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Diels–Alder cycloadditions of strained azacyclic allenes

Nature Chemistry volume 10, pages 953–960 (2018)Cite this article

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Abstract

For over a century, the structures and reactivities of strained organic compounds have captivated the chemical community. Whereas triple-bond-containing strained intermediates have been well studied, cyclic allenes have received far less attention. Additionally, studies of cyclic allenes that bear heteroatoms in the ring are scarce. We report an experimental and computational study of azacyclic allenes, which features syntheses of stable allene precursors, the mild generation and Diels–Alder trapping of the desired cyclic allenes, and explanations of the observed regio- and diastereoselectivities. Furthermore, we show that stereochemical information can be transferred from an enantioenriched silyl triflate starting material to a Diels–Alder cycloadduct by way of a stereochemically defined azacyclic allene intermediate. These studies demonstrate that heteroatom-containing cyclic allenes, despite previously being overlooked as valuable synthetic intermediates, may be harnessed for the construction of complex molecular scaffolds bearing multiple stereogenic centres.

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Fig. 1: Survey of strained cyclic intermediates and focus of present study.
Fig. 2: Comparison of geometry-optimized structures of allenes 13 and 14 (ωB97XD/6-31G(d)).
Fig. 3: Syntheses of silyl triflates 19, 20, 23 and 24.
Fig. 4: Computations provide insight into regio- and diastereoselectivities.
Fig. 5: Attempted transfer of stereochemical information from silyl triflates to cycloadducts via azacyclic allene intermediates.

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Acknowledgements

The authors acknowledge the NIH-NIGMS (R01 GM090007 to N.K.G., R01 GM109078 to K.N.H. and F32 GM122245 to E.R.D.), the National Science Foundation (NSF; CHE-1361104 to K.N.H. and DGE-1144087 to M.M.Y.), the University of California, Los Angeles, the UCLA Cota Robles Fellowship Program (M.R.) and the Chemistry–Biology Interface training program (J.S.B., USPHS National Research Service Award 5T32GM008496-20) for financial support. Pier Champagne is acknowledged for computational assistance. These studies were supported by shared instrumentation grants from the NSF (CHE-1048804) and the NIH NCRR (S10RR025631). Computations were performed with resources made available from the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI-1053575), as well as the UCLA Institute of Digital Research and Education (IDRE).

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  1. These authors contributed equally to this work: J. S. Barber, M. M. Yamano.

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Joyann S. Barber, Michael M. Yamano, Melissa Ramirez, Evan R. Darzi, Rachel R. Knapp, Fang Liu, K. N. Houk & Neil K. Garg

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Contributions

J.S.B., M.M.Y., E.R.D. and R.R.K. designed and performed experiments and analysed experimental data. M.R. and F.L. 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.

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

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Barber, J.S., Yamano, M.M., Ramirez, M. et al. Diels–Alder cycloadditions of strained azacyclic allenes. Nature Chem 10, 953–960 (2018). https://doi.org/10.1038/s41557-018-0080-1

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