RESEARCH HIGHLIGHTS Nature Reviews Chemistry | https://doi.org/10.1038/s41570-019-0150-y | Published online 13 November 2019 NATURAL PRODUCT SYNTHESIS could only be characterized at low temperature. However, 1H and 13C NMR spectra are indicative of its Tricyclic oxonium tamed formation with large downfield shifts of the signals for the three Natural products or secondary formal positive charge on oxygen carbons adjacent to the oxygen and metabolites have hugely diverse (a trialkyloxonium ion) proposed for the protons attached to them. We decided structures. Simple-looking linear for other biosyntheses have proved In addition, a new cross-peak was to try to precursors can, via highly reactive far more elusive. observed in the 1H–13C correlation intermediates, fold up into a variety “The structures of a number spectrum, indicating the formation investigate of complex 3D structures. Writing of Laurencia natural products had of a new transannular bond. 1H and whether these in the Journal of the American originally been misassigned,” explains 13C chemical shifts calculated somewhat Chemical Society, Jonathan Burton Burton. “Our work with Rob Paton on using density functional theory also exotic looking and co-workers from the University calculating the NMR spectra for the favoured the assigned structures and of Oxford, in collaboration with proposed structures of these natural formation of the oxonium ions. species might Robert Paton at Colorado State products led us to earlier proposals of Four different oxonium ions really exist University, describe the synthesis and tricyclic oxonium species. We decided derived from the diastereomers characterization of tricyclic oxonium to try to investigate whether these of laurediol were prepared and intermediates and their conversion somewhat exotic looking species characterized — the formation of into ten different natural products might really exist.” one of these, from 3Z, S,S-laurediol originally isolated from algae of the In the proposed biosyntheses, is pictured. Burton and co-workers genus Laurencia. the highly reactive oxonium ions then investigated the reactions of The proposal of a biosynthetic result from a transannular ring these intermediates with a variety pathway leading to a natural closing reaction with loss of a of nucleophiles, leading directly product is frequently the key to halide ion. Burton and co-workers to ten members of the Laurencia the development of a successful were able to characterize the oxo nium natural product family. “Using a synthetic route, and total synthesis by treatment of the precursor with closely related model compound, remains the gold standard of a silver(I) salt. The thermodynamic we were also able to characterize proof for structure assignment. driving force for the process is the the decomposition pathway of these Carbocationic intermediates in formation of silver bromide, but the oxonium ions, which we believe terpene biosyntheses are well key to the ultimate characterization occurs by a 1,2-hydride shift to form studied; they have been invoked in by NMR spectroscopy was the an oxocarbenium ion,” says Burton. the design of many natural product use of a large non-coordinating Such a decomposition pathway – syntheses and have been isolated counterion, Al[OC(CF3)3]4 , known further highlights the rich chemistry and characterized in the condensed as Krossing’s anion. of these exotic oxonium ions. states. Until now, however, the Even with the use of this “We’d like to continue our corresponding structures bearing a stabilizing anion, the oxonium ions work to try and show that these tricyclic oxonium ions are not only chemically reasonable species OH H but to show definitively that they Br (S) (S) Bromocyclizations O are involved in the biosynthesis O Me HO of these natural products,” says (Z) Br H Burton. “We’d also like to develop 3Z, S,S-laurediol Me the oxonium ion chemistry and AgAl[OC(CF3)3]4 AgBr(s) open up this relatively esoteric area of research to explore its full Br H O Direct derivatization potential for organic chemistry.” into natural H Me O H Br H products Br 10 Stephen G. Davey Cl O O O ORIGINAL article Chan, H. S. S. et al. H O 7 H Synthesis, characterization, and reactivity of Br H complex tricyclic oxonium ions, proposed Me Al[OC(CF3)3]4 intermediates in natural product biosynthesis. Me Full NMR and J. Am. Chem. Soc. 141, 15951–15962 (2019) Credit: Stephen G. Davey/Springer Nature Limited Stephen G. Davey/Springer Nature Credit: DFT characterization NATURE REVIEWS | CHEMISTRY VOLUME 3 | DECEMBER 2019 | 669.