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Biosynthetic consequences of multiple sequential post-transition-state bifurcations

Nature Chemistry volume 6, pages 104111 (2014) | Download Citation

Abstract

Selectivity in chemical reactions that form complex molecular architectures from simpler precursors is usually rationalized by comparing competing transition-state structures that lead to different possible products. Herein we describe a system for which a single transition-state structure leads to the formation of many isomeric products via pathways that feature multiple sequential bifurcations. The reaction network described connects the pimar-15-en-8-yl cation to miltiradiene, a tricyclic diterpene natural product, and isomers via cyclizations and/or rearrangements. The results suggest that the selectivity of the reaction is controlled by (post-transition-state) dynamic effects, that is, how the carbocation structure changes in response to the distribution of energy in its vibrational modes. The inherent dynamical effects revealed herein (characterized through quasiclassical direct dynamics calculations using density functional theory) have implications not only for the general principles of selectivity prediction in systems with complex potential energy surfaces, but also for the mechanisms of terpene synthase enzymes and their evolution. These findings redefine the challenges faced by nature in controlling the biosynthesis of complex natural products.

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Acknowledgements

This work was supported by the US National Science Foundation (CHE-0957416 and supercomputing resources through a grant from the XSEDE program: CHE030089). We also thank R. Pemberton for his advice and assistance in running dynamics calculations, R. Peters for encouraging us to investigate the biosynthesis of miltiradiene, D. Singleton for sharing his Progdyn program, J. Baek for technical assistance with data analysis and J. Lee and M. Lodewyk for helpful comments.

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  1. Department of Chemistry, University of California–Davis, One Shields Avenue, Davis, California 95616, USA

    • Young Joo Hong
    •  & Dean J. Tantillo

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Contributions

Y.J.H. and D.J.T. conceived and designed the project, Y.J.H. carried out the calculations, Y.J.H and D.J.T. analysed and interpreted the results, Y.J.H. designed the figures with assistance from D.J.T. and D.J.T. wrote the manuscript with assistance from Y.J.H.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dean J. Tantillo.

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DOI

https://doi.org/10.1038/nchem.1843