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Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies

Abstract

The Soai reaction has profoundly impacted chemists’ perspective of autocatalysis, chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Here we describe the unprecedented observation of asymmetry-amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc. Kinetic studies with a surrogate substrate and spectroscopic analysis of a series of zinc alkoxides that incorporate specific structural mutations reveal a ‘pyridine-assisted cube escape’. The new tetrameric cluster functions as a catalyst that activates the substrate through a two-point binding mode and poises a coordinated diisopropylzinc moiety for alkyl group transfer. Transition-state models leading to both the homochiral and heterochiral products were validated by density functional theory calculations. Moreover, experimental and computational analysis of the heterochiral complex provides a definitive explanation for the nonlinear behaviour of this system. Our deconstruction of the Soai system reveals the structural logic for autocatalyst evolution, function and substrate compatibility—a central mechanistic aspect of this iconic transformation.

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Fig. 1: The Soai reaction system, current mechanistic understanding and salient contributions from this work.
Fig. 2: A new asymmetry-amplifying, autocatalytic pyridine system and a structure–activity relationship of the (auto)catalyst.
Fig. 3: Spectroscopic characterization of zinc alkoxides reveals structure-dependent solution-state aggregation.
Fig. 4: Diastereomeric species possible in a racemic cubic tetramer with their relative peak distributions.
Fig. 5: Structural logic for the evolution of the catalytically active, PyII SMS tetramer.
Fig. 6: Substrate constraints and kinetic studies for the enantioselective, positive nonlinear alkyl transfer activity of PyII.
Fig. 7: Catalysis by the PyII SMS tetramer and DFT studies for floor-to-floor substrate docking and alkyl transfer.
Fig. 8: Origin of nonlinearity in the amplifying, autocatalytic reaction.

Data availability

All data mentioned in this manuscript are available as part of the main article or as Supplementary Information (Supplementary Figs. 1178 and Supplementary Tables 16). Initial rate kinetics data and DFT computation data are included in separate files.

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Acknowledgements

We are grateful for generous financial support from the University of Illinois. S.V.A. is grateful to the University of Illinois for Graduate Fellowships. A.S. acknowledges support from a NIH Chemistry–Biology Interface Research Training Grant (T32GM008496). We are also grateful for the support services of the NMR, mass spectrometry and microanalytical laboratories of the University of Illinois at Urbana-Champaign.

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S.V.A. conceptualized the project, designed and performed chemistry experiments, analysed data and wrote the manuscript. S.E.D. secured funding, supervised, analysed data and revised the manuscript. A.S. performed DFT calculations under the supervision of K.N.H. All authors contributed in assembling the final draft of the manuscript.

Corresponding author

Correspondence to Scott E. Denmark.

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Supplementary information

Supplementary Information

Complete experimental details, synthesis, spectroscopic characterizations, kinetics, computational studies and miscellaneous supporting data. Includes Supplementary Figs. 1–177 and Tables 1–6.

Data Tables for Initial Rate Experiments

Raw and processed data obtained from in situ infrared monitoring of aldehyde consumption in initial rate studies.

Data Tables for Cartesian Coordinates and Energies from DFT studies

Coordinates and energies for all DFT calculated structures.

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Athavale, S., Simon, A., Houk, K.N. et al. Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies. Nat. Chem. 12, 412–423 (2020). https://doi.org/10.1038/s41557-020-0421-8

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