Modern approaches to study plant–insect interactions in chemical ecology


Phytochemical variation among plant species is one of the most fascinating and perplexing features of the natural world and has implications for both human health and the functioning of ecosystems. A key area of research on phytochemical variation has focused on insects that feed on plants and the enormous diversity of plant-derived compounds that reduce or deter damage by insects. Empirical studies on the ecology and evolution of these chemically mediated plant–insect interactions have been guided by a long history of theoretical development. However, until recently, such theory was substantially limited by inadequate data, a situation that is rapidly changing as ecologists partner with chemists utilizing the latest technological advances. In this Review, we aim to facilitate the union of ecological theory with modern chemistry by discussing important theoretical frameworks for studying chemical ecology and outlining the steps by which hypotheses on insect–phytochemical interactions can be advanced using current methodologies and statistical approaches. We highlight unique approaches to isolation, synthesis, spectroscopy, metabolomics and genomics relevant to chemical ecology and describe future areas for research that will bring an unprecedented understanding of phytochemical variation.

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Fig. 1
Fig. 2: Crude 1H NMR spectra from leaves of two Piper species.
Fig. 3: Periplanone and mandelalide A structure determination by total synthesis.
Fig. 4: Syntheses of methyl jasmonate and proposed modifications for asymmetric synthesis.
Fig. 5: Early approaches to the biomimetic synthesis of natural products.
Fig. 6: Building diversity via biosynthesis and diversity-oriented synthesis.


  1. 1.

    Fraenkel, G. S. The raison d’être of secondary plant substances. Science 129, 1466–1470 (1959).

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Ehrlich, P. R. & Raven, P. H. Butterflies and plants: a study in coevolution. Evolution 18, 586 (1964).

    Article  Google Scholar 

  3. 3.

    Nicolaou, K. C., Snyder, S. A., Montagnon, T. & Vassilikogiannakis, G. The Diels–Alder reaction in total synthesis. Angew. Chem. Int. Ed. 41, 1668–1698 (2002).

    Article  CAS  Google Scholar 

  4. 4.

    Hay, M. E. & Fenical, W. Marine plant-herbivore interactions: the ecology of chemical defense. Annu. Rev. Ecol. Syst. 19, 111–145 (1988).

    Article  Google Scholar 

  5. 5.

    Felsenstein, J. Phylogenies and the comparative method. Am. Naturalist 125, 1–15 (1985).

    Article  Google Scholar 

  6. 6.

    Eisner, T. & Meinwald, Y. C. Defensive secretion of a caterpillar (Papilio). Science 150, 1733–1735 (1965).

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Meinwald, J. Where might we go from here? J. Chem. Ecol. 40, 222 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Romeo, J. Perspectives in chemical ecology: Into the mainstream. Planta Medica 80, IL16 (2014).

    Article  Google Scholar 

  9. 9.

    Hay, M. E. Challenges and opportunities in marine chemical ecology. J. Chem. Ecol. 40, 216 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Dyer, L. A. New synthesis-back to the future: new approaches and directions in chemical studies of coevolution. J. Chem. Ecol. 37, 669–669 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Jones, C. G. & Firn, R. D. On the evolution of plant secondary chemical diversity. Phil. Trans. R. Soc. Lond. B Biol Sci. 333, 273–280 (1991).

    Article  Google Scholar 

  12. 12.

    Thompson, J. N. The Geographic Mosaic of Coevolution. (Univ. of Chicago Press, 2005).

  13. 13.

    Raguso, R. A. et al. The raison d’être of chemical ecology. Ecology 96, 617–630 (2015).

    Article  PubMed  Google Scholar 

  14. 14.

    Rehr, S. S., Feeny, P. P. & Janzen, D. H. Chemical defence in Central American non-ant-acacias. J. Animal Ecol. 42, 405–416 (1973).

    Article  Google Scholar 

  15. 15.

    Romeo, J. T., Saunders, J. A. & Barbosa, P. Phytochemical Diversity and Redundancy in Ecological Interactions. (Plenum Press, 1996).

  16. 16.

    Berenbaum, M. & Neal, J. J. Synergism between myristicin and xanthotoxin, a naturally cooccurring plant toxicant. J. Chem. Ecol. 11, 1349–1358 (1985).

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Hunter, M. D. The Phytochemical Landscape: Linking Trophic Interactions and Nutrient Dynamics. (Princeton Univ. Press, 2016).

  18. 18.

    Hilker, M. New synthesis: parallels between biodiversity and chemodiversity. J. Chem. Ecol. 40, 225–226 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Richards, L. A. et al. Phytochemical diversity and synergistic effects on herbivores. Phytochem. Rev. 15, 1153–1166 (2016).

    Article  CAS  Google Scholar 

  20. 20.

    Dyer, L. A. et al. Synergistic effects of three Piper amides on generalist and specialist herbivores. J. Chem. Ecol. 29, 2499–2514 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Richards, L. A., Dyer, L. A., Smilanich, A. M. & Dodson, C. D. Synergistic effects of amides from two Piper species on generalist and specialist herbivores. J. Chem. Ecol. 36, 1105–1113 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Tallarida, R. J. Drug Synergism and Dose-Effect Data Analysis. (Chapman & Hall, 2000).

  23. 23.

    Dweck, H. K. M. et al. Pheromones mediating copulation and attraction in Drosophila. Proc. Natl Acad. Sci. USA 112, E2829–E2835 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Ebrahim, S. A. M. et al. Drosophila avoids parasitoids by sensing their semiochemicals via a dedicated olfactory circuit. PLoS Biol. 13, e1002318 (2015).

    Article  CAS  Google Scholar 

  25. 25.

    Whitehead, S. R. & Bowers, M. D. Chemical ecology of fruit defence: synergistic and antagonistic interactions among amides from Piper. Funct. Ecol. 28, 1094–1106 (2014).

    Article  Google Scholar 

  26. 26.

    Jones, C. G., Firn, R. D. & Malcolm, S. B. On the evolution of plant secondary chemical diversity. Phil. Trans. R. Soc. Lond. B Biol Sci. 333, 273–280 (1991).

    Article  Google Scholar 

  27. 27.

    Firn, R. D. & Jones, C. G. Natural products — a simple model to explain chemical diversity. Nat. Prod Rep. 20, 382 (2003).

    CAS  Google Scholar 

  28. 28.

    Becerra, J. X., Noge, K. & Venable, D. L. Macroevolutionary chemical escalation in an ancient plant-herbivore arms race. Proc. Natl Acad. Sci. USA 106, 18062–18066 (2009).

    Article  PubMed  Google Scholar 

  29. 29.

    Kursar, T. A. et al. The evolution of antiherbivore defenses and their contribution to species coexistence in the tropical tree genus Inga. Proc. Natl Acad. Sci. USA 106, 18073–18078 (2009).

    Article  PubMed  Google Scholar 

  30. 30.

    Moore, B., Andrew, R. L., Kulheim, C. & Foley, W. J. Explaining intraspecific diversity in plant secondary metabolites in an ecological context. New Phytol. 201, 733–750 (2014).

    Article  PubMed  Google Scholar 

  31. 31.

    Fiehn, O. Metabolomics — the link between genotypes and phenotypes. Plant Mol. Biol. 48, 155–171 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Glassmire, A. E. et al. Intraspecific phytochemical variation shapes community and population structure for specialist caterpillars. New Phytol. 212, 208–219 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Richards, L. A. et al. Phytochemical diversity drives plant–insect community diversity. Proc. Natl Acad. Sci. USA 112, 10973–10978 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Janzen, D. H. When is it coevolution? Evolution 34, 611–612 (1980).

    Article  PubMed  Google Scholar 

  35. 35.

    Carmona, D., Fitzpatrick, C. R. & Johnson, M. T. Fifty years of co-evolution and beyond: integrating co-evolution from molecules to species. Mol. Ecol. 24, 5315–5329 (2015).

    Article  PubMed  Google Scholar 

  36. 36.

    Parsons, J. A. Isolationof two digitalis-like substances from glandular secretion of a poisonous grasshopper, Poekilocerus bufonius. Klug. J. Physiol. 169, 80 (1963).

    Article  Google Scholar 

  37. 37.

    Honda, K. Chemical basis of differential oviposition by lepidopterous insects. Arch. Insect Biochem. Physiol. 30, 1–23 (1995).

    Article  CAS  Google Scholar 

  38. 38.

    Despres, L., David, J.-P. & Gallet, C. The evolutionary ecology of insect resistance to plant chemicals. Trends Ecol. Evol. 22, 298–307 (2007).

    Article  PubMed  Google Scholar 

  39. 39.

    Agrawal, A. A., Petschenka, G., Bingham, R. A., Weber, M. G. & Rasmann, S. Toxic cardenolides: chemical ecology and coevolution of specialized plant-herbivore interactions. New Phytol. 194, 28–45 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Spencer, K. C. in Chemical Mediation of Coevolution 1st edn (ed. Spencer, K. C.) 1–11 (Elsevier BV, 1988).

  41. 41.

    Brodie, E. D. et al. Parallel arms races between garter snakes and newts involving tetrodotoxin as the phenotypic interface of coevolution. J. Chem. Ecol. 31, 343–356 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Feldman, C. R., Brodie, E. D., Brodie, E. D. & Pfrender, M. E. The evolutionary origins of beneficial alleles during the repeated adaptation of garter snakes to deadly prey. Proc. Natl Acad. Sci. USA 106, 13415–13420 (2009).

    Article  PubMed  Google Scholar 

  43. 43.

    Meiners, T. Chemical ecology and evolution of plant–insect interactions: a multitrophic perspective. Curr. Opin. Insect Sci. 8, 22–28 (2015).

    Article  Google Scholar 

  44. 44.

    Mithofer, A. & Boland, W. Plant defense against herbivores: chemical aspects. Annu. Rev. Plant Biol. 63, 431–450 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Thompson, J. N. The Coevolutionary Process (Univ. of Chicago Press, 1994).

  46. 46.

    Berenbaum, M. R. & Zangerl, A. R. Chemical phenotype matching between a plant and its insect herbivore. Proc. Natl Acad. Sci. USA 95, 13743–13748 (1998).

    Article  CAS  Google Scholar 

  47. 47.

    Zangerl, A. R., Stanley, M. C. & Berenbaum, M. R. Selection for chemical trait remixing in an invasive weed after reassociation with a coevolved specialist. Proc. Natl Acad. Sci. USA 105, 4547–4552 (2008).

    Article  PubMed  Google Scholar 

  48. 48.

    Zangerl, A. R. & Berenbaum, M. R. Phenotype matching in wild parsnip and parsnip webworms: causes and consequences. Evolution 57, 806–815 (2003).

    Article  CAS  Google Scholar 

  49. 49.

    Althoff, D. M., Segraves, K. A. & Johnson, M. T. Testing for coevolutionary diversification: linking pattern with process. Trends Ecol. Evol. 29, 82–89 (2014).

    Article  PubMed  Google Scholar 

  50. 50.

    Hembry, D. H., Yoder, J. B. & Goodman, K. R. Coevolution and the diversification of life. Am. Naturalist 184, 425–438 (2014).

    Article  Google Scholar 

  51. 51.

    Agrawal, A. A., Conner, J. K. & Rasmann, S. in Evolution After Darwin: the First 150 Years (eds Bell, M.A., Futuyma, D. J., Eanes, W. F. & Levinton, J. S.) 243–268 (Oxford Univ. Press, 2010).

  52. 52.

    Fry, J. D. The evolution of host specialization: are trade-offs overrated? Am. Naturalist 148 (Suppl.), S84–S107 (1996).

    Article  Google Scholar 

  53. 53.

    Poisot, T., Bever, J. D., Nemri, A., Thrall, P. H. & Hochberg, M. E. A conceptual framework for the evolution of ecological specialisation. Ecol. Lett. 14, 841–851 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Forister, M. L. et al. Revisiting the evolution of ecological specialization, with emphasis on insect-plant interactions. Ecology 93, 981–991 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Gompert, Z. & Messina, F. J. Genomic evidence that resource-based trade-offs limit host-range expansion in a seed beetle. Evolution 70, 1249–1264 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. 56.

    Futuyma, D. J. & Moreno, B. The evolution of ecological specialization. Annu. Rev. Ecol. Systemat. 19, 207–233 (1988).

    Article  Google Scholar 

  57. 57.

    Zorgo, E. et al. Life history shapes trait heredity by accumulation of loss-of-function alleles in yeast. Mol. Biol. Evol. 29, 1781–1789 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Gompert, Z. et al. The evolution of novel host use is unlikely to be constrained by trade-offs or a lack of genetic variation. Mol. Ecol. 24, 2777–2793 (2015).

    Article  PubMed  Google Scholar 

  59. 59.

    Carrasco, D., Larsson, M. C. & Anderson, P. Insect host plant selection in complex environments. Curr. Opin. Insect Sci. 8, 1–7 (2015).

    Article  Google Scholar 

  60. 60.

    Janz, N. & Nylin, S. The role of female search behaviour in determining host plant range in plant feeding insects: a test of the information processing hypothesis. Proc. R. Soc. Lond. B Biol Sci. 264, 701–707 (1997).

    Article  Google Scholar 

  61. 61.

    Egan, S. P. & Funk, D. J. Individual advantages to ecological specialization: insights on cognitive constraints from three conspecific taxa. Proc. R. Soc. Lond. B Biol. Sci. 273, 843–848 (2006).

    Article  Google Scholar 

  62. 62.

    Baldwin, I. T. Jasmonate-induced responses are costly but benefit plants under attack in native populations. Proc. Natl Acad. Sci. USA 95, 8113–8118 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. 63.

    Massad, T. J., Dyer, L. A. & Vega, C. G. Costs of defense and a test of the carbon-nutrient balance and growth-differentiation balance hypotheses for two co-occurring classes of plant defense. PLoS ONE 7, e47554 (2012).

    Article  CAS  Google Scholar 

  64. 64.

    Stamp, N. Out of the quagmire of plant defense hypotheses. Quarterly Rev. Biol. 78, 23–55 (2003).

    Article  Google Scholar 

  65. 65.

    Cipollini, D., Walters, D. & Voelckel, C. in Annual Plant Reviews (eds Roberts, J. A., Evan, D., McManus, M. T. & Rose, J. K.) 263–307 (Wiley-Blackwell, 2014).

  66. 66.

    Smilanich, A. M., Fincher, R. M. & Dyer, L. A. Does plant apparency matter? Thirty years of data provide limited support but reveal clear patterns of the effects of plant chemistry on herbivores. New Phytol. 210, 1044–1057 (2016).

    Article  PubMed  Google Scholar 

  67. 67.

    McKey, D. Adaptive patterns in alkaloid physiology. Am. Naturalist 108, 305–320 (1974).

    Article  Google Scholar 

  68. 68.

    Rosenthal, G. A. & Janzen, D. H. Herbivores: Their Interactions with Secondary Plant Metabolites. Vol. 1 (Academic Press, 1979).

  69. 69.

    Feeney, P. in Biochemical Interactions Between Plants and Insects (eds Wallace, J. W. & Mansell, R. L.) 1–40 (Springer, 1976).

  70. 70.

    Rhoades, D. F. & Cates, R. G. in Biochemical Interaction Between Plants and Insects (eds Wallace, J. W. & Mansell, R. L.) 168–213 (Springer, 1976).

  71. 71.

    Bryant, J. P., Chapin, F. S. & Klein, D. R. Carbon/nutrient balance of boreal plants in relation to vertebrate herbivory. Oikos 40, 357 (1983).

    Article  CAS  Google Scholar 

  72. 72.

    Coley, P. D., Bryant, J. P. & Chapin, F. S. Resource availability and plant antiherbivore defense. Science 230, 895–899 (1985).

    Article  CAS  Google Scholar 

  73. 73.

    Herms, D. A. & Mattson, W. J. The dilemma of plants: to grow or defend. Quarterly Rev. Biol. 67, 283–335 (1992).

    Article  Google Scholar 

  74. 74.

    Bezemer, T. M. & Jones, T. H. Plant-insect herbivore interactions in elevated atmospheric CO2: quantitative analyses and guild effects. Oikos 82, 212 (1998).

    Article  Google Scholar 

  75. 75.

    Koricheva, J., Larsson, S., Haukioja, E., Keinänen, M. & Keinanen, M. Regulation of woody plant secondary metabolism by resource availability: hypothesis testing by means of meta-analysis. Oikos 83, 212 (1998).

    Article  CAS  Google Scholar 

  76. 76.

    Zvereva, E. L. & Kozlov, M. V. Consequences of simultaneous elevation of carbon dioxide and temperature for plant-herbivore interactions: a metaanalysis. Global Change Biol. 12, 27–41 (2006).

    Article  Google Scholar 

  77. 77.

    Stiling, P. & Cornelissen, T. How does elevated carbon dioxide (CO2) affect plant–herbivore interactions? A field experiment and meta-analysis of CO2-mediated changes on plant chemistry and herbivore performance. Global Change Biol. 13, 1823–1842 (2007).

    Article  Google Scholar 

  78. 78.

    Schuman, M. C. & Baldwin, I. T. The layers of plant responses to insect herbivores. Annu. Rev. Entomol. 61, 373–394 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. 79.

    Duffey, S. S. & Stout, M. J. Antinutritive and toxic components of plant defense against insects. Arch. Insect Biochem. Physiol. 32, 3–37 (1996).

    Article  CAS  Google Scholar 

  80. 80.

    Price, P. W. et al. Interactions among three trophic levels: influence of plants on interactions between insect herbivores and natural enemies. Annu. Rev. Ecol. Systemat. 11, 41–65 (1980).

    Article  Google Scholar 

  81. 81.

    Rosenthal, G. A. & Berenbaum, M. R. Herbivores: Their Interactions With Secondary Plant Metabolites: Ecological and Evolutionary Processes. Vol. 2 (Academic Press, 2012).

  82. 82.

    Rascio, N. & Navari-Izzo, F. Heavy metal hyperaccumulating plants: How and why do they do it? And what makes them so interesting? Plant Sci. 180, 169–181 (2011).

    Article  CAS  Google Scholar 

  83. 83.

    Berenbaum, M. Coumarins and caterpillars: a case for coevolution. Evolution 37, 163 (1983).

    Article  CAS  PubMed  Google Scholar 

  84. 84.

    Cornell, H. V. & Hawkins, B. A. Accumulation of native parasitoid species on introduced herbivores: a comparison of hosts as natives and hosts as invaders. Am. Naturalist 141, 847–865 (1993).

    Article  CAS  Google Scholar 

  85. 85.

    Jeschke, V., Gershenzon, J. & Vassão, D. G. in Advances in Botanical Research Vol. 80 (ed. Stanislav, S.) 199–245 (Academic Press, 2016).

  86. 86.

    Dyer, L. A. Tasty generalists and nasty specialists? Antipredator mechanisms tropical Lepidopteran larvae. Ecology 76, 1483–1496 (1995).

    Article  Google Scholar 

  87. 87.

    Ode, P. J. Plant chemistry and natural enemy fitness: effects on herbivore and natural enemy interactions. Annu. Rev. Entomol. 51, 163–185 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. 88.

    Smilanich, A. M., Dyer, L. A., Chambers, J. Q. & Bowers, M. D. Immunological cost of chemical defence and the evolution of herbivore diet breadth. Ecol. Lett. 12, 612–621 (2009).

    Article  PubMed  Google Scholar 

  89. 89.

    Dyer, L. A. in Tropical Forest Community Ecology (eds Carson, W. P. & Schnitzer, S. A.) 275-293 (Blackwell Publishing, 2008).

  90. 90.

    Pearson, C. V., Massad, T. J. & Dyer, L. A. Diversity cascades in alfalfa fields: from plant quality to agroecosystem diversity. Environ. Entomol. 37, 947–955 (2008).

    Article  PubMed  Google Scholar 

  91. 91.

    Martinsen, G. D., Driebe, E. M. & Whitham, T. G. Indirect interactions mediated by changing plant chemistry: beaver browsing benefits beetles. Ecology 79, 192 (1998).

    Article  Google Scholar 

  92. 92.

    Wimp, G. M. et al. Plant genetics predicts intra-annual variation in phytochemistry and arthropod community structure. Mol. Ecol. 16, 5057–5069 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. 93.

    Kessler, A. The information landscape of plant constitutive and induced secondary metabolite production. Curr. Opin. Insect Sci. 8, 47–53 (2015).

    Article  Google Scholar 

  94. 94.

    Turlings, T. C. J., Tumlinson, J. H. & Lewis, W. J. Exploitation of herbivore-induced plant odors by host-seeking parasitic wasps. Science 250, 1251–1253 (1990).

    Article  CAS  PubMed  Google Scholar 

  95. 95.

    Muller, M. S. et al. Tri-trophic effects of plant defenses: chickadees consume caterpillars based on host leaf chemistry. Oikos 114, 507–517 (2006).

    Article  CAS  Google Scholar 

  96. 96.

    Poelman, E. H. et al. Hyperparasitoids use herbivore-induced plant volatiles to locate their parasitoid host. PLoS Biol. 10, e1001435 (2012).

    Article  CAS  Google Scholar 

  97. 97.

    Aldrich, J. R. et al. Insect chemical ecology research in the United States Department of Agriculture — Agricultural Research Service. Pest Management Sci. 59, 777–787 (2003).

    Article  CAS  Google Scholar 

  98. 98.

    Nicolaou, K. C. & Snyder, S. A. Chasing molecules that were never there: misassigned natural products and the role of chemical synthesis in modern structure elucidation. Angew. Chem. Int. Ed Engl. 44, 1012–1044 (2005).

    Article  PubMed  Google Scholar 

  99. 99.

    Still, W. C. (.+-.)-Periplanone-B. Total synthesis and structure of the sex excitant pheromone of the American cockroach. J. Am. Chem. Soc. 101, 2493–2495 (1979).

    Article  CAS  Google Scholar 

  100. 100.

    Willwacher, J., Heggen, B., Wirtz, C., Thiel, W. & Fürstner, A. Total synthesis, stereochemical revision, and biological reassessment of mandelalide A: chemical mimicry of intrafamily relationships. Chemistry 21, 10416–10430 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. 101.

    Veerasamy, N. et al. Enantioselective total synthesis of mandelalide A and isomandelalide A: discovery of a cytotoxic ring-expanded isomer. J. Am. Chem. Soc. 138, 770–773 (2016).

    Article  CAS  PubMed  Google Scholar 

  102. 102.

    Nguyen, M. H., Imanishi, M., Kurogi, T., Amos, B. & Smith, I. Total synthesis of (−)-mandelalide A exploiting anion relay chemistry (ARC): identification of a type II ARC/CuCN cross-coupling protocol. J. Am. Chem. Soc. 138, 3675–3678 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Snyder, K. M. et al. Towards theory driven structure elucidation of complex natural products: mandelalides and coibamide A. Org. Biomol. Chem. 14, 5826–5831 (2016).

    Article  CAS  PubMed  Google Scholar 

  104. 104.

    Dunn, W. B. et al. Mass appeal: metabolite identification in mass spectrometry-focused untargeted metabolomics. Metabolomics 9, 44–66 (2013).

    Article  CAS  Google Scholar 

  105. 105.

    Kim, J. H., Lee, B. W., Schroeder, F. C. & Jander, G. Identification of indole glucosinolate breakdown products with antifeedant effects on Myzus persicae (green peach aphid). Plant J. 54, 1015–1026 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. 106.

    Dyer, L. A., Dodson, C. D., Beihoffer, J. & Letourneau, D. K. Trade-offs in antiherbivore defenses in Piper cenocladum: ant mutualists versus plant secondary metabolites. J. Chem. Ecol. 27, 581–592 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. 107.

    Dodson, C. D., Dyer, L. A., Searcy, J., Wright, Z. & Letourneau, D. K. Cenocladamide, a dihydropyridone alkaloid from Piper cenocladum. Phytochemistry 53, 51–54 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. 108.

    Dyer, L. A. et al. Ecological causes and consequences of variation in defensive chemistry of a neotropical shrub. Ecology 85, 2795–2803 (2004).

    Article  Google Scholar 

  109. 109.

    Stökl, J., Hofferberth, J., Pritschet, M., Brummer, M. & Ruther, J. Stereoselective chemical defense in the Drosophila parasitoid Leptopilina heterotoma is mediated by (−)-iridomyrmecin and (+)-isoiridomyrmecin. J. Chem. Ecol. 38, 331–339 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. 110.

    Rasmann, S. et al. Recruitment of entomopathogenic nematodes by insect-damaged maize roots. Nature 434, 732–737 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. 111.

    Beckett, J. S., Beckett, J. D. & Hofferberth, J. E. A divergent approach to the diastereoselective synthesis of several ant-associated iridoids. Org. Lett. 12, 1408–1411 (2010).

    Article  CAS  PubMed  Google Scholar 

  112. 112.

    Richards, L. A. et al. Synergistic effects of iridoid glycosides on the survival, development and immune response of a specialist caterpillar, Junonia coenia (Nymphalidae). J. Chem. Ecol. 38, 1276–1284 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. 113.

    Azmir, J. et al. Techniques for extraction of bioactive compounds from plant materials: a review. J. Food Eng. 117, 426–436 (2013).

    Article  CAS  Google Scholar 

  114. 114.

    Armenta, S., Garrigues, S. & de la Guardia, M. The role of green extraction techniques in Green Analytical Chemistry. Trends Analyt. Chem. 71, 2–8 (2015).

    Article  CAS  Google Scholar 

  115. 115.

    Bucar, F., Wube, A. & Schmid, M. Natural product isolation — how to get from biological material to pure compounds. Nat. Prod. Rep. 30, 525–545 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. 116.

    Demole, E., Lederer, E. & Mercier, D. Isolement et détermination de la structure du jasmonate de méthyle, constituant odorant caractéristique de l’essence de jasmin. Helv. Chim. Acta 45, 675–685 (1962).

    Article  CAS  Google Scholar 

  117. 117.

    Sisido, K., Kurozumi, S. & Utimoto, K. Synthesis of methyl dl-jasmonate. J. Org. Chem. 34, 2661–2664 (1969).

    Article  CAS  Google Scholar 

  118. 118.

    Luo, F. T. & Negishi, E. Nickel- or palladium-catalyzed cross coupling. 27. Palladium-catalyzed allylation of lithium 3-alkenyl-1-cyclopentenolates-triethylborane and its application to a selective synthesis of methyl (Z)-jasmonate. Tetrahedron Lett. 26, 2177–2180 (1985).

    Article  CAS  Google Scholar 

  119. 119.

    Kataoka, H., Yamada, T., Goto, K. & Tsuji, J. An efficient synthetic method of methyl (±)-jasmonate. Tetrahedron 43, 4107–4112 (1987).

    Article  CAS  Google Scholar 

  120. 120.

    Yoshioka, A. & Yamada, T. Development of methyl (±)-jasmonate production process on an industrial scale. J. Synthet. Org. Chem., Japan 48, 56–64 (1990).

    Article  CAS  Google Scholar 

  121. 121.

    Farmer, E. E. & Ryan, C. A. Interplant communication: airborne methyl jasmonate induces synthesis of proteinase inhibitors in plant leaves. Proc. Natl Acad. Sci. USA 87, 7713–7716 (1990).

    Article  CAS  PubMed  Google Scholar 

  122. 122.

    Posner, G. H. & Asirvatham, E. A short, asymmetric synthesis of natural (-)-methyl jasmonate. J. Org. Chem. 50, 2589–2591 (1985).

    Article  CAS  Google Scholar 

  123. 123.

    Weinges, K., Gethöffer, H., Huber-Patz, U., Rodewald, H. & Irngartinger, H. Chemie und Stereochemie der Iridoide, IX. EPC-Synthese von (1 R,2 R,2-Z)-(−)-Methyl-jasmonat aus Catalpol – Kristall- und Molekularstruktur von Methyl-dehydrojasmonat-semicarbazon. Liebigs Ann. Chem. 1987, 361–366 (1987).

    Article  Google Scholar 

  124. 124.

    Takeda, H., Watanabe, H. & Nakada, M. Asymmetric total synthesis of enantiopure (−)-methyl jasmonate via catalytic asymmetric intramolecular cyclopropanation of α-diazo-β-keto sulfone. Tetrahedron 62, 8054–8063 (2006).

    Article  CAS  Google Scholar 

  125. 125.

    Quinkert, G., Adam, F. & Dürner, G. Asymmetric synthesis of methyl jasmonate. Angew. Chem. Int. Ed. 21, 856–856 (1982).

    Article  Google Scholar 

  126. 126.

    Jansen, D. J. & Shenvi, R. A. Synthesis of (−)-neothiobinupharidine. J. Am. Chem. Soc. 135, 1209–1212 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. 127.

    Germain, N., Guénée, L., Mauduit, M. & Alexakis, A. Asymmetric conjugate addition to α-substituted enones/enolate trapping. Org. Lett. 16, 118–121 (2014).

    Article  CAS  PubMed  Google Scholar 

  128. 128.

    Mase, N. et al. Organocatalytic enantioselective Michael additions of malonates to 2-cyclopentenone. Synlett 2010, 2340–2344 (2010).

    Article  CAS  Google Scholar 

  129. 129.

    Zheljazkov, V. D., Shiwakoti, S., Jeliazkova, E. A. & Astatkie, T. in Medicinal and Aromatic Crops: Production, Phytochemistry, and Utilization (eds Jeliazkov (Zheljazkov), V D. & Cantrell, C. L.) 145–166 (ACS Publications, 2016).

  130. 130.

    Liu, W. C., Gong, T. & Zhu, P. Advances in exploring alternative Taxol sources. RSC Adv. 6, 48800–48809 (2016).

    Article  CAS  Google Scholar 

  131. 131.

    Li, D., Baldwin, I. T. & Gaquerel, E. Beyond the canon: within-plant and population-level heterogeneity in jasmonate signaling engaged by plant-insect interactions. Plants 5, 14 (2016).

    Article  PubMed Central  Google Scholar 

  132. 132.

    Chapuis, C. et al. Route scouting towards a methyl jasmonate precursor. Helvet. Chim. Acta 99, 95–109 (2016).

    Article  CAS  Google Scholar 

  133. 133.

    Robinson, R. LXIII. — A synthesis of tropinone. J. Chem. Soc., Trans. 111, 762–768 (1917).

    Article  CAS  Google Scholar 

  134. 134.

    Robinson, R. LXXV. — A theory of the mechanism of the phytochemical synthesis of certain alkaloids. J. Chem. Soc., Trans. 111, 876–899 (1917).

    Article  CAS  Google Scholar 

  135. 135.

    Yoder, R. A. & Johnston, J. N. A case study in biomimetic total synthesis: polyolefin carbocyclizations to terpenes and steroids. Chem. Rev. 105, 4730–4756 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Stork, G. & Burgstahler, A. W. The stereochemistry of polyene cyclization. J. Am. Chem. Soc. 77, 5068–5077 (1955).

    Article  CAS  Google Scholar 

  137. 137.

    Gamboni, G., Schinz, H. & Eschenmoser, A. Über den sterischen Verlauf der säurekatalysierten Cyclisation in der Terpenreihe. Cyclisation der cis-7-Methyl-octadien-(2,6)-säure-(1). Health Care Anal. 37, 964–971 (1954).

    CAS  Google Scholar 

  138. 138.

    de la Torre, M. C. & Sierra, M. A. Comments on recent achievements in biomimetic organic synthesis. Angew. Chem. Int. Ed. 43, 160–181 (2004).

    Article  Google Scholar 

  139. 139.

    Nielsen, T. E. & Schreiber, S. L. Towards the optimal screening collection: a synthesis strategy. Angew. Chem. Int. Ed. 47, 48–56 (2008).

    Article  CAS  Google Scholar 

  140. 140.

    Lee, D., Sello, J. K. & Schreiber, S. L. Pairwise use of complexity-generating reactions in diversity-oriented organic synthesis. Org. Lett. 2, 709–712 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. 141.

    Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964–1969 (2000).

    Article  CAS  Google Scholar 

  142. 142.

    Burke, M. D. & Schreiber, S. L. A planning strategy for diversity-oriented synthesis. Angew. Chem. Int. Ed. 43, 46–58 (2004).

    Article  CAS  Google Scholar 

  143. 143.

    Kato, N. et al. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature 538, 344–349 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Kurita, K. L., Glassey, E. & Linington, R. G. Integration of high-content screening and untargeted metabolomics for comprehensive functional annotation of natural product libraries. Proc. Natl Acad. Sci. USA 112, 11999–12004 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. 145.

    Wang, M. et al. Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nat. Biotechnol. 34, 828–837 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Kuhlisch, C. & Pohnert, G. Metabolomics in chemical ecology. Nat. Prod. Rep. 32, 937–955 (2015).

    Article  CAS  PubMed  Google Scholar 

  147. 147.

    Poulson-Ellestad, K. L. et al. Metabolomics and proteomics reveal impacts of chemically mediated competition on marine plankton. Proc. Natl Acad. Sci. USA 111, 9009–9014 (2014).

    Article  CAS  PubMed  Google Scholar 

  148. 148.

    Bais, P. et al. a web portal for plant metabolomics experiments. Plant Physiol. 152, 1807–1816 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Guo, A. C. et al. ECMDB: the E. coli metabolome database. Nucleic Acids Res. 41, D625–D630 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Jewison, T. et al. YMDB: the yeast metabolome database. Nucleic Acids Res. 40, D815–D820 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Mardis, E. R. Next-generation sequencing platforms. Annu. Rev. Anal. Chem. 6, 287–303 (2013).

    Article  CAS  Google Scholar 

  152. 152.

    Ellegren, H. Genome sequencing and population genomics in non-model organisms. Trends Ecol. Evol. 29, 51–63 (2014).

    Article  PubMed  Google Scholar 

  153. 153.

    Koboldt, D. C., Steinberg, K. M., Larson, D. E., Wilson, R. K. & Mardis, E. R. The next-generation sequencing revolution and its impact on genomics. Cell 155, 27–38 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Rubin, C.-J. et al. Whole-genome resequencing reveals loci under selection during chicken domestication. Nature 464, 587–591 (2010).

    Article  CAS  PubMed  Google Scholar 

  155. 155.

    McGettigan, P. A. Transcriptomics in the RNA-seq era. Curr. Opin. Chem. Biol. 17, 4–11 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. 156.

    Deagle, B. E., Jones, F. C., Absher, D. M., Kingsley, D. M. & Reimchen, T. E. Phylogeography and adaptation genetics of stickleback from the Haida Gwaii archipelago revealed using genome-wide single nucleotide polymorphism genotyping. Mol. Ecol. 22, 1917–1932 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Narum, S. R., Buerkle, C. A., Davey, J. W., Miller, M. R. & Hohenlohe, P. A. Genotyping-by-sequencing in ecological and conservation genomics. Mol. Ecol. 22, 2841–2847 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Adamski, J. Genome-wide association studies with metabolomics. Genome Med. 4, 34 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Carreno-Quintero, N., Bouwmeester, H. J. & Keurentjes, J. J. B. Genetic analysis of metabolome–phenotype interactions: from model to crop species. Trends Genet. 29, 41–50 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. 160.

    Keurentjes, J. J. B. et al. The genetics of plant metabolism. Nat. Genet. 38, 842–849 (2006).

    Article  CAS  PubMed  Google Scholar 

  161. 161.

    Chan, E. K. F., Rowe, H. C., Hansen, B. G. & Kliebenstein, D. J. The complex genetic architecture of the metabolome. PLoS Genet. 6, e1001198 (2010).

    Article  CAS  Google Scholar 

  162. 162.

    Fiehn, O. et al. Metabolite profiling for plant functional genomics. Nat. Biotechnol. 18, 1157–1161 (2000).

    Article  CAS  Google Scholar 

  163. 163.

    Matsuda, F. et al. Dissection of genotype-phenotype associations in rice grains using metabolome quantitative trait loci analysis. Plant J. 70, 624–636 (2012).

    Article  CAS  PubMed  Google Scholar 

  164. 164.

    Schauer, N. et al. Comprehensive metabolic profiling and phenotyping of interspecific introgression lines for tomato improvement. Nat. Biotechnol. 24, 447–454 (2006).

    Article  CAS  PubMed  Google Scholar 

  165. 165.

    Riedelsheimer, C. et al. Genome-wide association mapping of leaf metabolic profiles for dissecting complex traits in maize. Proc. Natl Acad. Sci. 109, 8872–8877 (2012).

    Article  PubMed  Google Scholar 

  166. 166.

    Wen, W. et al. Metabolome-based genome-wide association study of maize kernel leads to novel biochemical insights. Nat. Commun. 5, 3438 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Feng, J. et al. Characterization of metabolite quantitative trait loci and metabolic networks that control glucosinolate concentration in the seeds and leaves of Brassica napus. New Phytol. 193, 96–108 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Lau, W. & Sattely, E. S. Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone. Science 349, 1224–1228 (2015).

    Article  CAS  PubMed  Google Scholar 

  169. 169.

    Nützmann, H. W., Huang, A. & Osbourn, A. Plant metabolic clusters — from genetics to genomics. New Phytol. 211, 771–789 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Mitchell-Olds, T. Arabidopsis thaliana and its wild relatives: a model system for ecology and evolution. Trends Ecol. Evol. 16, 693–700 (2001).

    Article  Google Scholar 

  171. 171.

    Agrawal, A. A. Current trends in the evolutionary ecology of plant defence. Funct. Ecol. 25, 420–432 (2011).

    Article  Google Scholar 

  172. 172.

    Wilson, J. S. et al. Host conservatism, host shifts and diversification across three trophic levels in two Neotropical forests. J. Evol. Biol. 25, 532–546 (2012).

    Article  CAS  PubMed  Google Scholar 

  173. 173.

    Coley, P. D. & Kursar, T. A. On tropical forests and their pests. Science 343, 35–36 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. 174.

    Coley, P. D. et al. Divergent defensive strategies of young leaves in two species of Inga. Ecology 86, 2633–2643 (2005).

    Article  Google Scholar 

  175. 175.

    Endara, M.-J. et al. Divergent evolution in antiherbivore defences within species complexes at a single Amazonian site. J. Ecol. 103, 1107–1118 (2015).

    Article  Google Scholar 

  176. 176.

    Brenes-Arguedas, T. et al. Contrasting mechanisms of secondary metabolite accumulation during leaf development in two tropical tree species with different leaf expansion strategies. Oecologia 149, 91–100 (2006).

    Article  PubMed  Google Scholar 

  177. 177.

    Wu, S.-B., Meyer, R. S., Whitaker, B. D., Litt, A. & Kennelly, E. J. A new liquid chromatography–mass spectrometry-based strategy to integrate chemistry, morphology, and evolution of eggplant (Solanum) species. J. Chromatogr. A 1314, 154–172 (2013).

    Article  CAS  PubMed  Google Scholar 

  178. 178.

    McKey, D., Rosenthal, G. A. & Janzen, D. H. in Herbivores: Their Interaction With Secondary Plant Metabolites Vol. 1 (Rosenthal, G. A. & Berenbaum, M. R.) 55–133 (Academic Press, 1979).

  179. 179.

    Ohnmeiss, T. E. & Baldwin, I. T. Optimal defense theory predicts the ontogeny of an induced nicotine defense. Ecology 81, 1765 (2000).

    Article  Google Scholar 

  180. 180.

    Bolker, J. Model organisms: There’s more to life than rats and flies. Nature 491, 31–33 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. 181.

    Hamilton, J. G., Zangerl, A. R., DeLucia, E. H. & Berenbaum, M. R. The carbon-nutrient balance hypothesis: its rise and fall. Ecol. Lett. 4, 86–95 (2001).

    Article  Google Scholar 

  182. 182.

    Watrous, J. et al. Mass spectral molecular networking of living microbial colonies. Proc. Natl Acad. Sci. USA 109, E1743–E1752 (2012).

    Article  PubMed  Google Scholar 

  183. 183.

    Cordell, G. A. Biosynthesis of sesquiterpenes. Chem. Rev. 76, 425–460 (1976).

    Article  CAS  Google Scholar 

  184. 184.

    Tetzlaff, C. N. et al. A gene cluster for biosynthesis of the sesquiterpenoid antibiotic pentalenolactone in Streptomyces avermitilis. Biochemistry 45, 6179–6186 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    De Kraker, J.-W., Franssen, M. C., Joerink, M., De Groot, A. & Bouwmeester, H. J. Biosynthesis of costunolide, dihydrocostunolide, and leucodin. Demonstration of cytochrome P450-catalyzed formation of the lactone ring present in sesquiterpene lactones of chicory. Plant Physiol. 129, 257–268 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Bülow, N. & König, W. A. The role of germacrene D as a precursor in sesquiterpene biosynthesis: investigations of acid catalyzed, photochemically and thermally induced rearrangements. Phytochemistry 55, 141–168 (2000).

    Article  PubMed  Google Scholar 

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The authors dedicate this article to Professor Jerrold Meinwald for his transformative contributions to the field of chemical ecology. The authors thank M.A. Stanton and two anonymous reviewers for their excellent edits and suggestions to this manuscript. The authors’ research was funded by the National Science Foundation (DEB-1442103 and DEB-1638793), the FAPESP (São Paulo Research Foundation, 2014/50316-7) and by a generous donation from the Hitchcock Fund for Chemical Ecology Research.

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L.A.D., C.S.P., K.M.O., L.A.R., T.J.M., A.M.S., M.L.F., T.L.P., L.M.G., P.J.H., A.E.E., A.E.G., J.G.H., C.M., S.Y., N.A.P., N.D.M., J.P.J., H.L.S., O.S. and C.S.J. researched the data for the article and wrote the article. All authors contributed to discussion of the content and reviewed and/or edited the manuscript before revision.

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Correspondence to Christopher S. Jeffrey.

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Plant secondary metabolites

Organic compounds not associated with primary metabolic functions; in plants in particular, these compounds have been the subject of research in biomedical fields and in chemical ecology, in which they have been found to have largely defensive functions (for example, anti-herbivore and antibacterial functions).


The evolution of reciprocal adaptation in response to reciprocal natural selection occurring with respect to a pair or complex of interacting species; often hypothesized to be associated with adaptive radiation and co-diversification.


Combined effects of compounds in a mixture that are greater than the sum of effects for the individual compounds acting in isolation.


The evolutionary process that results in the formation of new species by the divergence of an ancestral population into two genetically independent populations. This process is most often characterized by the evolution of reproductive isolation and the subsequent independent evolution of lineages.


Organisms characterized by a unique form of parasitic lifestyle, in which the host is killed by the developing juvenile stage; the most diverse taxa, the wasps (insect order Hymenoptera) and flies (insect order Diptera), have a dramatic influence on the ecology of terrestrial ecosystems.

Antagonistic pleiotropy

A type of genetic architecture in which a single genetic locus affects more than one trait (which can include performance or fitness in more than one environment), with effects of one trait (or in one environment) being positive and effects of the other trait (or environment) being negative.

Dereplication methods

Fast identification of compounds using orthogonal physicochemical characteristics to compare spectroscopic data with molecular features gleaned from libraries of known compounds and to confirm identifications.


Phytochemicals that have antibacterial or antifungal properties.

Next-generation sequencing

Modern DNA sequencing platforms that leverage direct sequencing by synthesis technologies to simultaneously determine the DNA sequences of millions or hundreds of millions of DNA fragments. Also known as high-throughput or massively parallel sequencing, these methods have revolutionized genomics.

RNA sequencing

The use of next-generation DNA sequencing approaches to characterize and quantify RNA from biological samples. RNA extracted from tissue is converted into cDNA and directly sequenced on next-generation sequencing platforms such as Illumina. These approaches allow for efficient characterization of the coding regions of genomes (for example, transcriptome sequencing) and for analysis of differential gene expression.

Genome-wide association studies

Observational studies of a genome-wide set of genetic variants in a sample of phenotypically variable individuals aimed at detecting specific variants in which genotypic variation is associated with phenotypic variation.

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Dyer, L.A., Philbin, C.S., Ochsenrider, K.M. et al. Modern approaches to study plant–insect interactions in chemical ecology. Nat Rev Chem 2, 50–64 (2018).

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