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Pseudopterosin synthesis from a chiral cross-conjugated hydrocarbon through a series of cycloadditions

Abstract

The pseudopterosins are a family of diterpene marine natural products, which, by virtue of their interesting anti-inflammatory and analgesic properties, have attracted the attentions of many synthetic chemists. The most efficient syntheses reported to date are 14 and 20 steps in the longest linear sequence for chiral pool and enantioselective approaches, respectively, and all start with precursors that are easily mapped onto the natural product structure. Here, we describe an unconventional approach in which a chiral cross-conjugated hydrocarbon is used as the starting material for a series of three cycloadditions. Our approach has led to a significant reduction in the step count required to access these interesting natural products (10 steps chiral pool and 11 steps enantioselective). Furthermore it demonstrates that cross-conjugated hydrocarbons, erroneously considered by many to be too unstable and difficult to handle, are viable precursors for natural product synthesis.

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Figure 1: Strategic bond disconnections pursued in this study.
Figure 2: Two synthetic approaches to enantioenriched substituted 1,1-divinylallene 6.
Figure 3: Total synthesis of pseudopterosin (–)-G–J aglycone employing a diene-transmissive triple DA cycloaddition strategy.

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Acknowledgements

The authors thank R. Kerr and F. Berrué for providing authentic samples of the pseudopterosins, H-G. Schmalz for providing a copy of the PhD thesis of A. Majdalani, S. M. (M.) Tan and E. Lindeboom for preliminary experiments, and A. Herlt for assistance with HPLC. M.N.P-R. acknowledges that this research was undertaken with the assistance of resources provided at the NCI National Facility through the National Computational Merit Allocation Scheme supported by the Australian Government. This work was supported by the Australian Research Council.

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C.G.N., S.L.D., A.L.L. and M.S.S. conceived, designed and carried out the synthetic experiments. A.C.W. performed the crystallographic studies. M.N.P-R. designed and carried out the computational study. All authors discussed and co-wrote the manuscript.

Corresponding authors

Correspondence to Michael N. Paddon-Row or Michael S. Sherburn.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information

Crystallographic data for compound 20 (CIF 31 kb)

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Newton, C., Drew, S., Lawrence, A. et al. Pseudopterosin synthesis from a chiral cross-conjugated hydrocarbon through a series of cycloadditions. Nature Chem 7, 82–86 (2015). https://doi.org/10.1038/nchem.2112

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