Molecular complexity as a driving force for the advancement of organic synthesis

Rücker, C., Rücker, G. & Bertz, S. H. Organic synthesis — art or science? J. Chem. Inf. Comput. Sci. 44, 378–386 (2004).Article 
PubMed 

Google Scholar 
Whitesides, G. M. & Ismagilov, R. F. Complexity in chemistry. Science 284, 89–92 (1999).Article 
CAS 
PubMed 

Google Scholar 
Goldenfeld, N. & Kadanoff, L. P. Simple lessons from complexity. Science 284, 87–89 (1999).Article 
CAS 
PubMed 

Google Scholar 
Böttcher, T. From molecules to life: quantifying the complexity of chemical and biological systems in the universe. J. Mol. Evol. 86, 1–10 (2018).Article 
PubMed 

Google Scholar 
Parrish, J. K. & Edelstein-Keshet, L. Complexity, pattern, and evolutionary trade-offs in animal aggregation. Science 284, 99–101 (1999).Article 
CAS 
PubMed 

Google Scholar 
Weng, G., Bhalla, U. S. & Iyengar, R. Complexity in biological signaling systems. Science 284, 92–96 (1999).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Rind, D. Complexity and climate. Science 284, 105–107 (1999).Article 
CAS 
PubMed 

Google Scholar 
Marshall, S. M., Murray, A. R. G. & Cronin, L. A probabilistic framework for identifying biosignatures using pathway complexity. Philos. Trans. R. Soc. A Math. Phys. Eng. Sci. 375, 20160342 (2017).Article 

Google Scholar 
The Nobel Prize in Chemistry 1965. Nobel Media AB https://www.nobelprize.org/prizes/chemistry/1965/summary/ (2020).Corey, E. J. & Todd Wipke, W. Computer-assisted design of complex organic syntheses. Science 166, 178–192 (1969).Article 
CAS 
PubMed 

Google Scholar 
Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis (Wiley, 1996).Corey, E. J., Long, A. K. & Rubenstein, S. D. Computer-assisted analysis in organic synthesis. Science 228, 408–418 (1985).Article 
CAS 
PubMed 

Google Scholar 
Szymkuć, S. et al. Computer-assisted synthetic planning: the end of the beginning. Angew. Chem. Int. Ed. Engl. 55, 5904–5937 (2016).Article 
PubMed 

Google Scholar 
Li, J. & Eastgate, M. D. Current complexity: a tool for assessing the complexity of organic molecules. Org. Biomol. Chem. 13, 7164–7176 (2015).Article 
CAS 
PubMed 

Google Scholar 
Gao, W. & Coley, C. W. The synthesizability of molecules proposed by generative models. J. Chem. Inf. Model. https://doi.org/10.1021/acs.jcim.0c00174 (2020).Wender, P. A., Verma, V. A., Paxton, T. J. & Pillow, T. H. Function-oriented synthesis, step economy, and drug design. Acc. Chem. Res. 41, 40–49 (2008).Article 
CAS 
PubMed 

Google Scholar 
Willstätter, R. Synthesen in der tTropingruppe. I. Synthese des tropilidens. Justus Liebigs Ann. der Chem. 317, 204–265 (1901).Article 

Google Scholar 
Humphrey, A. J. & O’Hagan, D. Tropane alkaloid biosynthesis. A century old problem unresolved. Nat. Prod. Rep. 18, 494–502 (2001).Article 
CAS 
PubMed 

Google Scholar 
Medley, J. W. & Movassaghi, M. Robinson’s landmark synthesis of tropinone. Chem. Commun. 49, 10775–10777 (2013).Article 
CAS 

Google Scholar 
Robinson, R. LXIII. — a synthesis of tropinone. J. Chem. Soc. Trans. 111, 762–768 (1917).Article 
CAS 

Google Scholar 
Bélanger, A. et al. Total synthesis of ryanodol. Can. J. Chem. 57, 3348–3354 (1979).Article 

Google Scholar 
Nagatomo, M. et al. Total synthesis of ryanodol. J. Am. Chem. Soc. 136, 5916–5919 (2014).Article 
CAS 
PubMed 

Google Scholar 
Chuang, K. V., Xu, C. & Reisman, S. E. A 15-step synthesis of (+)-ryanodol. Science 353, 912–915 (2016).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Baran, P. S. Natural product total synthesis: as exciting as ever and here to stay. J. Am. Chem. Soc. 140, 4751–4755 (2018).Article 
CAS 
PubMed 

Google Scholar 
Holton, R. A. et al. First total synthesis of taxol. 1. Functionalization of the B ring. J. Am. Chem. Soc. 116, 1597–1598 (1994).Article 
CAS 

Google Scholar 
Holton, R. A. et al. First total synthesis of taxol. 2. Completion of the C and D rings. J. Am. Chem. Soc. 116, 1599–1600 (1994).Article 
CAS 

Google Scholar 
Nicolaou, K. C. et al. Total synthesis of taxol. Nature 367, 630–634 (1994).Article 
CAS 
PubMed 

Google Scholar 
Wender, P. A. et al. The pinene path to taxanes. 5. Stereocontrolled synthesis of a versatile taxane precursor. J. Am. Chem. Soc. 119, 2755–2756 (1997).Article 
CAS 

Google Scholar 
Wender, P. A. et al. The pinene path to taxanes. 6. A concise stereocontrolled synthesis of taxol. J. Am. Chem. Soc. 119, 2757–2758 (1997).Article 
CAS 

Google Scholar 
Masters, J. J., Link, J. T., Snyder, L. B., Young, W. B. & Danishefsky, S. J. A total synthesis of taxol. Angew. Chem. Int. Ed. Engl. 34, 1723–1726 (1995).Article 
CAS 

Google Scholar 
Mukaiyama, T. et al. Asymmetric total synthesis of taxol\R. Chem. A Eur. J. 5, 121–161 (1999).Article 
CAS 

Google Scholar 
Morihira, K. et al. Enantioselective total synthesis of taxol. J. Am. Chem. Soc. 120, 12980–12981 (1998).Article 
CAS 

Google Scholar 
Kanda, Y. et al. Two-phase synthesis of taxol. J. Am. Chem. Soc. 142, 10526–10533 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Nicolaou, K. C. et al. Total synthesis of calicheamicin γ1I. J. Am. Chem. Soc. 114, 10082–10084 (1992).Article 
CAS 

Google Scholar 
Groneberg, R. D. et al. Total synthesis of calicheamicin γ1I. 1. Synthesis of the oligosaccharide fragment. J. Am. Chem. Soc. 115, 7593–7611 (1993).Article 
CAS 

Google Scholar 
Smith, A. L. et al. Total synthesis of calicheamicin γ1I. 2. Development of an enantioselective route to (−)-calicheamicinone. J. Am. Chem. Soc. 115, 7612–7624 (1993).Article 
CAS 

Google Scholar 
Nicolaou, K. C. et al. Total synthesis of calicheamicin γ1I. 3. The final stages. J. Am. Chem. Soc. 115, 7625–7635 (1993).Article 
CAS 

Google Scholar 
Aicher, T. D. et al. Total synthesis of halichondrin B and norhalichondrin B. J. Am. Chem. Soc. 114, 3162–3164 (1992).Article 
CAS 

Google Scholar 
Jackson, K. L., Henderson, J. A., Motoyoshi, H. & Phillips, A. J. A total synthesis of norhalichondrin B. Angew. Chem. Int. Ed. Engl. 48, 2346–2350 (2009).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Armstrong, R. W. et al. Total synthesis of a fully protected palytoxin carboxylic acid. J. Am. Chem. Soc. 111, 7525–7530 (1989).Article 
CAS 

Google Scholar 
Armstrong, R. W. et al. Total synthesis of palytoxin carboxylic acid and palytoxin amide. J. Am. Chem. Soc. 111, 7530–7533 (1989).Article 
CAS 

Google Scholar 
Suh, E. M. & Kishi, Y. Synthesis of palytoxin from palytoxin carboxylic acid. J. Am. Chem. Soc. 116, 11205–11206 (1994).Article 
CAS 

Google Scholar 
Kuttruff, C. A., Eastgate, M. D. & Baran, P. S. Natural product synthesis in the age of scalability. Nat. Prod. Rep. 31, 419–432 (2014).Article 
CAS 
PubMed 

Google Scholar 
Pflüger, P. M. & Glorius, F. Molecular machine learning: the future of synthetic chemistry? Angew. Chem. Int. Ed. Engl. 59, 18860–18865 (2020).Article 
PubMed 

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

Google Scholar 
Liu, B. et al. Retrosynthetic reaction prediction using neural sequence-to-sequence models. ACS Cent. Sci. 3, 1103–1113 (2017).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Vamathevan, J. et al. Applications of machine learning in drug discovery and development. Nat. Rev. Drug Discov. 18, 463–477 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Reid, J. P. & Sigman, M. S. Holistic prediction of enantioselectivity in asymmetric catalysis. Nature 571, 343–348 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Reid, J. P. & Sigman, M. S. Comparing quantitative prediction methods for the discovery of small-molecule chiral catalysts. Nat. Rev. Chem. 2, 290–305 (2018).Article 
CAS 

Google Scholar 
Zhao, S. et al. Enantiodivergent Pd-catalyzed C–C bond formation enabled through ligand parameterization. Science 362, 670–674 (2018).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Nielsen, M. K., Ahneman, D. T., Riera, O. & Doyle, A. G. Deoxyfluorination with sulfonyl fluorides: navigating reaction space with machine learning. J. Am. Chem. Soc. 140, 5004–5008 (2018).Article 
CAS 
PubMed 

Google Scholar 
Ahneman, D. T., Estrada, J. G., Lin, S., Dreher, S. D. & Doyle, A. G. Predicting reaction performance in C–N cross-coupling using machine learning. Science 360, 186–190 (2018).Article 
CAS 
PubMed 

Google Scholar 
Sandfort, F., Strieth-Kalthoff, F., Kühnemund, M., Beecks, C. & Glorius, F. A structure-based platform for predicting chemical reactivity. Chem 6, 1379–1390 (2020).Article 
CAS 

Google Scholar 
Coley, C. W. et al. A graph-convolutional neural network model for the prediction of chemical reactivity. Chem. Sci. 10, 370–377 (2019).Article 
CAS 
PubMed 

Google Scholar 
Zahrt, A. F. et al. Prediction of higher-selectivity catalysts by computer-driven workflow and machine learning. Science 363, eaau5631 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Burai Patrascu, M. et al. From desktop to benchtop with automated computational workflows for computer-aided design in asymmetric catalysis. Nat. Catal. 3, 574–584 (2020).Article 
CAS 

Google Scholar 
Segler, M. H. S., Preuss, M. & Waller, M. P. Planning chemical syntheses with deep neural networks and symbolic AI. Nature 555, 604–610 (2018).Article 
CAS 
PubMed 

Google Scholar 
Schreck, J. S., Coley, C. W. & Bishop, K. J. M. Learning retrosynthetic planning through simulated experience. ACS Cent. Sci. 5, 970–981 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Coley, C. W. et al. A robotic platform for flow synthesis of organic compounds informed by AI planning. Science 365, eaax1566 (2019).Article 
CAS 
PubMed 

Google Scholar 
Trinajstić, N. Chemical Graph Theory (CRC, 1992).Gerry, C. J. et al. Real-time biological annotation of synthetic compounds. J. Am. Chem. Soc. 138, 8920–8927 (2016).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Singh, M., Gaskins, B., Johnson, D. R., Elles, C. G. & Boskovic, Z. Synthesis of cycloheptatriene-containing azetidine lactones. J. Org. Chem. 87, 15001–15010 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Shannon, C. E. A mathematical theory of communication. Bell Syst. Tech. J. 27, 379–423 (1948).Article 

Google Scholar 
Bonchev, D. & Trinajstić, N. Chemical information theory: structural aspects. Int. J. Quantum Chem. 22, 463–480 (1982).Article 

Google Scholar 
Cherkasov, A. et al. QSAR modeling: where have you been? Where are you going to? J. Med. Chem. 57, 4977–5010 (2014).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Böttcher, T. An additive definition of molecular complexity. J. Chem. Inf. Model. 56, 462–470 (2016).Article 
PubMed 

Google Scholar 
Smith, S. W. Chiral toxicology: it’s the same thing…only different. Toxicol. Sci. 110, 4–30 (2009).Article 
CAS 
PubMed 

Google Scholar 
Bertz, S. H. The first general index of molecular complexity. J. Am. Chem. Soc. 103, 3599–3601 (1981).Article 
CAS 

Google Scholar 
Hendrickson, J. B., Huang, P. & Toczko, A. G. Molecular complexity: a simplified formula adapted to individual atoms. J. Chem. Inf. Comput. Sci. 27, 63–67 (1987).Article 
CAS 

Google Scholar 
Rücker, G. & Rücker, C. On finding nonisomorphic connected subgraphs and distinct molecular substructures. J. Chem. Inf. Comput. Sci. 41, 314–320 (2001).Article 
PubMed 

Google Scholar 
Bertz, S. H. & Sommer, T. J. Rigorous mathematical approaches to strategic bonds and synthetic analysis based on conceptually simple new complexity indices. Chem. Commun. 16, 2409–2410 (1997).Article 

Google Scholar 
Ruecker, G. & Ruecker, C. Counts of all walks as atomic and molecular descriptors. J. Chem. Inf. Comput. Sci. 33, 683–695 (1993).Article 
CAS 

Google Scholar 
Randić, M. On characterization of molecular branching. J. Am. Chem. Soc. 97, 6609–6615 (1975).Article 

Google Scholar 
Randić, M., Brissey, G. M., Spencer, R. B. & Wilkins, C. L. Search for all self-avoiding paths for molecular graphs. Comput. Chem. 3, 5–13 (1979).Article 

Google Scholar 
Randić, M. & Plavšić, D. Characterization of molecular complexity. Int. J. Quantum Chem. 91, 20–31 (2002).Article 

Google Scholar 
Whitlock, H. W. On the structure of total synthesis of complex natural products. J. Org. Chem. 63, 7982–7989 (1998).Article 
CAS 

Google Scholar 
Barone, R. & Chanon, M. A new and simple approach to chemical complexity. Application to the synthesis of natural products. J. Chem. Inf. Comput. Sci. 41, 269–272 (2001).Article 
CAS 
PubMed 

Google Scholar 
Bonchev, D. The overall wiener index — a new tool for characterization of molecular topology. J. Chem. Inf. Comput. Sci. 41, 582–592 (2001).Article 
CAS 
PubMed 

Google Scholar 
Bonchev, D., Mekenyan, O. & Trinajstić, N. Topological characterization of cyclic structures. Int. J. Quantum Chem. 17, 845–893 (1980).Article 
CAS 

Google Scholar 
Proudfoot, J. R. A path based approach to assessing molecular complexity. Bioorg. Med. Chem. Lett. 27, 2014–2017 (2017).Article 
CAS 
PubMed 

Google Scholar 
Proudfoot, J. R. Molecular complexity and retrosynthesis. J. Org. Chem. 82, 6968–6971 (2017).Article 
CAS 
PubMed 

Google Scholar 
Bender, A. & Glen, R. C. Molecular similarity: a key technique in molecular informatics. Org. Biomol. Chem. 2, 3204–3218 (2004).Article 
CAS 
PubMed 

Google Scholar 
Bonchev, D. & Peev, T. Information theoretic study of chemical elements. Mean information content of a chemical element. Jahresber. Hochsch. Chem. Tech. Burgas. 10, 561 (1973).CAS 

Google Scholar 
Demoret, R. M. et al. Synthetic, mechanistic, and biological interrogation of ginkgo biloba chemical space en route to (−)-bilobalide. J. Am. Chem. Soc. 142, 18599–18618 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Herzon, S. B. Emergent properties of natural products. Synlett 29, 1823–1835 (2018).Article 
CAS 

Google Scholar 
Huffman, B. J. & Shenvi, R. A. Natural products in the ‘marketplace’: interfacing synthesis and biology. J. Am. Chem. Soc. 141, 3332–3346 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75, 311–335 (2012).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Krzyzanowski, A., Pahl, A., Grigalunas, M. & Waldmann, H. Spacial score — a comprehensive topological indicator for small-molecule complexity. J. Med. Chem. 66, 12739–12750 (2023).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Méndez-Lucio, O. & Medina-Franco, J. L. The many roles of molecular complexity in drug discovery. Drug Discov. Today 22, 120–126 (2017).Article 
PubMed 

Google Scholar 
Baker, M. A., Demoret, R. M., Ohtawa, M. & Shenvi, R. A. Concise asymmetric synthesis of (−)-bilobalide. Nature 575, 643–646 (2019).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Del Bel, M., Abela, A. R., Ng, J. D. & Guerrero, C. A. Enantioselective chemical syntheses of the furanosteroids (−)-viridin and (−)-viridiol. J. Am. Chem. Soc. 139, 6819–6822 (2017).Article 
PubMed 

Google Scholar 
Johnson, J. S. Counting steps. Nat. Synth. 2, 6–8 (2023).Article 
PubMed 
PubMed Central 

Google Scholar 
Ertl, P. & Schuffenhauer, A. Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions. J. Cheminform. 1, 8 (2009).Article 
PubMed 
PubMed Central 

Google Scholar 
Coley, C. W., Rogers, L., Green, W. H. & Jensen, K. F. SCScore: synthetic complexity learned from a reaction corpus. J. Chem. Inf. Model. 58, 252–261 (2018).Article 
CAS 
PubMed 

Google Scholar 
Klucznik, T. et al. Efficient syntheses of diverse, medicinally relevant targets planned by computer and executed in the laboratory. Chem 4, 522–532 (2018).Article 
CAS 

Google Scholar 
Gaich, T. & Baran, P. S. Aiming for the ideal synthesis. J. Org. Chem. 75, 4657–4673 (2010).Article 
CAS 
PubMed 

Google Scholar 
Bonnet, P. Is chemical synthetic accessibility computationally predictable for drug and lead-like molecules? A comparative assessment between medicinal and computational chemists. Eur. J. Med. Chem. 54, 679–689 (2012).Article 
CAS 
PubMed 

Google Scholar 
Sheridan, R. P. et al. Modeling a crowdsourced definition of molecular complexity. J. Chem. Inf. Model. 54, 1604–1616 (2014).Article 
CAS 
PubMed 

Google Scholar 
Corey, E. J., Iii, R. D. C. & Howe, W. J. Computer-assisted synthetic analysis for complex molecules. Methods and procedures for machine generation of synthetic intermediates. J. Am. Chem. Soc. 94, 440–459 (1972).Article 
CAS 

Google Scholar 
Corey, E. J. & Frank Feiner, N. Computer-assisted synthetic analysis. A rapid computer method for the semiquantitative assignment of conformation of six-membered ring systems. 1. Derivation of a preliminary conformational description of the six-membered ring. J. Org. Chem. 45, 757–764 (1980).Article 
CAS 

Google Scholar 
Corey, E. J., Long, A. K., Greene, T. W. & Miller, J. W. Computer-assisted synthetic analysis. Selection of protective groups for multistep organic syntheses. J. Org. Chem. 50, 1920–1927 (1985).Article 

Google Scholar 
Corey, E. J., Wipke, W. T., Iii, R. D. C. & Howe, W. J. Techniques for perception by a computer of synthetically significant structural features in complex molecules. J. Am. Chem. Soc. 94, 431–439 (1972).Article 
CAS 

Google Scholar 
Corey, E. J., Johnson, A. P. & Long, A. K. Computer-assisted synthetic analysis. Techniques for efficient long-range retrosynthetic searches applied to the Robinson annulation process. J. Org. Chem. 45, 2051–2057 (1980).Article 
CAS 

Google Scholar 
Corey, E. J., Howe, W. J. & Pensak, D. A. Computer-assisted synthetic analysis. Methods for machine generation of synthetic intermediates involving multistep look-ahead. J. Am. Chem. Soc. 96, 7724–7737 (1974).Article 
CAS 

Google Scholar 
Corey, E. J. & Frank Feiner, N. Computer-assisted synthetic analysis. A rapid computer method for the semiquantitative assignment of conformation of six-membered ring systems. 2. Assessment of conformational energies. J. Org. Chem. 45, 765–780 (1980).Article 
CAS 

Google Scholar 
Corey, E. J. & Jorgensen, W. L. Computer-assisted synthetic analysis. Generation of synthetic sequences involving sequential functional group interchanges. J. Am. Chem. Soc. 98, 203–209 (1976).Article 
CAS 

Google Scholar 
Corey, E. J. et al. Computer-assisted synthetic analysis. long-range search procedures for antithetic simplification of complex targets by application of the halolactonization transform. J. Chem. Inf. Comput. Sci. 20, 221–230 (1980).Article 
CAS 

Google Scholar 
Corey, E. J., Orf, H. W. & Pensak, D. A. Computer-assisted synthetic analysis. The identification and protection of interfering functionality in machine-generated synthetic intermediates. J. Am. Chem. Soc. 98, 210–221 (1976).Article 
CAS 

Google Scholar 
Corey, E. J., Long, A. K., Lotto, G. I. & Rubenstein, S. D. Computer‐assisted synthetic analysis. Quantitative assessment of transform utilities. Recl. Trav. Chim. Pays‐Bas 111, 304–309 (1992).Article 
CAS 

Google Scholar 
Bertz, S. H. & Rücker, C. In search of simplification: the use of topological complexity indices to guide retrosynthetic analysis. Croat. Chem. Acta 77, 221–235 (2004).CAS 

Google Scholar 
Rücker, G. & Rücker, C. Substructure, subgraph, and walk counts as measures of the complexity of graphs and molecules. J. Chem. Inf. Comput. Sci. 41, 1457–1462 (2001).Article 
PubMed 

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

Google Scholar 
Marth, C. J. et al. Network-analysis-guided synthesis of weisaconitine D and liljestrandinine. Nature 528, 493–498 (2015).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Kou, K. G. M. et al. A unifying synthesis approach to the C18-, C19-, and C20-diterpenoid alkaloids. J. Am. Chem. Soc. 139, 13882–13896 (2017).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Yudin, A. K. Macrocycles: lessons from the distant past, recent developments, and future directions. Chem. Sci. 6, 30–49 (2015).Article 
CAS 
PubMed 

Google Scholar 
Martí-Centelles, V., Pandey, M. D., Burguete, M. I. & Luis, S. V. Macrocyclization reactions: the importance of conformational, configurational, and template-induced preorganization. Chem. Rev. 115, 8736–8834 (2015).Article 
PubMed 

Google Scholar 
Mortensen, K. T., Osberger, T. J., King, T. A., Sore, H. F. & Spring, D. R. Strategies for the diversity-oriented synthesis of macrocycles. Chem. Rev. 119, 10288–10317 (2019).Article 
CAS 
PubMed 

Google Scholar 
Saridakis, I., Kaiser, D. & Maulide, N. Unconventional macrocyclizations in natural product synthesis. ACS Cent. Sci. 6, 1869–1889 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Fürstner, A. Lessons from natural product total synthesis: macrocyclization and postcyclization strategies. Acc. Chem. Res. 54, 861–874 (2021).Article 
PubMed 
PubMed Central 

Google Scholar 
Hendrickson, J. B. Organic synthesis in the age of computers. Angew. Chem. Int. Ed. Engl. 29, 1286–1295 (1990).Article 

Google Scholar 
Bøgevig, A. et al. Route design in the 21st century: the IC SYNTH software tool as an idea generator for synthesis prediction. Org. Process Res. Dev. 19, 357–368 (2015).Article 

Google Scholar 
Schwaller, P. et al. Predicting retrosynthetic pathways using transformer-based models and a hyper-graph exploration strategy. Chem. Sci. 11, 3316–3325 (2020).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Genheden, S. et al. AiZynthFinder: a fast robust and flexible open-source software for retrosynthetic planning. J. Cheminform. 12, 70 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Gasteiger, J., Ihlenfeldt, W. D. & Röse, P. A collection of computer methods for synthesis design and reaction prediction. Recl. Trav. Chim. Pays-Bas 111, 270–290 (1992).Article 
CAS 

Google Scholar 
Somnath, V. R., Bunne, C., Coley, C. W., Krause, A. & Barzilay, R. Learning graph models for template-free retrosynthesis. Preprint at https://doi.org/10.48550/arXiv.2006.07038 (2020).Mo, Y. et al. Evaluating and clustering retrosynthesis pathways with learned strategy. Chem. Sci. 12, 1469–1478 (2021).Article 
CAS 

Google Scholar 
Gasteiger, J., Ihlenfeldt, W. D., Fick, R. & Rose, J. R. Similarity concepts for the planning of organic reactions and syntheses. J. Chem. Inf. Comput. Sci. 32, 700–712 (1992).Article 
CAS 

Google Scholar 
Willett, P. Similarity-based virtual screening using 2D fingerprints. Drug Discov. Today 11, 1046–1053 (2006).Article 
CAS 
PubMed 

Google Scholar 
Tanimoto, T. T. IBM Internal Report (IBM, 1957).Bottou, L., Curtis, F. E. & Nocedal, J. Optimization methods for large-scale machine learning. SIAM Rev. 60, 223–311 (2018).Article 

Google Scholar 
Reymond, J.-L. The chemical space project. Acc. Chem. Res. 48, 722–730 (2015).Article 
CAS 
PubMed 

Google Scholar 
Bohacek, R. S., McMartin, C. & Guida, W. C. The art and practice of structure‐based drug design: a molecular modeling perspective. Med. Res. Rev. 16, 3–50 (1996).Article 
CAS 
PubMed 

Google Scholar 
Lin, Y., Zhang, R., Wang, D. & Cernak, T. Computer-aided key step generation in alkaloid total synthesis. Science 379, 453–457 (2023).Article 
CAS 
PubMed 

Google Scholar 
Burns, N. Z., Baran, P. S. & Hoffmann, R. W. Redox economy in organic synthesis. Angew. Chem. Int. Ed. Engl. 48, 2854–2867 (2009).Article 
CAS 
PubMed 

Google Scholar 
Trost, B. The atom economy — a search for synthetic efficiency. Science 254, 1471–1477 (1991).Article 
CAS 
PubMed 

Google Scholar 
Newhouse, T., Baran, P. S. & Hoffmann, R. W. The economies of synthesis. Chem. Soc. Rev. 38, 3010–3021 (2009).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Barone, R., Petitjean, M., Baralotto, C., Piras, P. & Chanon, M. Information theory description of synthetic strategies. A new similarity index. J. Phys. Org. Chem. 16, 9–15 (2003).Article 
CAS 

Google Scholar 
Johnson, W. S., Semmelhack, M. F., Sultanbawa, M. U. S. & Dolak, L. A. A new approach to steroid total synthesis. A nonenzymic biogenetic-like olefinic cyclization involving the stereospecific formation of five asymmetric centers. J. Am. Chem. Soc. 90, 2994–2996 (1968).Article 
CAS 

Google Scholar 
Yoder, R. A. & Johnston, J. N. A case study in biomimetic total synthesis: polyolefin carbocyclizations to terpenes and steroids. Chem. Rev. 105, 4730–4756 (2005).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Johnson, W. S. Nonenzymic biogenetic-like olefinic cyclizations. Acc. Chem. Res. 1, 1–8 (1968).Article 

Google Scholar 
Abe, I., Rohmer, M. & Prestwich, G. D. Enzymatic cyclization of squalene and oxidosqualene to sterols and triterpenes. Chem. Rev. 93, 2189–2206 (1993).Article 
CAS 

Google Scholar 
George, D. T., Kuenstner, E. J. & Pronin, S. V. A concise approach to paxilline indole diterpenes. J. Am. Chem. Soc. 137, 15410–15413 (2015).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Sun, Y. et al. Bioinspired total synthesis of sespenine. Angew. Chem. Int. Ed. Engl. 53, 9012–9016 (2014).Article 
CAS 
PubMed 

Google Scholar 
Brill, Z. G., Grover, H. K. & Maimone, T. J. Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade. Science 352, 1078–1082 (2016).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Hung, K., Hu, X. & Maimone, T. J. Total synthesis of complex terpenoids employing radical cascade processes. Nat. Prod. Rep. 35, 174–202 (2018).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Nicolaou, K. C., Petasis, N. A., Zipkin, R. E. & Uenishi, J. The endiandric acid cascade. Electrocyclizations in organic synthesis. I. Stepwise, stereocontrolled total synthesis of endiandric acids A and B. J. Am. Chem. Soc. 104, 5555–5557 (1982).Article 
CAS 

Google Scholar 
Nicolaou, K. C., Petasis, N. A., Uenishi, J. & Zipkin, R. E. The endiandric acid cascade. Electrocyclizations in organic synthesis. 2. Stepwise, stereocontrolled total synthesis of endiandric acids C-G. J. Am. Chem. Soc. 104, 5557–5558 (1982).Article 
CAS 

Google Scholar 
Nicolaou, K. C., Zipkin, R. E. & Petasis, N. A. The endiandric acid cascade. Electrocyclizations in organic synthesis. 3. ‘Biomimetic’ approach to endiandric acids A-G. Synthesis of precursors. J. Am. Chem. Soc. 104, 5558–5560 (1982).Article 
CAS 

Google Scholar 
Nicolaou, K. C., Petasis, N. A. & Zipkin, R. E. The endiandric acid cascade. Electrocyclizations in organic synthesis. 4. “Biomimetic” approach to endiandric acids A-G. Total synthesis and thermal studies. J. Am. Chem. Soc. 104, 5560–5562 (1982).Article 
CAS 

Google Scholar 
Piettre, S. & Heathcock, C. H. Biomimetic total synthesis of proto-daphniphylline. Science 248, 1532–1534 (1990).Article 
CAS 
PubMed 

Google Scholar 
Heathcock, C. H. Nature knows best: an amazing reaction cascade is uncovered by design and discovery. Proc. Natl Acad. Sci. USA 93, 14323–14327 (1996).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Chattopadhyay, A. K. & Hanessian, S. Recent progress in the chemistry of daphniphyllum alkaloids. Chem. Rev. 117, 4104–4146 (2017).Article 
CAS 
PubMed 

Google Scholar 
Evans, D. A. & Starr, J. T. A cascade cycloaddition strategy leading to the total synthesis of (−)-FR182877. Angew. Chem. Int. Ed. Engl. 41, 1787–1790 (2002).Article 
CAS 
PubMed 

Google Scholar 
Vosburg, D. A., Vanderwal, C. D. & Sorensen, E. J. A synthesis of (+)-FR182877, featuring tandem transannular Diels–Alder reactions inspired by a postulated biogenesis. J. Am. Chem. Soc. 124, 4552–4553 (2002).Article 
CAS 
PubMed 

Google Scholar 
Sierra, M. A. & de la Torre, M. C. Dead ends and detours en route to total syntheses of the 1990s. Angew. Chem. Int. Ed. Engl. 39, 1538–1559 (2000).Article 
CAS 
PubMed 

Google Scholar 
Crimmins, M. T. et al. The total synthesis of (±)-ginkgolide B. J. Am. Chem. Soc. 122, 8453–8463 (2000).Article 
CAS 

Google Scholar 
Schneider, F., Samarin, K., Zanella, S. & Gaich, T. Total synthesis of the complex taxane diterpene canataxpropellane. Science 367, 676–681 (2020).Article 
CAS 
PubMed 

Google Scholar 
McKerrall, S. J., Jørgensen, L., Kuttruff, C. A., Ungeheuer, F. & Baran, P. S. Development of a concise synthesis of (+)-ingenol. J. Am. Chem. Soc. 136, 5799–5810 (2014).Article 
CAS 
PubMed 

Google Scholar 
Jørgensen, L. et al. 14-step synthesis of (+)-ingenol from (+)-3-carene. Science 341, 878–882 (2013).Article 
PubMed 

Google Scholar 
Kawamura, S., Chu, H., Felding, J. & Baran, P. S. Nineteen-step total synthesis of (+)-phorbol. Nature 532, 90–93 (2016).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Mendoza, A., Ishihara, Y. & Baran, P. S. Scalable enantioselective total synthesis of taxanes. Nat. Chem. 4, 21–25 (2012).Article 
CAS 

Google Scholar 
Wilde, N. C., Isomura, M., Mendoza, A. & Baran, P. S. Two-phase synthesis of (−)-taxuyunnanine D. J. Am. Chem. Soc. 136, 4909–4912 (2014).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Yuan, C., Jin, Y., Wilde, N. C. & Baran, P. S. Short, enantioselective total synthesis of highly oxidized taxanes. Angew. Chem. Int. Ed. Engl. 55, 8280–8284 (2016).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Brill, Z. G., Condakes, M. L., Ting, C. P. & Maimone, T. J. Navigating the chiral pool in the total synthesis of complex terpene natural products. Chem. Rev. 117, 11753–11795 (2017).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Condakes, M. L., Hung, K., Harwood, S. J. & Maimone, T. J. Total syntheses of (−)-majucin and (−)-jiadifenoxolane A, complex majucin-type illicium sesquiterpenes. J. Am. Chem. Soc. 139, 17783–17786 (2017).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Hung, K. et al. Development of a terpene feedstock-based oxidative synthetic approach to the illicium sesquiterpenes. J. Am. Chem. Soc. 141, 3083–3099 (2019).Article 
CAS 
PubMed 
PubMed Central 

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

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

Google Scholar 
Wender, P. A. Toward the ideal synthesis and molecular function through synthesis-informed design. Nat. Prod. Rep. 31, 433–440 (2014).Article 
CAS 
PubMed 

Google Scholar 
Mikulak-Klucznik, B. et al. Computational planning of the synthesis of complex natural products. Nature 588, 83–88 (2020).Article 
CAS 
PubMed 

Google Scholar 
Hoffmann, R. W. Elements of Synthesis Planning (Springer, 2009).Cherney, E. C., Green, J. C. & Baran, P. S. Synthesis of ent-kaurane and beyerane diterpenoids by controlled fragmentations of overbred intermediates. Angew. Chem. Int. Ed. Engl. 52, 9019–9022 (2013).Article 
CAS 
PubMed 

Google Scholar 
Sarpong, R., Wang, B. & Perea, M. A. Transition metal-mediated C–C single bond cleavage: making the cut in total synthesis. Angew. Chem. Int. Ed. Engl. 59, 18898–18919 (2020).Article 
PubMed 
PubMed Central 

Google Scholar 
Wender, P. A. & Howbert, J. J. Synthetic studies on arene-olefin cycloadditions: total synthesis of (±)-α-cedrene. J. Am. Chem. Soc. 103, 688–690 (1981).Article 
CAS 

Google Scholar 
Oppolzer, W. & Godel, T. A new and efficient total synthesis of (±)-longifolene. J. Am. Chem. Soc. 100, 2583–2584 (1978).Article 
CAS 

Google Scholar 
Hafeman, N. J. et al. The total synthesis of (−)-scabrolide A. J. Am. Chem. Soc. 142, 8585–8590 (2020).Article 
CAS 
PubMed 

Google Scholar 
Foy, N. J. & Pronin, S. V. Synthesis of pleuromutilin. J. Am. Chem. Soc. 144, 10174–10179 (2022).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Chuang, K. V., Gunsalus, L. M. & Keiser, M. J. Learning molecular representations for medicinal chemistry. J. Med. Chem. https://doi.org/10.1021/acs.jmedchem.0c00385 (2020).Bemis, G. W. & Murcko, M. A. The properties of known drugs. 1. Molecular frameworks. J. Med. Chem. 39, 2887–2893 (1996).Article 
CAS 
PubMed 

Google Scholar 
Weininger, D. SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules. J. Chem. Inf. Comput. Sci. 28, 31–36 (1988).Article 
CAS 

Google Scholar 
Selzer, P., Roth, H. J., Ertl, P. & Schuffenhauer, A. Complex molecules: do they add value? Curr. Opin. Chem. Biol. 9, 310–316 (2005).Article 
CAS 
PubMed 

Google Scholar 
Hann, M. M., Leach, A. R. & Harper, G. Molecular complexity and its impact on the probability of finding leads for drug discovery. J. Chem. Inf. Comput. Sci. 41, 856–864 (2001).Article 
CAS 
PubMed 

Google Scholar 
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 
Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3–25 (1997).Article 
CAS 

Google Scholar 
Lovering, F. Escape from flatland 2: complexity and promiscuity. MedChemComm 4, 515–519 (2013).Article 
CAS 

Google Scholar 
Galloway, W. R. J. D., Isidro-Llobet, A. & Spring, D. R. Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat. Commun. 1, 80 (2010).Article 
PubMed 

Google Scholar 
Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964–1969 (2000).Article 
CAS 
PubMed 

Google Scholar 
Clemons, P. A. et al. Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles. Proc. Natl Acad. Sci. USA 107, 18787–18792 (2010).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 
Beckmann, H. S. G. et al. A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling. Nat. Chem. 5, 861–867 (2013).Article 
CAS 
PubMed 

Google Scholar 
Kato, N. et al. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature 538, 344–349 (2016).Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Hot Topics

Related Articles