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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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.
The authors declare no competing interests.
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Complete experimental details, synthesis, spectroscopic characterizations, kinetics, computational studies and miscellaneous supporting data. Includes Supplementary Figs. 1–177 and Tables 1–6.
Raw and processed data obtained from in situ infrared monitoring of aldehyde consumption in initial rate 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