina, M. Kassiou, J. Med. Chem. 2019, 62, 1078.
         | Crossref | GoogleScholarGoogle Scholar |

[52]  (a) L. Velluz, J. Valls, J. Mathieu, Angew. Chem. Int. Ed. 1967, 6, 778.[Angew. Chem. 1967, 79, 774]
         | Crossref | GoogleScholarGoogle Scholar |
      (b) D. Urabe, T. Asaba, M. Inoue, Chem. Rev. 2015, 115, 9207.
         | Crossref | GoogleScholarGoogle Scholar |

[53]  C. M. Williams, in Strategies and Tactics in Organic Synthesis (Ed. M. Harmata) 2014, Vol 10, Ch. 11, pp. 249–270 (Academic Press: New York, NY). 10.1016/B978-0-12-417185-5.00011-9

[54]  J. E. Aho, P. M. Pihko, T. K. Rissa, Chem. Rev. 2005, 105, 4406.
         | Crossref | GoogleScholarGoogle Scholar | 16351049PubMed |

[55]  L. F. Tietze, H. Geissler, J. A. Gewert, U. Jakobi, Synlett 1994, 511.
         | Crossref | GoogleScholarGoogle Scholar |

[56]  A. B. Smith, C. M. Adams, Acc. Chem. Res. 2004, 37, 365.
         | Crossref | GoogleScholarGoogle Scholar | 15196046PubMed |

[57]  N. Choukchou-Braham, Y. Asakawa, J.-P. Lepoittevin, Tetrahedron Lett. 1994, 35, 3949.
         | Crossref | GoogleScholarGoogle Scholar |

[58]  K.-M. Chen, G. E. Hardtmann, K. Prasad, O. Repič, M. J. Shapiro, Tetrahedron Lett. 1987, 28, 155.
         | Crossref | GoogleScholarGoogle Scholar |

[59]  M. Nakatsuka, J. A. Ragan, T. Sammakia, D. B. Smith, D. E. Uehling, S. L. Schreiber, J. Am. Chem. Soc. 1990, 112, 5583.and references therein.
         | Crossref | GoogleScholarGoogle Scholar |

[60]  L. Dong, V. A. Gordon, R. L. Grange, J. Johns, P. G. Parsons, A. Porzelle, P. Reddell, H. Schill, C. M. Williams, J. Am. Chem. Soc. 2008, 130, 15262.
         | Crossref | GoogleScholarGoogle Scholar | 18950180PubMed |

[61]  L. Dong, H. Schill, R. L. Grange, A. Porzelle, J. P. Johns, P. G. Parsons, V. A. Gordon, P. W. Reddell, C. M. Williams, Chem. – Eur. J. 2009, 15, 11307.
         | Crossref | GoogleScholarGoogle Scholar | 19750529PubMed |

[62]  (a) T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001, 34, 18.
         | Crossref | GoogleScholarGoogle Scholar | 11170353PubMed |
      (b) S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am. Chem. Soc. 2000, 122, 8168.
         | Crossref | GoogleScholarGoogle Scholar |

[63]  D. A. Evans, B. W. Trotter, P. J. Coleman, B. Côté, L. C. Dias, H. A. Rajapakse, A. N. Tyler, Tetrahedron 1999, 55, 8671.
         | Crossref | GoogleScholarGoogle Scholar |

[64]  J. R. Hanson, Sci. Prog. 2017, 100, 63.
         | Crossref | GoogleScholarGoogle Scholar | 28693673PubMed |

[65]  R. B. Woodward, F. G. Brutschy, H. Baer, J. Am. Chem. Soc. 1948, 70, 4216.
         | Crossref | GoogleScholarGoogle Scholar | 18105974PubMed |

[66]  (a) W. O. Kermack, R. Robinson, J. Chem. Soc. Trans. 1922, 121, 427.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) M. Saltzman, J. Chem. Educ. 1972, 49, 750.
         | Crossref | GoogleScholarGoogle Scholar |

[67]  L. Birladeanu, Angew. Chem. Int. Ed. 2003, 42, 1202.
         | Crossref | GoogleScholarGoogle Scholar |

[68]  M. Kahler, Arch. Pharm. 1830, 34, 318.
         | Crossref | GoogleScholarGoogle Scholar |

[69]  (a) G. R. Clemo, R. D. Haworth, E. J. Walton, J. Chem. Soc. 1929, 2368.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) G. R. Clemo, R. D. Haworth, E. J. Walton, J. Chem. Soc. 1930, 1110.
         | Crossref | GoogleScholarGoogle Scholar |

[70]  J. W. Huffman, W. T. Pennington, D. W. Bearden, J. Nat. Prod. 1992, 55, 1087.
         | Crossref | GoogleScholarGoogle Scholar |

[71]  A. P. J. Brunskill, H. W. Thompson, R. A. Lalancette, Acta Crystallogr. C 1999, 55, 566.
         | Crossref | GoogleScholarGoogle Scholar |

[72]  A. C. Willis, P. D. O’Connor, W. C. Taylor, L. N. Mander, Aust. J. Chem. 2006, 59, 629.
         | Crossref | GoogleScholarGoogle Scholar |

[73]  L. N. Mander, A. C. Willis, A. J. Herlt, W. C. Taylor, Tetrahedron Lett. 2009, 50, 7089.
         | Crossref | GoogleScholarGoogle Scholar |

[74]  T. A. Bradford, A. C. Willis, J. M. White, A. J. Herlt, W. C. Taylor, L. N. Mander, Tetrahedron Lett. 2011, 52, 188.
         | Crossref | GoogleScholarGoogle Scholar |

[75]  P. Lan, A. J. Herlt, A. C. Willis, W. C. Taylor, L. N. Mander, ACS Omega 2018, 3, 1912.
         | Crossref | GoogleScholarGoogle Scholar | 31458503PubMed |

[76]  S. V. Binns, P. J. Dunstan, G. M. Guise, G. M. Holder, A. F. Hollis, R. S. McCredie, J. T. Pinhey, R. H. Prager, M. Rasmussen, E. Ritchie, W. Taylor, Aust. J. Chem. 1965, 18, 569.
         | Crossref | GoogleScholarGoogle Scholar |

[77]  L. N. Mander, E. Ritchie, W. C. Taylor, Aust. J. Chem. 1967, 20, 981.
         | Crossref | GoogleScholarGoogle Scholar |

[78]  L. N. Mander, R. H. Prager, M. Rasmussen, E. Ritchie, W. C. Taylor, Aust. J. Chem. 1967, 20, 1473.
         | Crossref | GoogleScholarGoogle Scholar |

[79]  L. N. Mander, R. H. Prager, M. Rasmussen, E. Ritchie, W. C. Taylor, Aust. J. Chem. 1967, 20, 1705.
         | Crossref | GoogleScholarGoogle Scholar |

[80]  L. N. Mander, M. M. McLachlan, J. Am. Chem. Soc. 2003, 125, 2400.
         | Crossref | GoogleScholarGoogle Scholar | 12603121PubMed |

[81]  L. N. Mander, C. M. Williams, Tetrahedron 2003, 59, 1105.
         | Crossref | GoogleScholarGoogle Scholar |

[82]  A. J. Birch, J. Chem. Soc. 1944, 430.
         | Crossref | GoogleScholarGoogle Scholar |

[83]  L. N. Mander, in Comprehensive Organic Synthesis (Eds B. M. Trost, I. Fleming) 1991, Vol 8, pp. 489–521 (Pergamon: Oxford).10.1016/B978-0-08-052349-1.00237-7

[84]  U. Shah, S. Chackalamannil, A. K. Ganguly, M. Chelliah, S. Kolotuchin, A. Buevich, A. McPhail, J. Am. Chem. Soc. 2006, 128, 12654.
         | Crossref | GoogleScholarGoogle Scholar | 17002352PubMed |

[85]  D. A. Evans, D. J. Adams, J. Am. Chem. Soc. 2007, 129, 1048.
         | Crossref | GoogleScholarGoogle Scholar | 17263383PubMed |

[86]  (a) R. T. Larson, M. D. Clift, R. J. Thomson, Angew. Chem. Int. Ed. 2012, 51, 2481.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) R. T. Larson, R. P. Pemberton, J. M. Franke, D. J. Tantillo, R. J. Thomson, J. Am. Chem. Soc. 2015, 137, 11197.
         | Crossref | GoogleScholarGoogle Scholar |

[87]  (a) M. D. Levin, K. Subrahamanian, H. Katz, M. B. Smith, D. J. Burlett, S. M. Hecht, J. Am. Chem. Soc. 1980, 102, 1452.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) Y. Aoyagi, K. Katano, H. Suguna, J. Primeau, L.-H. Chang, S. M. Hecht, J. Am. Chem. Soc. 1982, 104, 5537.
         | Crossref | GoogleScholarGoogle Scholar |

[88]  T. Kametani, K. Fukumoto, Acc. Chem. Res. 1976, 9, 319.
         | Crossref | GoogleScholarGoogle Scholar |

[89]  A. Pagani, S. Gaeta, A. I. Savchenko, C. M. Williams, G. Appendino, Beilstein J. Org. Chem. 2017, 13, 1361.
         | Crossref | GoogleScholarGoogle Scholar | 28781702PubMed |

[90]  (a) Z. Liu, Z. Ding, K. Chen, M. Xu, T. Yu, G. Tong, H. Zhang, P. Li, Nat. Prod. Rep. 2021,
         | Crossref | GoogleScholarGoogle Scholar | 33508045PubMed |
      (b) S. Chow, T. Krainz, P. V. Bernhardt, C. M. Williams, Org. Lett. 2019, 21, 8761.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) S. Chow, T. Krainz, C. J. Bettencourt, N. Broit, B. Ferguson, M. Zhu, K. G. Hull, G. K. Pierens, P. V. Bernhardt, P. G. Parsons, D. Romo, G. M. Boyle, C. M. Williams, Chem. – Eur. J. 2020, 26, 13372.
         | Crossref | GoogleScholarGoogle Scholar |

[91]  (a) L. N. Mander, Acc. Chem. Res. 1983, 16, 48.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) L. N. Mander, Nat. Prod. Rep. 1988, 5, 541.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) L. N. Mander, Chem. Rev. 1992, 92, 573.
         | Crossref | GoogleScholarGoogle Scholar |
      (d) L. N. Mander, Nat. Prod. Rep. 2003, 20, 49.
         | Crossref | GoogleScholarGoogle Scholar |

[92]  R. D. Dawe, L. N. Mander, J. V. Turner, Tetrahedron Lett. 1985, 26, 363.
         | Crossref | GoogleScholarGoogle Scholar |

[93]  (a) I. Ojima, I. Habus, M. Zhao, M. Zucco, Y. H. Parr, C. M. Sun, T. Brigaud, Tetrahedron 1992, 48, 6985.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) Y. Kanda, H. Nakamura, S. Umemiya, R. K. Puthukanoori, V. R. M. Appala, G. K. Gaddamanugu, B. R. Paraselli, P. S. Baran, J. Am. Chem. Soc. 2020, 142, 10526.and references therein.
         | Crossref | GoogleScholarGoogle Scholar |

[94]  M. Boehm, P. C. Fuenfschilling, M. Krieger, E. Kuesters, F. Struber, Org. Process Res. Dev. 2007, 11, 336.
         | Crossref | GoogleScholarGoogle Scholar |

[95]  H. M. E. Cardwell, J. W. Cornforth, S. R. Duff, H. Holtermann, R. Robinson, Chem. Ind. 1951, 389.

[96]  Y. Shi, J. T. Wilmot, L. U. Nordstrøm, D. S. Tan, D. Y. Gin, J. Am. Chem. Soc. 2013, 135, 14313.and references therein.
         | Crossref | GoogleScholarGoogle Scholar | 24040959PubMed |

[97]  (a) N. A. Doering, R. Sarpong, R. W. Hoffmann, Angew. Chem. Int. Ed. 2020, 59, 10722.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) S. V. McCowen, N. A. Doering, R. Sarpong, Chem. Sci. 2020, 11, 7538.
         | Crossref | GoogleScholarGoogle Scholar |

[98]  (a) For Williams group efforts in the synthesis of C20-diterpene alkaloids see: C. M. Williams, L. N. Mander, Org. Lett. 2003, 5, 3499.
         | Crossref | GoogleScholarGoogle Scholar | 12967309PubMed |
      (b) C. M. Williams, L. N. Mander, P. V. Bernhardt, A. C. Willis, Tetrahedron 2005, 61, 3759.
         | Crossref | GoogleScholarGoogle Scholar |

[99]  H. Zhang, M. S. Reddy, S. Phoenix, P. Deslongchamps, Angew. Chem. Int. Ed. 2008, 47, 1272.
         | Crossref | GoogleScholarGoogle Scholar |

[100]  See for example: A. Greule, J. E. Stok, J. J. De Voss, M. J. Cryle, Nat. Prod. Rep. 2018, 35, 757.and references therein.
         | Crossref | GoogleScholarGoogle Scholar | 29667657PubMed |

[101]  X. Zhang, E. King-Smith, L.-Bi. Dong, L.-C. Yang, J. D. Rudolf, B. Shen, H. Renata, Science 2020, 369, 799.
         | Crossref | GoogleScholarGoogle Scholar | 32792393PubMed |

[102]  (a) D. M. Pinkerton, T. J. Vanden Berg, P. V. Bernhardt, C. M. Williams, Chem. – Eur. J. 2017, 23, 2282.
         | Crossref | GoogleScholarGoogle Scholar | 28042894PubMed |
      (b) D. M. Pinkerton, P. V. Bernhardt, G. P. Savage, C. M. Williams, Asian J. Org. Chem. 2017, 6, 583.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) D. M. Pinkerton, S. Chow, N. H. Eisa, K. Kainth, T. J. Vanden Berg, J. M. Burns, L. W. Guddat, G. P. Savage, A. Chadli, C. M. Williams, Chem. – Eur. J. 2019, 25, 1451.
         | Crossref | GoogleScholarGoogle Scholar |

[103]  IBX has sufficient acidity to promote side reactions and/or acid catalysed deprotections, see ref. [28] and T. Waters, J. Boulton, T. Clark, M. J. Gallen, C. M. Williams, R. A. J. O’Hair, Org. Biomol. Chem. 2008, 6, 2530.
         | Crossref | GoogleScholarGoogle Scholar | 18600274PubMed |

[104]  (a) M. J. Schnermann, R. A. Shenvi, Nat. Prod. Rep. 2015, 32, 543.
         | Crossref | GoogleScholarGoogle Scholar | 25514696PubMed |
      (b) M. J. Garson, J. S. Simpson, Nat. Prod. Rep. 2004, 21, 164.
         | Crossref | GoogleScholarGoogle Scholar |

[105]  E. J. Corey, P. A. Magriotis, J. Am. Chem. Soc. 1987, 109, 287.
         | Crossref | GoogleScholarGoogle Scholar |

[106]  (a) K. A. Fairweather, L. N. Mander, Org. Lett. 2006, 8, 3395.
         | Crossref | GoogleScholarGoogle Scholar | 16836414PubMed |
         (b) K. A. Fairweather, S. R. Crabtree, L. N. Mander, in Strategies and Tactics in Organic Synthesis (Ed. M. Harmata) 2008, Vol 7. Ch. 2, pp. 35–58 (Academic Press: New York, NY). 10.1016/S1874-6004(08)80006-8

[107]  J. S. Simpson, M. J. Garson, Org. Biomol. Chem. 2004, 2, 939.
         | Crossref | GoogleScholarGoogle Scholar | 15007426PubMed |

[108]  H. Miyaoka, Y. Okubo, M. Muroi, H. Mitome, E. Kawashima, Chem. Lett. 2011, 40, 246.
         | Crossref | GoogleScholarGoogle Scholar |

[109]  P. C. Roosen, C. D. Vanderwal, Angew. Chem. Int. Ed. 2016, 55, 7180.
         | Crossref | GoogleScholarGoogle Scholar |

[110]  E. E. Robinson, R. J. Thomson, J. Am. Chem. Soc. 2018, 140, 1956.
         | Crossref | GoogleScholarGoogle Scholar | 29309727PubMed |

[111]  A. S. Karns, B. D. Ellis, P. C. Roosen, Z. Chahine, K. G. Le Roch, C. D. Vanderwal, Angew. Chem. Int. Ed. 2019, 58, 13749.
         | Crossref | GoogleScholarGoogle Scholar |

[112]  The Claisen Rearrangement: Methods and Applications (Eds M. Hiersemann, U. Nubbemeyer) 2007 (Wiley-VCH: Chichester).

[113]  B. D. Schwartz, J. R. Denton, H. M. L. Davies, C. M. Williams, Aust. J. Chem. 2009, 62, 980.
         | Crossref | GoogleScholarGoogle Scholar | 21297900PubMed |

[114]  B. D. Schwartz, J. R. Denton, Y. Lian, H. M. L. Davies, C. M. Williams, J. Am. Chem. Soc. 2009, 131, 8329.
         | Crossref | GoogleScholarGoogle Scholar | 19445507PubMed |

[115]  Y. Fukuyama, H. Minami, A. Matsuo, K. Kitamura, M. Akizuki, M. Kubo, M. Kodama, Chem. Pharm. Bull. 2002, 50, 368.and references therein.
         | Crossref | GoogleScholarGoogle Scholar |

[116]  B. D. Schwartz, C. M. Williams, P. V. Bernhardt, Beilstein J. Org. Chem. 2008, 4.
         | Crossref | GoogleScholarGoogle Scholar |

[117]  H. M. L. Davies, Ø. Loe, D. G. Stafford, Org. Lett. 2005, 7, 5561.
         | Crossref | GoogleScholarGoogle Scholar |

[118]  C. M. Williams, in Strategies and Tactics in Organic Synthesis (Ed. M. Harmata) 2012, Vol 8. Ch. 15, pp. 395–412 (Academic Press: New York, NY). 10.1016/B978-0-12-386540-3.00017-4

[119]  B. D. Schwartz, C. M. Williams, E. Anders, P. V. Bernhardt, Tetrahedron 2008, 64, 6482.
         | Crossref | GoogleScholarGoogle Scholar |

[120]  B. D. Schwartz, J. R. Denton, P. V. Bernhardt, H. M. L. Davies, C. M. Williams, Synthesis 2009, 2840.
         | Crossref | GoogleScholarGoogle Scholar | 20725592PubMed |

[121]  S. B. Jones, B. Simmons, A. Mastracchio, D. W. C. MacMillan, Nature 2011, 475, 183.
         | Crossref | GoogleScholarGoogle Scholar | 21753848PubMed |

[122]  (a) See for example: J. Wang, S.-G. Chen, B.-F. Sun, G.-Q. Lin, Y.-J. Shang, Chem. – Eur. J. 2013, 19, 2539.
         | Crossref | GoogleScholarGoogle Scholar | 23292997PubMed |
      (b) W. Xu, J. Zhao, C. Tao, H. Wang, Y. Li, B. Cheng, H. Zhai, Org. Lett. 2018, 20, 1509.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) C. Qiao, W. Zhang, J.-C. Han, W.-M. Dai, C.-C. Li, Tetrahedron 2019, 75, 1739.
         | Crossref | GoogleScholarGoogle Scholar |
      (d) D.-W. Zhang, H.-L. Fan, W. Zhang, C.-J. Li, S. Luo, H.-B. Qin, Chem. Commun. 2020, 10066.
         | Crossref | GoogleScholarGoogle Scholar |
      (e) S.-H. Wang, R.-Q. Si, Q.-B. Zhuang, X. Guo, T. Ke, X.-M. Zhang, F.-M. Zhang, Y.-Q. Tu, Angew. Chem. Int. Ed. 2020, 59, 21954.
         | Crossref | GoogleScholarGoogle Scholar |

[123]  (a) V. Lakshmi, P. Gupta, Nat. Prod. Res. 2008, 22, 1197.
         | Crossref | GoogleScholarGoogle Scholar | 18932084PubMed |
      (b) D. A. Mulholland, B. Parel, P. H. Coombes, Curr. Org. Chem. 2000, 4, 1011.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) J. Wu, Q. Xiao, J. Xu, M.-Y. Li, J.-Y. Pan, M.-h. Yang, Nat. Prod. Rep. 2008, 25, 955.
         | Crossref | GoogleScholarGoogle Scholar |

[124]  J. M. Faber, C. M. Williams, Chem. Commun. 2011, 2258.
         | Crossref | GoogleScholarGoogle Scholar |

[125]  J. M. Faber, W. A. Eger, C. M. Williams, J. Org. Chem. 2012, 77, 8913.
         | Crossref | GoogleScholarGoogle Scholar | 22994389PubMed |

[126]  J. D’Angelo, M. B. Smith, Hybrid Retrosynthesis Organic Synthesis Using Reaxys and SciFinder 2015 (Elsevier: Amsterdam).

[127]  G. É. Vléduts, V. K. Finn, Inf. Storage Retr. 1963, 1, 101.
         | Crossref | GoogleScholarGoogle Scholar |

[128]  M. Bersohn, A. Esack, Chem. Rev. 1976, 76, 269.
         | Crossref | GoogleScholarGoogle Scholar |

[129]  (a) M. H. Todd, Chem. Soc. Rev. 2005, 34, 247.
         | Crossref | GoogleScholarGoogle Scholar | 15726161PubMed |
      (b) A. Cook, A. P. Johnson, J. Law, M. Mirzazadeh, O. Ravitz, A. Simon, WIREs Comput. Mol. Sci. 2012, 2, 79.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) O. Engkvist, P. O. Norrby, N. Selmi, Y. Lam, Z. Peng, E. C. Sherer, W. Amberg, T. Erhard, L. A. Smyth, Drug Discov. Today 2018, 23, 1203.
         | Crossref | GoogleScholarGoogle Scholar |
      (d) F. Feng, L. Lai, J. Pei, Front. Chem. 2018, 6, 199.
         | Crossref | GoogleScholarGoogle Scholar |
      (e) F. Strieth-Kalthoff, F. Sandfort, M. H. S. Segler, F. Glorius, Chem. Soc. Rev. 2020, 49, 6154.
         | Crossref | GoogleScholarGoogle Scholar |
      (f) P. M. Pflüger, F. Glorius, Angew. Chem. Int. Ed. 2020, 59, 18860.
         | Crossref | GoogleScholarGoogle Scholar |
      (g) W.-D. Ihlenfeldt, J. Gasteiger, Angew. Chem. Int. Ed. Engl. 1996, 34, 2613.
         | Crossref | GoogleScholarGoogle Scholar |
      (h) G. Schneider, D. E. Clark, Angew. Chem. Int. Ed. 2019, 58, 10792.
         | Crossref | GoogleScholarGoogle Scholar |
      (i) A. Thakkar, S. Johansson, K. Jorner, D. Buttar, J.-L. Reymond, O. Engkvist, React. Chem. Eng. 2021, 6, 27.
         | Crossref | GoogleScholarGoogle Scholar |

[130]     (a) A. Bondy, U. S. R. Murty, Graph Theory 2008 (Springer-Verlag: London).
      (b) L. David, A. Thakkar, R. Mercado, O. Engkvist, J. Cheminform. 2020, 12, 56.
         | Crossref | GoogleScholarGoogle Scholar |

[131]  T. Fink, H. Bruggesser, J.-L. Reymond, Angew. Chem. Int. Ed. 2005, 44, 1504.
         | Crossref | GoogleScholarGoogle Scholar |

[132]  IBM Corporation, IBM: Icons of Progress. Deep Blue. Available at: https://www.ibm.com/ibm/history/ibm100/us/en/icons/deepblue (accessed 18 Nov 2020)

[133]  (a) D. Silver, J. Schrittwieser, K. Simonyan, I. Antonoglou, A. Huang, A. Guez, T. Hubert, L. Baker, M. Lai, A. Bolton, Y. Chen, T. Lillicrap, F. Hui, L. Sifre, G. van den Driessche, T. Graepel, D. Hassabis, Nature 2017, 550, 354.
         | Crossref | GoogleScholarGoogle Scholar | 29052630PubMed |
      (b) D. Silver, T. Hubert, J. Schrittwieser, I. Antonoglou, M. Lai, A. Guez, M. Lanctot, L. Sifre, D. Kumaran, T. Graepel, T. Lillicrap, K. Simonyan, D. Hassabis, Science 2018, 362, 1140.
         | Crossref | GoogleScholarGoogle Scholar |
         (c) M. MacDonald, How Computers Are Reinventing Chess. 15 Nov 2019. Available at: https://medium.com/young-coder/how-computers-play-chess-today-d4f921ce8c4c (accessed 10 Feb 2021)

[134]  D. Heaven, Nature 2019, 574, 163.
         | Crossref | GoogleScholarGoogle Scholar | 31597977PubMed |

[135]  E. J. Corey, Q. Rev. Chem. Soc. 1971, 25, 455.
         | Crossref | GoogleScholarGoogle Scholar |

[136]  (a) T. Klucznik, B. Mikulak-Klucznik, M. P. McCormack, H. Lima, S. Szymkuć, M. Bhowmick, K. Molga, Y. Zhou, L. Rickershauser, E. P. Gajewska, A. Toutchkine, P. Dittwald, M. P. Startek, G. J. Kirkovits, R. Roszak, A. Adamski, B. Sieredzińska, M. Mrksich, S. L. J. Trice, B. A. Grzybowski, Chem 2018, 4, 522.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) K. Molga, S. Szymkuć, B. A. Grzybowski, Acc. Chem. Res. 2021, 54, 1094.
         | Crossref | GoogleScholarGoogle Scholar |

[137]  J. B. Hendrickson, Anal. Chim. Acta 1990, 235, 103.
         | Crossref | GoogleScholarGoogle Scholar |

[138]     (a) J. Gasteiger, C. Jochum, in Organic Compounds. Topics in Current Chemistry 1978, Vol 74, pp. 93–126 (Springer: Berlin).10.1007/BFB0050147
         (b) J. Gasteiger, M. G. Hutchings, B. Christoph, L. Gann, C. Hiller, P. Löw, M. Marsili, H. Saller, K. Yuki, in Organic Synthesis, Reactions and Mechanisms. Topics in Current Chemistry 1987, Vol 137, pp. 19–73 (Springer: Berlin). 10.1007/3-540-16904-0_14

[139]  T. D. Salatin, W. L. Jorgensen, J. Org. Chem. 1980, 45, 2043.
         | Crossref | GoogleScholarGoogle Scholar |

[140]  (a) S. Hanessian, J. Franco, B. Larouche, Pure Appl. Chem. 1990, 62, 1887.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) S. Hanessian, J. Org. Chem. 2012, 77, 6657.
         | Crossref | GoogleScholarGoogle Scholar |

[141]  W. T. Wipke, D. Rogers, J. Chem. Inf. Comput. Sci. 1984, 24, 71.
         | Crossref | GoogleScholarGoogle Scholar | 6547445PubMed |

[142]  (a) J. B. Hendrickson, A. G. Toczko, J. Chem. Inf. Comput. Sci. 1989, 29, 137.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) J. B. Hendrickson, A. G. Toczko, Pure Appl. Chem. 1989, 61, 589.
         | Crossref | GoogleScholarGoogle Scholar |

[143]  E. S. Blurock, J. Chem. Inf. Comput. Sci. 1990, 30, 505.
         | Crossref | GoogleScholarGoogle Scholar |

[144]  J. Gasteiger, W. D. Ihlenfeldt, in Software Development in Chemistry 4 (Ed. J. Gasteiger) 1990, pp. 57–65 (Springer: Berlin). 10.1007/978-3-642-75430-2_7

[145]  G. Sello, J. Chem. Inf. Model. 1992, 32, 713.
         | Crossref | GoogleScholarGoogle Scholar |

[146]  H. Satoh, K. Funatsu, J. Chem. Inf. Comput. Sci. 1995, 35, 34.
         | Crossref | GoogleScholarGoogle Scholar |

[147]  G. Mehta, R. Barone, M. Chanon, Eur. J. Org. Chem. 1998, 1409.
         | Crossref | GoogleScholarGoogle Scholar |

[148]  K. Satoh, K. Funatsu, J. Chem. Inf. Comput. Sci. 1999, 39, 316.
         | Crossref | GoogleScholarGoogle Scholar |

[149]  I. M. Socorro, K. Taylor, J. M. Goodman, Org. Lett. 2005, 7, 3541.
         | Crossref | GoogleScholarGoogle Scholar | 16048337PubMed |

[150]  A. Bøgevig, H.-J. Federsel, F. Huerta, M. G. Hutchings, H. Kraut, T. Langer, P. Löw, C. Oppawsky, T. Rein, H. Saller, Org. Process Res. Dev. 2015, 19, 357.
         | Crossref | GoogleScholarGoogle Scholar |

[151]  M. A. Kayala, P. Baldi, J. Chem. Inf. Model. 2012, 52, 2526.
         | Crossref | GoogleScholarGoogle Scholar | 22978639PubMed |

[152]  (a) B. A. Grzybowski, S. Szymkuć, E. P. Gajewska, K. Molga, P. Dittwald, A. Wołos, T. Klucznik, Chem 2018, 4, 390.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) E. P. Gajewska, S. Szymkuć, P. Dittwald, M. Startek, O. Popik, J. Mlynarski, B. A. Grzybowski, Chem 2020, 6, 280.
         | Crossref | GoogleScholarGoogle Scholar |

[153]  C. M. Gothard, N. A. Gothard, B. A. Grzybowski, in Abstracts of Papers, 245th ACS National Meeting & Exposition (American Chemical Society: New Orleans, LA) 2013, COMP 276. Poster abstract. Available at https://tpa.acs.org/abstract/245tNM-353448/analysis-of-chemical-networks-a-novel-paradigm-for-optimal-synthesis

[154]  B. Liu, B. Ramsundar, P. Kawthekar, J. Shi, J. Gomes, Q. Luu Nguyen, S. Ho, J. Sloane, P. Wender, V. Pande, ACS Cent. Sci. 2017, 3, 1103.
         | Crossref | GoogleScholarGoogle Scholar | 29104927PubMed |

[155]  (a) P. Schwaller, T. Gaudin, D. Lányi, C. Bekas, T. Laino, Chem. Sci. 2018, 9, 6091.
         | Crossref | GoogleScholarGoogle Scholar | 30090297PubMed |
      (b) A. C. Vaucher, F. Zipoli, J. Geluykens, V. H. Nair, P. Schwaller, T. Laino, Nat. Commun. 2020, 11, 3601.
         | Crossref | GoogleScholarGoogle Scholar |

[156]  IBM Corporation, ReactionSeq2Seq_Dataset. Available at: https://ibm.box.com/v/ReactionSeq2SeqDataset (accessed 4 Dec 2020)

[157]  I. A. Watson, J. Wang, C. A. Nicolaou, J. Cheminform. 2019, 11, 1.
         | Crossref | GoogleScholarGoogle Scholar | 30604073PubMed |

[158]  Spaya, a community-enriched algorithm for data-driven retrosynthetic planning developed by Iktos, spaya.ai, 2020.

[159]  S. Genheden, A. Thakkar, V. Chadimová, J.-L. Reymond, O. Engkvist, E. Bjerrum, J. Cheminform. 2020, 12, 70.
         | Crossref | GoogleScholarGoogle Scholar | 33292482PubMed |

[160]  E. J. Corey, M. Ohno, R. B. Mitra, P. A. Vatakencherry, J. Am. Chem. Soc. 1964, 86, 478.
         | Crossref | GoogleScholarGoogle Scholar |

[161]  W. L. Jorgensen, E. R. Laird, A. J. Gushurst, J. M. Fleischer, S. A. Gothe, H. E. Helson, G. D. Paderes, S. Sinclair, Pure Appl. Chem. 1990, 62, 1921.
         | Crossref | GoogleScholarGoogle Scholar |

[162]  J. M. Fleischer, A. J. Gushurst, W. L. Jorgensen, J. Org. Chem. 1995, 60, 490.
         | Crossref | GoogleScholarGoogle Scholar |

[163]  W. L. Jorgensen, J. Phys. Chem. B 2015, 119, 624.
         | Crossref | GoogleScholarGoogle Scholar | 25608799PubMed |

[164]  M. Kubat, An Introduction to Machine Learning, 2nd Edn 2017 (Springer International Publishing: Cham, Switzerland). 10.1007/978-3-319-63913-0

[165]  S. Lemonick, ‘CAS opens data vault to MIT scientists’, C&EN Chemical & Engineering News, 10 November 2020. Available at: https://cen.acs.org/physical-chemistry/computational-chemistry/CAS-opens-data-vault-MIT/98/web/2020/11. 10.47287/CEN-09844-SCICON1

[166]  A. Thakkar, T. Kogej, J.-L. L. Reymond, O. Engkvist, E. J. Bjerrum, Chem. Sci. 2020, 11, 154.
         | Crossref | GoogleScholarGoogle Scholar | 32110367PubMed |

[167]  E. J. Corey, S. Nozoe, J. Am. Chem. Soc. 1965, 87, 5728.
         | Crossref | GoogleScholarGoogle Scholar | 5891788PubMed |

[168]  For other examples of direct protection group interconversion, see: C. M. Williams, L. N. Mander, Tetrahedron Lett. 2004, 45, 667.
         | Crossref | GoogleScholarGoogle Scholar |

[169]  E. J. Corey, S. G. Pyne, W.-g. Su, Tetrahedron Lett. 1983, 24, 4883.
         | Crossref | GoogleScholarGoogle Scholar |

[170]  S. Hanessian, Organic Chemistry Series, Volume 3: Total Synthesis of Natural Products: The ‘Chiron’ Approach 1983 (Pergamon Press: New York, NY).

[171]  (a) M. H. S. Segler, M. Preuss, M. P. Waller, Nature 2018, 555, 604.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) J. N. Wei, D. Duvenaud, A. Aspuru-Guzik, ACS Cent. Sci. 2016, 2, 725.
         | Crossref | GoogleScholarGoogle Scholar |
         (c) Weir  H.Thompson  K.Choi  B.Woodward  A.Braun  A.Martínez  T. J.ChemRxiv 2021 . 10.26434/CHEMRXIV.14156957.V1

[172]  (a) C. W. Coley, L. Rogers, W. H. Green, K. F. Jensen, ACS Cent. Sci. 2017, 3, 1237.
         | Crossref | GoogleScholarGoogle Scholar | 29296663PubMed |
      (b) C. W. Coley, W. H. Green, K. F. Jensen, Acc. Chem. Res. 2018, 51, 1281.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) H. Gao, T. J. Struble, C. W. Coley, Y. Wang, W. H. Green, K. F. Jensen, ACS Cent. Sci. 2018, 4, 1465.
         | Crossref | GoogleScholarGoogle Scholar |
         (d) C. W. Coley, T. J. Struble, H. Gao, X. Wang, W. Lin, R. Barzilay, T. Jaakkola, W. H. Green, K. F. Jensen, in Abstracts of Papers, 258th ACS National Meeting & Exposition (American Chemical Society: San Diego, CA, USA) 2019, ORGN 274. Poster abstract. Available at: https://tpa.acs.org/abstract/acsnm258-3212520/machine-learning-for-organic-chemistry-reaction-prediction-and-retrosynthesis
      (e) M. E. Fortunato, C. W. Coley, B. C. Barnes, K. F. Jensen, J. Chem. Inf. Model. 2020, 60, 3398.
         | Crossref | GoogleScholarGoogle Scholar |

[173]  (a) K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed. 2005, 44, 1012.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) M. E. Maier, Nat. Prod. Rep. 2009, 26, 1105.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) Y. Usami, Mar. Drugs 2009, 7, 314.
         | Crossref | GoogleScholarGoogle Scholar |
      (d) T. L. Suyama, W. H. Gerwick, K. L. McPhail, Bioorg. Med. Chem. 2011, 19, 6675.
         | Crossref | GoogleScholarGoogle Scholar |
      (e) B. Khatri Chhetri, S. Lavoie, A. M. Sweeney-Jones, J. Kubanek, Nat. Prod. Rep. 2018, 35, 514.
         | Crossref | GoogleScholarGoogle Scholar |

[174]  (a) P. Wipf, Y. Uto, J. Org. Chem. 2000, 65, 1037.
         | Crossref | GoogleScholarGoogle Scholar | 10814052PubMed |
      (b) P. Wipf, Y. Uto, Tetrahedron Lett. 1999, 40, 5165.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) B. McKeever, G. Pattenden, Tetrahedron Lett. 2001, 42, 2573.
         | Crossref | GoogleScholarGoogle Scholar |
      (d) B. McKeever, G. Pattenden, Tetrahedron 2003, 59, 2713.
         | Crossref | GoogleScholarGoogle Scholar |

[175]  B. Verbraeken, J. Hullaert, J. van Guyse, K. Van Hecke, J. Winne, R. Hoogenboom, J. Am. Chem. Soc. 2018, 140, 17404.
         | Crossref | GoogleScholarGoogle Scholar | 30508478PubMed |

[176]  Rita, M. H. bin Abdul Rahman, S. S. M. Chong, R. W. Bates, Synlett 2020, 31, 1479.
         | Crossref | GoogleScholarGoogle Scholar |

[177]  L. A. Maslovskaya, A. I. Savchenko, E. H. Krenske, S. Chow, T. Holt, V. A. Gordon, P. W. Reddell, C. J. Pierce, P. G. Parsons, G. M. Boyle, A. G. Kutateladze, C. M. Williams, Chem. – Eur. J. 2020, 26, 11862.
         | Crossref | GoogleScholarGoogle Scholar | 32864777PubMed |

[178]  D. Zhang, D. Ruan, J. Li, Z. Chen, W. Zhu, F. Guo, K. Chen, Y. Li, R. Wang, Phytochemistry 2020, 174, 112337.
         | Crossref | GoogleScholarGoogle Scholar | 32163787PubMed |

[179]  A. I. Savchenko, C. M. Williams, Eur. J. Org. Chem. 2013, 7263.
         | Crossref | GoogleScholarGoogle Scholar |

[180]  (a) J. Y. W. Mak, R. H. Pouwer, C. M. Williams, Angew. Chem. Int. Ed. 2014, 53, 13664.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) E. H. Krenske, C. M. Williams, Angew. Chem. Int. Ed. 2015, 54, 10608.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) A. G. Kutateladze, E. H. Krenske, C. M. Williams, Angew. Chem. Int. Ed. 2019, 58, 7107.
         | Crossref | GoogleScholarGoogle Scholar |

[181]  M. Jaspars, Nat. Prod. Rep. 1999, 16, 241.
         | Crossref | GoogleScholarGoogle Scholar |

[182]  S. G. Smith, J. M. Goodman, J. Am. Chem. Soc. 2010, 132, 12946.
         | Crossref | GoogleScholarGoogle Scholar | 20795713PubMed |

[183]  (a) A. G. Kutateladze, D. M. Kuznetsov, A. A. Beloglazkina, T. Holt, J. Org. Chem. 2018, 83, 8341.
         | Crossref | GoogleScholarGoogle Scholar | 29912559PubMed |
      (b) For additional DU8+ structural revisions see: T. A. Holt, D. S. Reddy, D. B. Huple, L. M. West, A. D. Rodriguez, M. T. Crimmins, A. G. Kutateladze, J. Org. Chem. 2020, 85, 6201.and references therein.
         | Crossref | GoogleScholarGoogle Scholar |

[184]  (a) M. M. Zanardi, F. A. Biglione, M. A. Sortino, A. M. Sarotti, J. Org. Chem. 2018, 83, 11839.
         | Crossref | GoogleScholarGoogle Scholar | 30180574PubMed |
      (b) N. Grimblat, J. A. Gavín, A. H. Daranas, A. M. Sarotti, Org. Lett. 2019, 21, 4003.
         | Crossref | GoogleScholarGoogle Scholar |

[185]  M. O. Marcarino, M. M. Zanardi, A. M. Sarotti, Org. Lett. 2020, 22, 3561.
         | Crossref | GoogleScholarGoogle Scholar | 32286840PubMed |

[186]  (a) J. M. Humphrey, Y. Liao, A. Ali, T. Rein, Y.-L. Wong, H.-J. Chen, A. K. Courtney, S. F. Martin, J. Am. Chem. Soc. 2002, 124, 8584.and references therein.
         | Crossref | GoogleScholarGoogle Scholar | 12121099PubMed |
      (b) S. F. Martin, H.-J. Chen, A. K. Courtney, Y. Liao, M. Pätzel, M. N. Ramser, A. S. Wagman, Tetrahedron 1996, 52, 7251.
         | Crossref | GoogleScholarGoogle Scholar |

[187]  A. M. Dilmaç, E. Spuling, A. de Meijere, S. Bräse, Angew. Chem. Int. Ed. 2017, 56, 5684.
         | Crossref | GoogleScholarGoogle Scholar |

[188]  (a) M. A. Sierra, M. C. de la Torre, Angew. Chem. Int. Ed. 2000, 39, 1538.
         | Crossref | GoogleScholarGoogle Scholar |
         (b) M. A. Sierra, M. C. de la Torre, Dead Ends and Detours: Direct Ways to Successful Total Synthesis 2004 (Wiley-VCH: Weinheim).

[189]  (a) M. Wernerova, T. Hudlický, Synlett 2010, 2701.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) T. Hudlický, Chem. Rev. 1996, 96, 3.
         | Crossref | GoogleScholarGoogle Scholar |

[190]     (a) P. J. Kocieński, Protecting Groups, 3rd Edn 2005 (Georg Thieme Verlag: Stuttgart).
         (b) For another leading text in this regard see: Greene’s Protective Groups in Organic Synthesis, 5th Edn (Ed. P. G. M. Wuts) 2014 (John Wiley & Sons Inc.: Hoboken, NJ). 10.1002/9781118905074

[191]  B. Mikulak-Klucznik, P. Gołębiowska, A. A. Bayly, O. Popik, T. Klucznik, S. Szymkuć, E. P. Gajewska, P. Dittwald, O. Staszewska-Krajewska, W. Beker, T. Badowski, K. A. Scheidt, K. Molga, J. Mlynarski, M. Mrksich, B. A. Grzybowski, Nature 2020, 588, 83.
         | Crossref | GoogleScholarGoogle Scholar | 33049755PubMed |

[192]  (a) I. S. Young, P. S. Baran, Nat. Chem. 2009, 1, 193.
         | Crossref | GoogleScholarGoogle Scholar | 21378848PubMed |
      (b) For an example of a protecting group free synthesis of an advanced intermediate, see: R. Heim, S. Wiedemann, C. M. Williams, P. V. Bernhardt, Org. Lett. 2005, 7, 1327.
         | Crossref | GoogleScholarGoogle Scholar |

[193]  J. Mulzer, Nat. Prod. Rep. 2014, 31, 595.
         | Crossref | GoogleScholarGoogle Scholar | 24589568PubMed |

[194]  See for example: C. D. G. Read, P. W. Moore, C. M. Williams, Green Chem. 2015, 17, 4537.
         | Crossref | GoogleScholarGoogle Scholar |

[195]  C&EN Media Group, SYNTHIA™ Retrosynthesis Software for Practicing Chemists: A Look at Recent Applications in the Laboratory 15 Sep 2020. Available at: https://cen.acs.org/media/webinar/milliporesigma_091520.html (accessed 28 Sep 2020)

[196]  R. Chen, Y. Shen, S. Yang, Y. Zhang, Angew. Chem. Int. Ed. 2020, 59, 14198.
         | Crossref | GoogleScholarGoogle Scholar |

[197]  I. Fleming, D. Williams, Spectroscopic Methods in Organic Chemistry, 7th Edn 2019 (Springer: Cham, Switzerland). 10.1007/978-3-030-18252-6

[198]  P. J. Stevenson, Org. Biomol. Chem. 2011, 9, 2078.
         | Crossref | GoogleScholarGoogle Scholar | 21340082PubMed |

[199]  T. J. Vanden Berg, D. M. Pinkerton, C. M. Williams, Org. Biomol. Chem. 2017, 15, 7102.
         | Crossref | GoogleScholarGoogle Scholar | 28820535PubMed |

[200]  (a) K. M. Peese, D. Y. Gin, J. Am. Chem. Soc. 2006, 128, 8734.
         | Crossref | GoogleScholarGoogle Scholar | 16819859PubMed |
      (b) K. M. Peese, D. Y. Gin, Chem. – Eur. J. 2008, 14, 1654.
         | Crossref | GoogleScholarGoogle Scholar |
         (c) The Williams group has taken a second-order approach to this system.[98]

[201]  J. Li, M. D. Eastgate, Org. Biomol. Chem. 2015, 13, 7164.
         | Crossref | GoogleScholarGoogle Scholar | 25962620PubMed |

[202]  (a) T. J. Zerk, P. W. Moore, C. M. Williams, P. V. Bernhardt, Chem. Commun. 2016, 10301.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) T. J. Zerk, P. W. Moore, J. S. Harbort, S. Chow, L. Byrne, G. A. Koutsantonis, J. R. Harmer, M. Martínez, C. M. Williams, P. V. Bernhardt, Chem. Sci. 2017, 8, 8435.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) P. W. Moore, T. J. Zerk, J. M. Burns, P. V. Bernhardt, C. M. Williams, Eur. J. Org. Chem. 2019, 303.
         | Crossref | GoogleScholarGoogle Scholar |

[203]  (a) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc. Chem. Res. 1995, 28, 446.
         | Crossref | GoogleScholarGoogle Scholar |
      (b) O. M. Ogba, N. C. Warner, D. J. O’Leary, R. H. Grubbs, Chem. Soc. Rev. 2018, 47, 4510.
         | Crossref | GoogleScholarGoogle Scholar |

[204]  (a) B. Burger, P. M. Maffettone, V. V. Gusev, C. M. Aitchison, Y. Bai, X. Wang, X. Li, B. M. Alston, B. Li, R. Clowes, N. Rankin, B. Harris, R. S. Sprick, A. I. Cooper, Nature 2020, 583, 237.
         | Crossref | GoogleScholarGoogle Scholar | 32641813PubMed |
      (b) C. W. Coley, N. S. Eyke, K. F. Jensen, Angew. Chem. Int. Ed. 2020, 59, 22858.
         | Crossref | GoogleScholarGoogle Scholar |

[205]  A. Turing, Mind 1950, LIX, 433.
         | Crossref | GoogleScholarGoogle Scholar |

[206]  J. R. Searle, Behav. Brain Sci. 1980, 3, 417.
         | Crossref | GoogleScholarGoogle Scholar |

[207]  J. R. Searle, Proc. Addresses Am. Philos. Assoc. 1990, 64, 21.
         | Crossref | GoogleScholarGoogle Scholar |

[208]  C. M. Signorelli, Front. Robot. AI 2018, 5, 121.
         | Crossref | GoogleScholarGoogle Scholar | 33501000PubMed |

[209]  E. A. Feigenbaum, J. ACM 2003, 50, 32.
         | Crossref | GoogleScholarGoogle Scholar |

[210]  See for example: P. A. Wender, B. L. Miller, Nature 2009, 460, 197.
         | Crossref | GoogleScholarGoogle Scholar | 19587760PubMed |

[211]  J. W. Cornforth, Aust. J. Chem. 1993, 46, 157.
         | Crossref | GoogleScholarGoogle Scholar |

[212]  D. Seebach, Angew. Chem. Int. Ed. Engl. 1990, 29, 1320.
         | Crossref | GoogleScholarGoogle Scholar |

[213]  P. Judson, Knowledge-based Expert Systems in Chemistry: Not Counting on Computers 2009 (RSC: Cambridge). 10.1039/9781847559807

[214]  H. Else, ‘Need to make a molecule? Ask this AI for instructions’, Nature News, 28 March 2018. 10.1038/D41586-018-03977-W

[215]  A. R. Battersby, D. W. Young, Biogr. Mem. Fellows R. Soc. 2016, 62, 19.
         | Crossref | GoogleScholarGoogle Scholar |