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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All experimental procedures and data are available in the main text and Supplementary Information.
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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
