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Total synthesis of terpenes via palladium-catalysed cyclization strategy

Abstract

Nature’s synthetic plans to construct molecules have been developed over millions of years of evolution and frequently prove to be among the most sophisticated. Mimicking nature’s route can be a direct and feasible way for synthetic organic chemists to construct complicated molecules. However, lacking nature’s ability to manipulate enzymes often prevents us from reproducing the same route. Modifying nature’s approaches can provide a simpler synthetic alternative to access complex structural target molecules. Here we report a strategy that simplifies the synthesis of terpenes by inverting the order of nature’s two-phase biosynthesis route. We first unite simple molecules into a polyfunctionalized linear polyenyne, with all the desired carbons and oxygens in the targeted places. This compound then undergoes polyenyne cycloisomerization, in the presence of all the functional groups, to give polyoxidized terpenes. The key reaction is a palladium-catalysed polyenyne cycloisomerization that not only tolerates the presence of all of the oxygen functionalities, but also is facilitated by them.

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Fig. 1: Biosynthetic and biomimetic strategies of terpene syntheses from linear precursors.
Fig. 2: Application of Pd-catalysed cyclization strategy in the synthesis of tremulanes.
Fig. 3: Pd-catalysed polyenyne cycloisomerization as a potential tool for the synthesis of terpenes.
Fig. 4: Synthetic sequence and conditions of total synthesis of conocenolide C, 10-acetoxy-conocenolide C and conocenolide E using the Pd-catalysed cyclization strategy.
Fig. 5: Synthetic sequence and conditions for the construction of (+)-10,11,12-trihydroxytremulenone 26 and the 5–8 fused ring through a key acyl radical cyclization as our second stage of cyclization.

Data availability

The data supporting the finding of this study are available in this article and the Supplementary Information.

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Acknowledgements

We thank the Tamaki Foundation and Chugai Pharmaceuticals for their generous, partial funding of our programme.

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B.M.T. and C.M. conceived the idea, designed the experiments, analysed the data and prepared the manuscript. C.M. performed the experiments and collected all the data.

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Correspondence to Barry M. Trost.

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Supplementary information

Supplementary information

General information, detailed experiment procedures, characterization data and spectra of the new products.

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Trost, B.M., Min, C. Total synthesis of terpenes via palladium-catalysed cyclization strategy. Nat. Chem. 12, 568–573 (2020). https://doi.org/10.1038/s41557-020-0439-y

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