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Intercepting fleeting cyclic allenes with asymmetric nickel catalysis


Strained cyclic organic molecules, such as arynes, cyclic alkynes and cyclic allenes, have intrigued chemists for more than a century with their unusual structures and high chemical reactivity1. The considerable ring strain (30–50 kilocalories per mole)2,3 that characterizes these transient intermediates imparts high reactivity in many reactions, including cycloadditions and nucleophilic trappings, often generating structurally complex products4. Although strategies to control absolute stereochemistry in these reactions have been reported using stoichiometric chiral reagents5,6, catalytic asymmetric variants to generate enantioenriched products have remained difficult to achieve. Here we report the interception of racemic cyclic allene intermediates in a catalytic asymmetric reaction and provide evidence for two distinct mechanisms that control absolute stereochemistry in such transformations: kinetic differentiation of allene enantiomers and desymmetrization of intermediate π-allylnickel complexes. Computational studies implicate a catalytic mechanism involving initial kinetic differentiation of the cyclic allene enantiomers through stereoselective olefin insertion, loss of the resultant stereochemical information, and subsequent introduction of absolute stereochemistry through desymmetrization of an intermediate π-allylnickel complex. These results reveal reactivity that is available to cyclic allenes beyond the traditional cycloadditions and nucleophilic trappings previously reported, thus expanding the types of product accessible from this class of intermediates. Additionally, our computational studies suggest two potential strategies for stereocontrol in reactions of cyclic allenes. Combined, these results lay the foundation for the development of catalytic asymmetric reactions involving these classically avoided strained intermediates.

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Fig. 1: Historical context of strained cyclic intermediates and current reaction design.
Fig. 2: Scope of benzotriazinones and cyclic allenes in the racemic annulation reaction.
Fig. 3: Optimization and scope of the asymmetric annulation.
Fig. 4: Computational study of the asymmetric annulation reaction mechanism.

Data availability

Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 1987661. The authors declare that all other data supporting the findings of this study are available within the paper and its Supplementary Information files.


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We are grateful to the NIH-NIGMS (R01 GM123299 and R01 GM132432 for N.K.G., and T32 GM067555 for A.V.K.), the NSF (CHE-1764328 for K.N.H., DGE-1144087 for M.M.Y. and B.J.S., and DGE-1650604 for A.V.K.), the Trueblood family (for N.K.G.), and the Swiss National Science Foundation for an Early Mobility Postdoctoral Fellowship (M.G.). These studies were supported by shared instrumentation grants from the NSF (CHE-1048804) and the NIH NCRR (S10RR025631). Calculations were performed on the Hoffman2 cluster and the UCLA Institute of Digital Research and Education (IDRE) at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (OCI-1053575).

Author information




M.M.Y., A.V.K., M.G. and B.J.S. designed and performed experiments and analysed experimental data. Q.S., B.L. and S.C. designed, performed, and analysed computational data. K.N.H. and N.K.G. directed the investigations and prepared the manuscript with contributions from all authors; all authors contributed to discussions.

Corresponding authors

Correspondence to K. N. Houk or Neil K. Garg.

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Competing interests

The authors declare no competing interests.

Extended data figures and tables

Extended Data Fig. 1 Proposed catalytic cycle.

Computational studies support a mechanism involving activation of the benzotriazinone by the Ni catalyst, migratory insertion across one olefin of the cyclic allene, isomerization to a Ni π-allyl complex, and enantioselective outer-sphere attack to provide the observed phenanthridinone.

Supplementary information

Supplementary Information

This file contains: General Procedures; Reaction Optimization Data; Single Crystal X-Ray Diffraction Data; Supercritical Fluid Chromatography Data; 1H and 13C NMR Spectral Data; Computational Methods; Detailed Computational Mechanistic Analysis, Atomic Coordinates for all Structures Studied Computationally and Supplementary References.

Supplementary Data

This file contains the CheckCIF and CIF file for Compound 69 CCDC reference 1987661.

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Yamano, M.M., Kelleghan, A.V., Shao, Q. et al. Intercepting fleeting cyclic allenes with asymmetric nickel catalysis. Nature 586, 242–247 (2020).

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