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Automated radial synthesis of organic molecules

Abstract

Automated synthesis platforms accelerate and simplify the preparation of molecules by removing the physical barriers to organic synthesis. This provides unrestricted access to biopolymers and small molecules via reproducible and directly comparable chemical processes. Current automated multistep syntheses rely on either iterative1,2,3,4 or linear processes5,6,7,8,9, and require compromises in terms of versatility and the use of equipment. Here we report an approach towards the automated synthesis of small molecules, based on a series of continuous flow modules that are radially arranged around a central switching station. Using this approach, concise volumes can be exposed to any reaction conditions required for a desired transformation. Sequential, non-simultaneous reactions can be combined to perform multistep processes, enabling the use of variable flow rates, reuse of reactors under different conditions, and the storage of intermediates. This fully automated instrument is capable of both linear and convergent syntheses and does not require manual reconfiguration between different processes. The capabilities of this approach are demonstrated by performing optimizations and multistep syntheses of targets, varying concentrations via inline dilutions, exploring several strategies for the multistep synthesis of the anticonvulsant drug rufinamide10, synthesizing eighteen compounds of two derivative libraries that are prepared using different reaction pathways and chemistries, and using the same reagents to perform metallaphotoredox carbon–nitrogen cross-couplings11 in a photochemical module—all without instrument reconfiguration.

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Fig. 1: Approaches to organic synthesis.
Fig. 2: The radial synthesizer.
Fig. 3: Direct comparison of synthetic routes towards rufinamide.
Fig. 4: Generation of a library of rufinamide derivatives.
Fig. 5: Modular expansion of the capabilities of the system.

Data availability

All data generated or analysed during this study are included in this Article and its Supplementary Information file.

Code availability

The complete software package and instructions necessary for assembling and operating the radial synthesizer are freely available to academic users by request at http://synthesizer.mpikg.mpg.de/.

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Acknowledgements

We acknowledge financial support from the Max-Planck Society, the Army Research Office under contract W911NF-16-1-0557, and the DFG InCHeM (FOR 2177). We thank B. Pieber, J. Malik, S. Moon and F. Hentschel for suggestions and support; J. von Szada-Borryszkowski and J. Petersen for construction of the instrument housing; and Vapourtec for software support with the incorporation of their equipment.

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Contributions

K.G. designed the approach and system, and refined the instrument and chemistries. M.G. and K.G. wrote the draft of the manuscript, and all authors participated in revising the manuscript. S.C. designed, wrote and developed the software, controls, user interface and hardware layout. M.G. developed chemistry, designed and executed optimizations, developed pathways for multistep processes and refined the system. P.H.S. and K.G. provided oversight to the project and secured funding.

Corresponding author

Correspondence to Kerry Gilmore.

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Competing interests

The Max-Planck Society has been granted patent EP3386628B1, which covers the system described here and lists S.C., P.H.S. and K.G. as inventors.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures S1–S146, Supplementary Tables S1–S23 and Supplementary Schemes S1–S34.

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Chatterjee, S., Guidi, M., Seeberger, P.H. et al. Automated radial synthesis of organic molecules. Nature 579, 379–384 (2020). https://doi.org/10.1038/s41586-020-2083-5

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