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From desktop to benchtop with automated computational workflows for computer-aided design in asymmetric catalysis

Abstract

The organic chemist’s toolbox is vast, with technologies to accelerate the synthesis of novel chemical matter. The field of asymmetric catalysis is one approach to accessing new areas of chemical space and computational power is today sufficient to assist in this exploration. Unfortunately, existing techniques generally require computational expertise and are therefore underutilized in synthetic chemistry. Here we present our platform Virtual Chemist, which allows bench chemists to predict outcomes of asymmetric chemical reactions ahead of testing in the laboratory, in just a few clicks. Modular workflows facilitate the simulation of various sets of experiments, including the four realistic scenarios discussed: one-by-one design, library screening, hit optimization and substrate-scope evaluation. Catalyst candidates are screened within hours and the enantioselectivity predictions provide substantial enrichments compared to random testing. The achieved accuracies within ~1 kcal mol–1 provide opportunities for computational chemistry in the field of asymmetric catalyst design, allowing bench chemists to guide the design and discovery of asymmetric catalysts.

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Fig. 1: Experimental versus computational catalyst discovery.
Fig. 2: Screening catalysts for diethylzinc addition to aldehydes.
Fig. 3: ACE-optimized TS structures for selected reactions.
Fig. 4: Accuracy of the programs for scenario 1.
Fig. 5: Investigating the failures.
Fig. 6: Accuracy of the programs for scenario 2.
Fig. 7: Optimization of asymmetric organocatalysts for Diels–Alder cycloaddition.
Fig. 8: Substrate-scope study with (DHQD)2PHAL.

Data availability

The sets of molecules used in this study (Supplementary Tables 18) and representative computed data (Supplementary Tables 918) are available as Supplementary Information. A tutorial for the use of this platform is provided as Supplementary Data 1. The programs are available (free of charge for academic research) at www.molecularforecaster.com. All the data, parameter files and structures are available on moitessier-group.mcgill.ca/software.html.

All other data is available from the authors upon reasonable request.

Code availability

Description and pseudocode of all the programs used in this study are provided in the Supplementary Methods. The programs are available for download upon request from the authors (www.molecularforecaster.com).

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Acknowledgements

We thank NSERC (Discovery programme) for financial support. Calcul Québec and Compute Canada are acknowledged for generous CPU allocations.

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Affiliations

Authors

Contributions

N.M., M.B.P. and J.P. designed and wrote the programs REACT2D, FINDERS and CONTRUCTS (J.P., N.M.), QUEMIST (M.B.P.), UI, REDUCE, SELECT and ACE (N.M.). S.P. and M.B.P. have tested the usability and contributed to the design of the platform. P.O.N. contributed to the design of the platform. The testing (four scenarios) and data analysis were performed by S.P., M.B.P. and N.M. All the authors contributed to the manuscript.

Corresponding author

Correspondence to Nicolas Moitessier.

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Competing interests

Virtual Chemist is distributed by Molecular Forecaster (free of charge for academic research) co-founded by N.M. (CEO: J.P.).

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Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1,2, Tables 1–18, and References.

Supplementary Data 1

Supplementary Data 1.

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Burai Patrascu, M., Pottel, J., Pinus, S. et al. From desktop to benchtop with automated computational workflows for computer-aided design in asymmetric catalysis. Nat Catal 3, 574–584 (2020). https://doi.org/10.1038/s41929-020-0468-3

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