Abstract
Automation has fuelled dramatic advances in fields such as proteomics and genomics by enabling non-experts to prepare, test and analyse complex biological molecules, including proteins and nucleic acids. However, the field of automated organic synthesis lags far behind, partly because of the complexity and variety of organic molecules. As a result, only a handful of relatively simple organic molecules, requiring a small number of synthetic steps, have been made in an automated fashion. Here we report an automated assembly-line synthesis that allows iterative formation of C(sp3)–C(sp3) bonds with high stereochemical control and reproducibility, enabling access to complex organic molecules. This was achieved on a commercially available robotic platform capable of handling air-sensitive reactants and performing low-temperature reactions, which enabled six sequenced one-carbon homologations of organoboron substrates to be performed iteratively without human intervention. Together with other automated functional group manipulations, this methodology has been exploited to rapidly build the core fragment of the natural product (+)-kalkitoxin, thus expanding the field of automated organic synthesis.
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References
Merrifield, R. B. Automated synthesis of peptides: solid-phase peptide synthesis, a simple and rapid synthetic method, has now been automated. Science 150, 178–185 (1965).
Caruthers, M. H. Gene synthesis machines: DNA chemistry and its uses. Science 230, 281–285 (1985).
Plante, O. J., Palmacci, E. R. & Seeberger, P. H. Automated solid-phase synthesis of oligosaccharides. Science 291, 1523–1527 (2001).
Joseph, A. A., Pardo-Vargas, A. & Seeberger, P. H. Total synthesis of polysaccharides by automated glycan assembly. J. Am. Chem. Soc. 142, 8561–8564 (2020).
Burger, B. et al. A mobile robotic chemist. Nature 583, 237–241 (2020).
Steiner, S. et al. Organic synthesis in a modular robotic system driven by a chemical programming language. Science 363, eaav2211 (2019).
Liu, C. et al. Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis. Nat. Chem. 13, 451–457 (2021).
Mehr, S. H. M., Craven, M., Leonov, A., Keenan, G. & Cronin, L. A universal system for digitization and automatic execution of the chemical synthesis literature. Science 370, 101–108 (2020).
Coley, C. W. et al. A robotic platform for flow synthesis of organic compounds informed by AI planning. Science 365, eaax1566 (2019).
Tu, N. P., Searle, P. A. & Sarris, K. An automated microwave-assisted synthesis purification system for rapid generation of compound libraries. J. Lab. Autom. 21, 459–469 (2016).
Li, T. et al. An automated platform for the enzyme-mediated assembly of complex oligosaccharides. Nat. Chem. 11, 229–236 (2019).
Chatterjee, S., Guidi, M., Seeberger, P. H. & Gilmore, K. Automated radial synthesis of organic molecules. Nature 579, 379–384 (2020).
Li, J. et al. Synthesis of many different types of organic small molecules using one automated process. Science 347, 1221–1226 (2015).
Blair, D. J. et al. Automated iterative Csp3-C bond formation. Nature 604, 92–97 (2022).
Aiken, S. G, Bateman, J. M & Aggarwal, V. K. in Advances in Organoboron Chemistry towards Organic Synthesis, Ch. 13 (Thieme, 2019).
Casoni, G. et al. α‑Sulfinyl benzoates as precursors to Li and Mg carbenoids for the stereoselective iterative homologation of boronic esters. J. Am. Chem. Soc. 139, 11877–11886 (2017).
Yeung, K., Mykura, R. C. & Aggarwal, V. K. Lithiation–borylation methodology in the total synthesis of natural products. Nat. Synth. 1, 117–126 (2022).
Fiorito, D. et al. Stereocontrolled total synthesis of bastimolide B using iterative homologation of boronic esters. J. Am. Chem. Soc. 144, 7995–8001 (2022).
Leonori, D. & Aggarwal, V. K. Lithiation–borylation methodology and its application in synthesis. Acc. Chem. Res. 47, 3174–3183 (2014).
Matteson, D. S. α-Halo boronic esters: intermediates for stereodirected synthesis. Chem. Rev. 89, 1535–1551 (1989).
Matteson, D. S., Collins, B. S. L., Aggarwal, V. K. & Ciganek, E. The Matteson reaction. Organic Reactions https://doi.org/10.1002/0471264180.or105.03 (2021).
Matteson, D. S. & Ray, R. Directed chiral synthesis with pinanediol boronic esters. J. Am. Chem. Soc. 102, 7590–7591 (1980).
Matteson, D. S., Ray, R., Rocks, R. R. & Tsai, D. J. S. Directed chiral synthesis by way of α-chloro boronic esters. Organometallics 2, 1536–1543 (1983).
Burns, M. et al. Assembly-line synthesis of organic molecules with tailored shapes. Nature 513, 183–1188 (2014).
Leonori, D. & Aggarwal, V. K. in Synthesis and Application of Organoboron Compounds, Vol. 49, 271–295 (Springer, 2015).
Balieu, S. et al. Toward ideality: the synthesis of (+)-kalkitoxin and (+)-hydroxyphthioceranic acid by assembly-line synthesis. J. Am. Chem. Soc. 137, 4398–4403 (2015).
Mlynarski, S. N., Karns, A. S. & Morken, J. P. Direct stereospecific amination of alkyl and aryl pinacol boronates. J. Am. Chem. Soc. 134, 16449–16451 (2012).
Edelstein, E. K., Grote, A. C., Palkowitz, M. D. & Morken, J. P. A protocol for direct stereospecific amination of primary, secondary, and tertiary alkylboronic esters. Synlett 29, 1749–1752 (2018).
Acknowledgements
V.F. thanks the University of Bristol for awarding the Engineering and Physical Sciences Research Council (EPSRC) Doctoral Prize Fellowship. R.C.M., J.M.F. and J.J.R. thank the Bristol Chemical Synthesis Centre for doctoral training. We thank the EPSRC for funding (EP/R513179/1, V.F.; EP/L015366/1, R.C.M.; EP/G036764/1, J.M.F. and J.J.R.; EP/T033584/1, V.K.A.; EP/R008795/1, B.B). We thank Chemspeed for technical support.
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V.K.A. conceived the project and directed the research. V.F., R.C.M., J.M.F., A.N. and V.K.A. prepared the manuscript. V.F., R.C.M., J.M.F., J.J.R. and B.B. performed the experimental work. All authors analysed the results.
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Fasano, V., Mykura, R.C., Fordham, J.M. et al. Automated stereocontrolled assembly-line synthesis of organic molecules. Nat. Synth 1, 902–907 (2022). https://doi.org/10.1038/s44160-022-00158-6
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DOI: https://doi.org/10.1038/s44160-022-00158-6
