Iterative syntheses comprise sequences of organic reactions in which the substrate molecules grow with each iteration and the functional groups, which enable the growth step, are regenerated to allow sustained cycling. Typically, iterative sequences can be automated, for example, as in the transformative examples of the robotized syntheses of peptides, oligonucleotides, polysaccharides and even some natural products. However, iterations are not easy to identify—in particular, for sequences with cycles more complex than protection and deprotection steps. Indeed, the number of catalogued examples is in the tens to maybe a hundred. Here, a computer algorithm using a comprehensive knowledge base of individual reactions constructs and evaluates myriads of putative, but chemically plausible, sequences and discovers an unprecedented number of iterative sequences. Some of these iterations are validated by experiment and result in the synthesis of motifs commonly found in natural products. This computer-driven discovery expands the pool of iterative sequences that may be automated in the future.
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All data in support of the findings of this study are available within the Article and its Supplementary Information.
All iterative sequences described in this work are available for use by academic users at https://iterator.allchemy.net/. Please see Supplementary Section 12 for the user manual and login details. The pseudocode of the algorithm to identify iterative sequences is included in Supplementary Section 14. This algorithm is adaptable to any set of reactions coded as described in detail in ref. 20. Reaction rules used here were proprietary collections from Chematica/Synthia (property of Merck KGaA) or Allchemy (Allchemy, Inc.).
Staunton, J. & Weissman, K. J. Polyketide biosynthesis: a millennium review. Nat. Prod. Rep.18, 380–416 (2001).
Trobe, M. & Burke, M. D. The molecular industrial revolution: automated synthesis of small molecules. Angew. Chem. Int. Ed.57, 4192–4214 (2018).
Lehmann, J. W., Blair, D. J. & Burke, M. D. Towards the generalized iterative synthesis of small molecules. Nat. Rev. Chem.2, 0115 (2018).
Lee, S. J., Gray, K. C., Paek, J. S. & Burke, M. D. Simple, efficient, and modular syntheses of polyene natural products via iterative cross-coupling. J. Am. Chem. Soc.130, 466–468 (2008).
Merrified, R. B. Automated synthesis of peptides. Science150, 178–185 (1965).
Caruthers, M. H. Gene synthesis machines: DNA chemistry and its uses. Science230, 281–285 (1985).
Plante, O. J., Palmacci, E. R. & Seeberger, P. H. Automated solid-phase synthesis of oligosaccharides. Science291, 1523–1527 (2001).
Seeberger, P. H. & Haase, W. C. Solid-phase oligosaccharide synthesis and combinatorial carbohydrate libraries. Chem. Rev.100, 4349–4394 (2000).
Li, J. Q. et al. Synthesis of many different types of organic small molecules using one automated process. Science347, 1221–1226 (2015).
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).
Zhang, Z., Huang, J., Ma, B. & Kishi, Y. Further improvement on sulfonamide-based ligand for catalytic asymmetric 2-haloallylation and allylation. Org. Lett.10, 3073–3076 (2008).
Zhang, Z., Aubry, S. & Kishi, Y. Iterative Cr-mediated catalytic asymmetric allylation to synthesize syn/syn- and anti/anti-1,3,5-triols. Org. Lett.10, 3077–3080 (2008).
Des Mazery, R. et al. An iterative catalytic route to enantiopure deoxypropionate subunits: asymmetric conjugate addition of Grignard reagents to α,β-unsaturated thioesters. J. Am. Chem. Soc.127, 9966–9967 (2005).
Zhang, K., Cai, L., Jiang, X., Garcia-Garibay, M. A. & Kwon, O. Phosphine-mediated iterative arene homologation using allenes. J. Am. Chem. Soc.137, 11258–11261 (2015).
Szymkuć, S. et al. Computer-assisted synthetic planning: the end of the beginning. Angew. Chem. Int. Ed.55, 5904–5937 (2016).
Klucznik, T. et al. Efficient syntheses of diverse, medicinally relevant targets planned by computer and executed in the laboratory. Chem4, 522–532 (2018).
Gajewska, E. P. et al. Algorithmic discovery of tactical combinations for advanced organic syntheses. Chem6, 280–293 (2020).
Mikulak-Klucznik, B. et al. Computational planning of the synthesis of complex natural products. Nature588, 83–88 (2020).
Wołos, A. et al. Synthetic connectivity, emergence, and self-regeneration in the network of prebiotic chemistry. Science369, eaaw1955 (2020).
Molga, K., Gajewska, E. P., Szymkuć, S. & Grzybowski, B. A. The logic of translating chemical knowledge into machine-processable forms: a modern playground for physical-organic chemistry. React. Chem. Eng.4, 1506–1521 (2019).
Lin, Y. et al. Reinforcing the supply chain of COVID-19 therapeutics with expert-coded retrosynthetic software. Preprint at https://doi.org/10.26434/chemrxiv.12765410.v1 (2020).
Fialkowski, M. et al. Architecture and evolution of organic chemistry. Angew. Chem. Int. Ed.44, 7263–7269 (2005).
Gothard, C. M. et al. Rewiring chemistry: algorithmic discovery and experimental validation of one-pot reactions in the network of organic chemistry. Angew. Chem. Int. Ed.51, 7922–7927 (2012).
Qu, S. et al. Self-assembly of highly luminescent bi-1,3,4-oxadiazole derivatives through electron donor–acceptor interactions in three-dimensional crystals, two-dimensional layers and mesophases. J. Mater. Chem.18, 3954–3964 (2008).
Nakamura, K., Yasuda, N. & Maeda, H. Dimension-controlled assemblies of modified bipyrroles stabilized by electron-withdrawing moieties. Chem. Commun.52, 7157–7160 (2016).
Magnus, P., Danikiewicz, W., Katoh, T., Huffman, J. C. & Folting, K. Synthesis of helical poly-β-pyrroles. Multiple atropisomerism resulting in helical enantiomorphic conformations. J. Am. Chem. Soc.112, 2465–2468 (1990).
Gu, P.-Y., Wang, Z. & Zhang, Q. Azaacenes as active elements for sensing and bio applications. J. Mater. Chem. B4, 7060–7074 (2016).
Zhao, H. et al. Isoxazole carboxylic acids as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Bioorg. Med. Chem. Lett.14, 5543–5546 (2004).
Tiwari, D. K., Pogula, J. & Tiwari, D. K. A general and practical route to 4,5-disubstituted oxazoles using acid chlorides and isocyanides. RSC Adv.5, 53111–53116 (2015).
Augustine, J. K., Vairaperumal, V., Narasimhan, S., Alagarsamy, P. & Radhakrishnan, A. Propylphosphonic anhydride (T3P®): an efficient reagent for the one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles. Tetrahedron65, 9989–9996 (2009).
Li, B.-L. et al. One-pot four-component synthesis of highly substituted pyrroles in gluconic acid aqueous solution. Tetrahedron69, 7011–7018 (2013).
Turks, M., Laclef, S. & Vogel, P. in Stereoselective Synthesis of Drugs and Natural Products (eds. Andrushko V. & Andrushko, N.) Ch. 10 (Wiley, 2013).
ter Horst, B., Feringa, B. L. & Minnaard, A. J. Iterative strategies for the synthesis of deoxypropionates. Chem. Commun.46, 2535–2547 (2010).
Flamme, E. M. & Roush, W. R. Enantioselective synthesis of 1,5-anti- and 1,5-syn-diols using a highly diastereoselective one-pot double allylboration reaction sequence. J. Am. Chem. Soc.124, 13644–13645 (2002).
Breit, B. & Herber, C. Iterative deoxypropionate synthesis based on a copper-mediated directed allylic substitution. Angew. Chem. Int. Ed.43, 3790–3792 (2004).
Roush, W. R. & Palkowitz, A. D. Application of tartrate ester modified allylic boronates in organic synthesis: an efficient, highly stereoselective synthesis of the carbon(19)-carbon(29) segment of rifamycin S. J. Am. Chem. Soc.109, 953–955 (1987).
Lin, H., Tian, L. & Krauss, I. J. Enantioselective syn and anti homocrotylation of aldehydes: application to the formal synthesis of spongidepsin. J. Am. Chem. Soc.137, 13176–13182 (2015).
Ko, S. Y. et al. Total synthesis of the l-hexoses. Science220, 949–951 (1983).
Yoshida, J., Maekawa, T., Morita, Y. & Isoe, S. A new iterative route to optically active polyols using α-alkoxy silanes as key intermediates. J. Org. Chem.57, 1321–1322 (1992).
Hassan, A., Lu, Y. & Krische, M. J. Elongation of 1,3-polyols via iterative catalyst-directed carbonyl allylation from the alcohol oxidation level. Org. Lett.11, 3112–3115 (2009).
Enders, D. & Hundertmark, T. Iterative asymmetric synthesis of protected anti-1,3-polyols. Tetrahedron Lett.40, 4169–4172 (1999).
Lin, L. et al. Catalytic asymmetric iterative/domino aldehyde cross-aldol reactions for the rapid and flexible synthesis of 1,3-polyols. J. Am. Chem. Soc.137, 15418–15421 (2015).
Reddy, D. S. & Mohapatra, D. K. Total synthesis and structure confirmation of cryptocaryol A. Eur. J. Org. Chem.2013, 1051–1057 (2013).
Dwivedi, N., Tripathi, D. & Kumar, P. An organocatalytic route to the synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one and ravensara lactones. Tetrahedron Asymmetry22, 1749–1756 (2011).
Kim, I. S., Ngai, M.-Y. & Krische, M. J. Enantioselective iridium-catalyzed carbonyl allylation from the alcohol or aldehyde oxidation level using allyl acetate as an allyl metal surrogate. J. Am. Chem. Soc.130, 6340–6341 (2008).
Nemoto, K., Nagafuchi, T., Tominaga, K.-I. & Sato, K. Efficient nickel-catalyzed hydrocyanation of alkenes using acetone cyanohydrin as a safer cyano source. Tetrahedron Lett.57, 3199–3203 (2016).
Hoye, T. R., Jeffrey, C. S. & Shao, F. Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons. Nat. Protoc.2, 2451–2458 (2007).
Konno, H., Hiura, N., Makabe, H., Abe, M. & Miyoshi, H. Synthesis and mitochondrial complex I inhibition of dihydroxy-cohibin A, non-THF annonaceous acetogenin analogue. Bioorg. Med. Chem. Lett.14, 629–632 (2004).
Liaw, C.-C. et al. Novel cytotoxic monotetrahydrofuranic annonaceous acetogenins from Annona montana. Bioorg. Med. Chem.13, 4767–4776 (2005).
Liaw, C.-C. et al. Mono-tetrahydrofuran annonaceous acetogenins from Annona squamosa as cytotoxic agents and calcium ion chelators. J. Nat. Prod.71, 764–771 (2008).
Takahashi, S. et al. Synthesis of all possible isomers corresponding to the proposed structure of montanacin E, and their antitumor activity. J. Org. Chem.74, 6382–6385 (2009).
Wang, T.-L., Hu, X. E. & Cassady, J. M. Total synthesis of (+)-13,14-threo-densicomacin. Tetrahedron Lett.36, 9301–9304 (1995).
Zhong, G. Tandem aminoxylation–allylation reactions: a rapid, asymmetric conversion of aldehydes to mono-substituted 1,2-diols. Chem. Commun. 606–607 (2004)
Simek, M., Bartova, K., Pohl, R., Cisarova, I. & Jahn, U. Tandem anionic oxy-Cope rearrangement/oxygenation reactions as a versatile method for approaching diverse scaffolds. Angew. Chem. Int. Ed.59, 6160–6165 (2020).
Barrett, A. G. M., Doubleday, W. W., Kasdorf, K. & Tustin, G. J. Stereochemical elucidation of the pentacyclopropane antifungal agent FR-900848. J. Org. Chem.61, 3280–3288 (1996).
Newman, D. & Cragg, G. Natural products from marine invertebrates and microbes as modulators of antitumor targets. Curr. Drug Targets7, 279–304 (2006).
Kahan, B. D. Forty years of publication of Transplantation Proceedings—the second decade: the cyclosporine revolution. Transplant. Proc.41, 1423–1437 (2009).
Shao, C.-L. et al. Bastimolide A, a potent antimalarial polyhydroxy macrolide from the marine cyanobacterium Okeania hirsuta. J. Org. Chem.80, 7849–7855 (2015).
Sinz, C. J. & Rychnovsky, S. D. Total synthesis of dermostatin A. Angew. Chem. Int. Ed.40, 3224–3227 (2001).
Perez, F., Waldeck, A. R. & Krische, M. J. Total synthesis of cryptocaryol A by enantioselective iridium-catalyzed alcohol C–H allylation. Angew. Chem. Int. Ed.55, 5049–5052 (2016).
Gesinski, M. R. & Rychnovsky, S. D. Total synthesis of the cyanolide A aglycon. J. Am. Chem. Soc.133, 9727–9729 (2011).
Sumimoto, S. et al. Minnamide A, a linear lipopeptide from the marine cyanobacterium Okeania hirsuta. Org. Lett.21, 1187–1190 (2019).
Love, K. Routenberg & Seeberger, P. H. Automated solid-phase synthesis of protected tumor-associated antigen and blood group determinant oligosaccharides. Angew. Chem. Int. Ed.43, 602–605 (2004).
Liaw, C. C. et al. The calcium-chelating capability of tetrahydrofuranic moieties modulates the cytotoxicity of annonaceous acetogenins. Angew. Chem. Int. Ed.50, 7885–7891 (2011).
Weise, C. F., Pischl, M. C., Pfaltz, A. & Schneider, C. A general, asymmetric, and noniterative synthesis of trideoxypropionates. Straightforward syntheses of the pheromones (+)-vittatalactone and (+)-norvittatalactone. J. Org. Chem.77, 1477–1488 (2012).
Nagamitsu, T. et al. Total synthesis of borrelidin. J. Org. Chem.72, 2744–2756 (2007).
Baj, A. et al. Convergent Synthesis of menaquinone-7 (MK-7). Org. Process Res. Dev.20, 1026–1033 (2016).
Sum, F. W. & Weiler, L. Synthesis of mokupalide. J. Am. Chem. Soc.101, 4401–4403 (1979).
The theoretical part of this research was developed with funding from the Defense Advanced Research Projects Agency (DARPA). The views, opinions and/or findings expressed are those of the author and should not be interpreted as representing the official views or policies of the Department of Defense or the US Government. The synthetic part of the work (Fig. 5) was supported by the National Science Center, NCN, Poland under the Maestro Award (#2018/30/A/ST5/00529 to B.A.G.) and the Foundation for Polish Science (award TEAM/2017-4/38 to J.M.). B.A.G. also gratefully acknowledges personal support from the Institute for Basic Science Korea, project code IBS-R020-D1.
K.M., S.S., M.M., R.R. and B.A.G. are contractors and/or stakeholders of Allchemy, Inc. whose proprietary and broader platform also supports the free-of-charge web-app for iterative chemistry described in this work. The remaining authors declare no competing interests.
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Iterative syntheses of polypeptides: synthatodin5610 (top) and cyclosporin A5730 (bottom). The scaffolds were constructed via known iterative coupling (shown in blue) using appropriate building blocks 2, 5, 7, 9, 12, 17, 19, 21, 26 (C, coupling; D, deprotection). Non-iterative parts of the syntheses do not have square markers next to the reaction arrows. Boc, tert-butoxycarbonyl; HOBt, hydroxybenzotriazole; EDC, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; DiPEA, N,N-diisopropylethylamine; DCM, dichloromethane; TFA, trifluoroacetic acid; Bn, benzyl; TBS, tert-butyldimethylsilyl; TBAF, tetra-n-butylammonium fluoride; THF, tetrahydrofuran.
Plausible iterative synthesis of bastimolide A58. The construction of the polyhydroxylated scaffold takes advantage of iterative construction of 1,5-diols identified by our algorithm (newly discovered iterations marked yellow/orange: A, allylation; P, protection; C, cyanation, R, reduction). In addition, two known iterative sequences are shown (blue and green: A, allylation; P, protection; O, ozonolysis; H, hydroboration, S, Suzuki coupling) depicting the installation of the 1,3-diol and the unsaturated ester. The final step is not part of an iteration and does not have a square marker next to the reaction arrow. Bz, benzoyl; cod, cyclooctadiene; TBAI, tetra-n-butylammonium iodide; PMB, p-methoxybenzyl; DMF, dimethylformamide; dppp, 1,3-bis(diphenylphosphino)propane; DMAP, 4-dimethylaminopyridine; DiBAL-H, diisobutylaluminium hydride; 9-BBN, 9-borabicyclo(3.3.1)nonane; dppf, 1,1’-bis(diphenylphosphino)ferrocene; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
Extended Data Fig. 3 Proposed iterative synthesis of dermostatin A, cryptocaryol A, and cyanolide A aglycon.
Proposed iterative synthesis of dermostatin A59 (top), cryptocaryol A60 (middle), and cyanolide A aglycon61 (bottom). The iterations underlying these syntheses are all known. The repeating 1,3-diol fragment is constructed via known iterative allylation controlled by the chiral borane (marked blue: A, allylation; P, protection; O, ozonolysis) while the desired polyene fragment of Dermostatin A is prepared via iterative vinylogous Horner-Wadsworth-Emmons (HWE) olefination (marked green: H, HWE olefination; R, reduction). Non-iterative parts of the syntheses do not have square markers next to the reaction arrows. Ipc, isopinocampheyl; MOM, methoxymethyl; DMSO, dimethylsulfoxide; pTsOH, p-toluenesulfonic acid.
Proposed iterative synthesis of minnamide A62. The repeating structural fragment is prepared via iterative homocrotylation of an aldehyde (newly discovered iterations marked yellow/orange: A, allylation; P, protection; H, hydroformylation) while the peptide fragment is constructed via known iterative amide coupling shown in blue (C, coupling; D, deprotection). Non-iterative parts of the syntheses do not have square markers next to the reaction arrows. acac, acetylacetonate; MS, molecular sieves.
Iterative synthesis of acenes14 (top, known) and azaacenes (bottom, proposed based on a newly discovered iteration). During construction of acenes, in each iteration (marked blue: C, condensation; R, reduction; O, oxidation) one additional phenyl ring is constructed via phosphine-mediated condensation of allenoate with dialdehyde. During construction of azaacenes in each iteration (marked yellow/orange: C, condensation; R, reduction) one additional quinoxaline ring is constructed via palladium-mediated coupling of aniline with aryl halide.
Seeberger’s iterative automated synthesis of saccharides63. In each iteration (marked blue: G, glycosylation; D, deprotection) the glycosyl acceptor is regenerated via the removal of temporary protecting group (here, Fmoc or levulinoyl ester). The cleavage of the product from the solid support following the assembly is performed via hydrolysis of the ester linkage. The final step is not part of the iteration and does not have a square marker next to the reaction arrow. Piv, pivaloyl; TMS, trimethylsilyl; Tf, triflyl; Fmoc, 9-fluorenylmethoxycarbonyl; Lev, levulinoyl.
Plausible iterative synthesis of squadiolin A50 and monhexocin64. In each iteration (newly discovered iterations marked yellow/orange: A, aminoxylation/allylation; P, protection; H, hydroformylation) the enolizable aldehyde is regenerated via the hydroformylation of the terminal alkene. The remaining part of the Monhexocin is constructed via known iterative (marked blue: M, halogenation followed by magnesiation; O, ring opening of epoxides) addition of Grignard reagent to appropriate oxiranes. Non-iterative parts of the syntheses do not have square markers next to the reaction arrows. TES, triethylsilyl; Ms, mesyl; NaHMDS, sodium bis(trimethylsilyl)amide; HMPA, hexamethylphosphoramide.
Iterative synthesis of vittatalactone65 (top) and of a fragment of borrelidin A66 (bottom). In each known iteration (marked blue: M, methylation; R, reduction, O, olefination) the aldehyde is regenerated from the thioester via reduction and Horner–Wadsworth–Emmons olefination. Non-iterative parts of the syntheses do not have square markers next to the reaction arrows. MTBE, methyl t-butyl ether.
Extended Data Fig. 9 Plausible synthesis of farnesol, menaquinone-7 (vitamin K2) and mokupalide via previously unknown iterative carboalumination of alkynes.
Plausible synthesis of farnesol, menaquinone-767 (vitamin K2) and mokupalide68 via previously unknown iterative carboalumination of alkynes. In each newly discovered iteration (marked yellow/orange: C, carboalumination; B, bromination followed by magnesiation) the Grignard reagent is regenerated via Appel reaction and metalation. Non-iterative parts of the syntheses do not have square markers next to the reaction arrows. CAN, ceric ammonium nitrate.
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Molga, K., Szymkuć, S., Gołębiowska, P. et al. A computer algorithm to discover iterative sequences of organic reactions. Nat Synth 1, 49–58 (2022). https://doi.org/10.1038/s44160-021-00010-3
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