Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Biosynthetic consequences of multiple sequential post-transition-state bifurcations

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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Biosynthetic route to miltiradiene.
Figure 2: Features of the pimar-15-en-8-yl cation PES.
Figure 3: Cascading array of bifurcations.
Figure 4: Outcomes for dynamics trajectories.
Figure 5: Motion associated with post-transition-state PES bifurcations.
Figure 6: Representative trajectories.

References

  1. Davis, E. M. & Croteau, R. Cyclization enzymes in the biosynthesis of monoterpenes, sesquiterpenes, and diterpenes. Top. Curr. Chem. 209, 53–95 (2000).

    CAS  Article  Google Scholar 

  2. Cane, D. E. Enzymatic formation of sesquiterpenes. Chem. Rev. 90, 1089–1103 (1990).

    CAS  Article  Google Scholar 

  3. Christianson, D. W. Structural biology and chemistry of terpenoid cyclases. Chem. Rev. 106, 3412–3442 (2006).

    CAS  Article  Google Scholar 

  4. Miller, D. J. & Allemann, R. K. Sesquiterpene synthases: passive catalysts or active players? Nat. Prod. Rep. 29, 60–71 (2012).

    CAS  Article  Google Scholar 

  5. Gao, W., et al. A functional genomics approach to tanshinone biosynthesis provides stereochemical insights. Org. Lett. 11, 5170–5173 (2009).

    CAS  Article  Google Scholar 

  6. Zhou, Y. J. et al. Modular pathway engineering of diterpenoid synthases and the mevalonic acid pathway for miltiradiene production. J. Am. Chem. Soc. 134, 3234–3241 (2012).

    CAS  Article  Google Scholar 

  7. Ess, D. H. et al. Bifurcations on potential energy surfaces of organic reactions. Angew. Chem. Int. Ed. 47, 7592–7601 (2008).

    CAS  Article  Google Scholar 

  8. Thomas, J. B., Waas, J. R., Harmata, M. & Singleton, D. A. Control elements in dynamically determined selectivity on a bifurcating surface. J. Am. Chem. Soc. 130, 14544–14555 (2008).

    CAS  Article  Google Scholar 

  9. Birney, D. M. Theory, experiment and unusual features of potential energy surfaces of pericyclic and pseudopericyclic reactions with sequential transition structures. Curr. Org. Chem. 14, 1658–1668 (2010).

    CAS  Article  Google Scholar 

  10. Hansen J. H. et al. On the mechanism and selectivity of the combined C−H activation/Cope rearrangement. J. Am. Chem. Soc. 133, 5076–5085 (2011).

    CAS  Article  Google Scholar 

  11. Quapp, W. How does a reaction path branching take place? A classification of bifurcation events. J. Molec. Struc. 695-696, 95–101 (2004).

    Article  Google Scholar 

  12. Rehbein, J. & Carpenter, B. K. Do we fully understand what controls chemical selectivity? Phys. Chem. Chem. Phys. 13, 20906–20922 (2011).

    CAS  Article  Google Scholar 

  13. Hong, Y. J. & Tantillo, D. J. A potential energy surface bifurcation in terpene biosynthesis. Nature Chem. 1, 384–389 (2009).

    CAS  Article  Google Scholar 

  14. Siebert, M. R., Zhang, J., Addepalli, S. V., Tantillo, D. J. & Hase, W. L. The need for enzymatic steering in abietic acid biosynthesis: gas-phase chemical dynamics simulation of carbocation rearrangements on a bifurcating potential energy surface. J. Am. Chem. Soc. 133, 8335–8343 (2011).

    CAS  Article  Google Scholar 

  15. Siebert, M. R., Manikandan, P., Sun, R., Tantillo, D. J. & Hase, W. L. Gas-phase chemical dynamics simulations on the bifurcating pathway of the pimaradienyl cation rearrangement. Role of enzymatic steering in abietic acid biosynthesis. J. Chem. Theor. Comput. 8, 1212–1222 (2012).

    CAS  Article  Google Scholar 

  16. Tao, P., Gatti, D. L. & Schlegel, H. B. The energy landscape of 3-deoxy-D-manno-octulosonate 8-phosphate synthase. Biochemistry 48, 11706 (2009).

    CAS  Article  Google Scholar 

  17. Carpenter, B. K. Intramolecular dynamics for the organic chemist. Acc. Chem. Res. 25, 520–528 (1992).

    CAS  Article  Google Scholar 

  18. Black, K., Liu, P., Xu, L., Doubleday, C. & Houk, K. N. Dynamics, transition states, and timing of bond formation in Diels–Alder reactions. Proc. Natl Acad. Sci. USA 109, 12860–12865 (2012).

    CAS  Article  Google Scholar 

  19. Bogle, X. S. & Singleton, D. A. Dynamic origin of the stereoselectivity of a nucleophilic substitution reaction. Org. Lett. 14, 2528–2531 (2012).

    CAS  Article  Google Scholar 

  20. Paranjothy, M., Sun, R., Zhuang, Y. & Hase, W. L. Direct chemical dynamics simulations: coupling of classical and quasiclassical trajectories with electronic structure theory. WIREs Comput. Mol. Sci. 3, 296–316 (2013).

    CAS  Article  Google Scholar 

  21. Marx, D. & Hutter, J. Ab Initio Molecular Dynamics: Basic Theory and Advanced Methods (Cambridge Univ. Press, 2009).

    Book  Google Scholar 

  22. Allemann, R. K., Young, N. J., Ma, S., Truhlar, D. G. & Gao, J. Synthetic efficiency in enzyme mechanisms involving carbocations: aristolochene synthase. J. Am. Chem. Soc. 129, 13008–13013 (2007).

    CAS  Article  Google Scholar 

  23. Glowacki, D. R., Liang, C. H., Marsden, S. P., Harvey, J. N. & Pilling, M. J. Alkene hydroboration: hot intermediates that react while they are cooling. J. Am. Chem. Soc. 132, 13621–13623 (2010).

    CAS  Article  Google Scholar 

  24. Zheng, J., Papajak, E. & Truhlar, D. G. Phase space prediction of product branching ratios: canonical competitive nonstatistical model. J. Am. Chem. Soc. 131, 15754–15760 (2009).

    CAS  Article  Google Scholar 

  25. Vaughan, M. M., et al. Formation of the unusual semivolatile diterpene rhizathalene by the Arabidopsis Class I terpene synthase TPS08 in the root stele is involved in defense against belowground herbivory. Plant Cell 25, 1108–11025 (2013).

    CAS  Article  Google Scholar 

  26. Gutierrez, O. & Tantillo, D. J. Analogies between synthetic and biosynthetic reactions in which [1,2]-alkyl shifts are combined with other events – dyotropic, Schmidt and carbocation rearrangements. J. Org. Chem. 77, 8845–8850 (2012).

    CAS  Article  Google Scholar 

  27. Zhou, K. & Peters, R. J. Electrostatic effects on (di)terpene synthase product outcome. Chem. Commun. 47, 4074–4080 (2011).

    CAS  Article  Google Scholar 

  28. Tantillo, D. J. The carbocation continuum in terpene biosynthesis – where are the secondary cations? Chem. Soc. Rev. 39, 2847–2854 (2010).

    CAS  Article  Google Scholar 

  29. Tantillo, D. J. Biosynthesis via carbocations: theoretical studies on terpene formation. Nat. Prod. Rep. 28, 1035–1053 (2011).

    CAS  Article  Google Scholar 

  30. Sheppard, A. N. & Acevedo, O. Multidimensional exploration of valley-ridge inflection points on potential-energy surfaces. J. Am. Chem. Soc. 131, 2530–2540 (2009).

    CAS  Article  Google Scholar 

  31. Karplus, M., Porter, R. N. & Sharma, R. D. Exchange reactions with activation energy. I. Simple barrier potential for (H, H2). J. Chem. Phys. 43, 3259 (1965).

    CAS  Article  Google Scholar 

  32. Aue, D. Bifurcation on reaction pathways for pinacol-type rearrangements. 33rd Reaction Mechanisms Conference, University of Massachusetts, Amherst, 23–26 June (2010).

    Google Scholar 

  33. Townsend, D. et al. The roaming atom: straying from the reaction path in formaldehyde decomposition. Science 306, 1158–1161 (2004).

    CAS  Article  Google Scholar 

  34. Bowman, J. M. & Suits, A. G. Roaming reactions: the third way. Phys. Today 64, 33 (November 2011).

    CAS  Article  Google Scholar 

  35. Ammal, S. C., Yamataka, H., Aida, M. & Dupuis, M. Dynamics-driven reaction pathway in an intramolecular rearrangement. Science 299, 1555–1557 (2003).

    CAS  Article  Google Scholar 

  36. Frisch, M. J. et al. Gaussian03, revision D.01 (Gaussian, Pittsburgh, Pennsylvania, 2003).

    Google Scholar 

  37. Frisch, M. J. et al. Gaussian09, revision A.02 (Gaussian, Pittsburgh, Pennsylvania, 2009).

    Google Scholar 

  38. Becke, A. D. Density-functional thermochemistry. 3. The role of exact exchange. J. Chem. Phys. 98, 5648–5652 (1993).

    CAS  Article  Google Scholar 

  39. Becke, A. D. A new mixing of Hartree–Fock and local density-function theories. J. Chem. Phys. 98, 1372–1377 (1993).

    CAS  Article  Google Scholar 

  40. Lee, C., Yang, W. & Parr, R. G. Development of the Colle–Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 6, 785–789 (1988).

    Article  Google Scholar 

  41. Stephens, P. J., Devlin, F. J., Chabalowski, C. F. & Frisch, M. J. Ab initio calculation of vibrational absorption and circular-dichroism spectra using density-functional force-fields. J. Phys. Chem. 98, 11623–11627 (1994).

    CAS  Article  Google Scholar 

  42. Matsuda, S. P. T. et al. Mechanistic insights into triterpene synthesis from quantum mechanical calculations. Detection of systematic errors in B3LYP cyclization energies. Org. Biomol. Chem. 4, 530–543 (2006).

    CAS  Article  Google Scholar 

  43. Zhao, Y. & Truhlar, D. G. Hybrid meta density functional theory methods for thermochemistry, thermochemical kinetics, and noncovalent interactions: the MPW1B95 and MPWB1K models and comparative assessments for hydrogen bonding and van der Waals interactions. J. Phys. Chem. A 108, 6908–6918 (2004).

    CAS  Article  Google Scholar 

  44. Zheng, J., Zhao, Y. & Truhlar, D. G. Representative benchmark suites for barrier heights of diverse reaction types and assessment of electronic structure methods for thermochemical kinetics. J. Chem. Theory Comput. 3, 569–582 (2007).

    CAS  Article  Google Scholar 

  45. Fukui, K. The path of chemical reactions – the IRC approach. Acc. Chem. Res. 14, 363–368 (1981).

    CAS  Article  Google Scholar 

  46. Gonzalez, C. & Schlegel, H. B. Reaction path following in mass-weighted internal coordinates. J. Phys. Chem. 94, 5523–5527 (1990).

    CAS  Article  Google Scholar 

  47. Müller, N., Falk, A. & Gsaller, G. Ball & Stick V.4.0a12, Molecular Graphics Application for MacOS Computers (Johannes Kepler University, Linz, 2004).

  48. Kelly, K. K., Hirschi, J. S. & Singleton, D. A. Newtonian kinetic isotope effects. Observation, prediction, and origin of heavy-atom dynamic isotope effects. J. Am. Chem. Soc. 131, 8382–8383 (2009).

    CAS  Article  Google Scholar 

  49. Wang, Z., Hirschi, J. S. & Singleton, D. A. Dynamic matching effects on selectivity in a Diels–Alder reaction, Angew. Chem. Int. Ed. 48, 9156–9159 (2009).

    CAS  Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Dean J. Tantillo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 6362 kb)

Supplementary information

Supplementary movie 1 (MOV 1856 kb)

Supplementary information

Supplementary movie 2 (MOV 3130 kb)

Supplementary information

Supplementary movie 3 (MOV 3999 kb)

Supplementary information

Supplementary movie 4 (MOV 15133 kb)

Supplementary information

Supplementary movie 5 (MOV 14456 kb)

Supplementary information

Supplementary movie 6 (MOV 12249 kb)

Supplementary information

Supplementary movie 7 (MOV 6144 kb)

Supplementary information

Supplementary movie 8 (MOV 9743 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hong, Y., Tantillo, D. Biosynthetic consequences of multiple sequential post-transition-state bifurcations. Nature Chem 6, 104–111 (2014). https://doi.org/10.1038/nchem.1843

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing