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A computer algorithm to discover iterative sequences of organic reactions

Nature Synthesis volume 1, pages 49–58 (2022)Cite this article

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Abstract

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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Fig. 1: Diversity and complexity of molecules synthesizable with the use of iterative sequences.
Fig. 2: Algorithmic discovery of iterative sequences.
Fig. 3: Examples of computer-discovered iterative sequences for the synthesis of conjugated poly(heterocyclic) systems (two iterations are shown for each example).
Fig. 4: Examples of computer-generated, stereoselective iterative sequences (two iterations are shown for each example).
Fig. 5: Experimental validation of newly discovered iterative sequences (two iterations were performed for each example).
Fig. 6: Exploration of reaction networks generated by iterative sequences.

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Data availability

All data in support of the findings of this study are available within the Article and its Supplementary Information.

Code availability

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.).

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Acknowledgements

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.

Author information

Authors and Affiliations

  1. Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland

    Karol Molga, Sara Szymkuć, Patrycja Gołębiowska, Oskar Popik, Piotr Dittwald, Martyna Moskal, Rafal Roszak, Jacek Mlynarski & Bartosz A. Grzybowski

  2. Allchemy, Inc., Highland, IN, USA

    Karol Molga, Sara Szymkuć, Martyna Moskal, Rafal Roszak & Bartosz A. Grzybowski

  3. IBS Center for Soft and Living Matter, UNIST, Ulsan, South Korea

    Bartosz A. Grzybowski

  4. Department of Chemistry, UNIST, Ulsan, South Korea

    Bartosz A. Grzybowski

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Contributions

K.M. and S.S. coded most of the underlying reaction rules, helped design the algorithm to find iterative sequences, and analysed results. P.G. and O.P. performed the syntheses described in Fig. 5. P.D. encoded the algorithm to identify iterative sequences. M.M. and R.R. developed the web-app. J.M. supervised syntheses from Fig. 5a,b. B.A.G. conceived and supervised research, and also wrote the paper with contributions from other authors.

Corresponding authors

Correspondence to Jacek Mlynarski or Bartosz A. Grzybowski.

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Competing interests

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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Extended data

Extended Data Fig. 1 Iterative syntheses of polypeptides: synthatodin and cyclosporin A.

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.

Extended Data Fig. 2 Plausible iterative synthesis of bastimolide A.

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.

Extended Data Fig. 4 Proposed iterative synthesis of minnamide A.

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.

Extended Data Fig. 5 Iterative synthesis of acenes and azaacenes.

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.

Extended Data Fig. 6 Seeberger’s iterative automated synthesis of saccharides.

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.

Extended Data Fig. 7 Plausible iterative synthesis of squadiolin A and monhexocin.

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.

Extended Data Fig. 8 Iterative synthesis of vittatalactone and of a fragment of borrelidin A.

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.

Supplementary information

Supplementary Information

Supplementary Figs. 1–59, Tables 1–5 and Schemes 1–3.

Source data

Source Data Fig. 6

Screenshot from Iterator software.

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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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  • DOI: https://doi.org/10.1038/s44160-021-00010-3

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