Article | Published:

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

Nature Chemistry volume 7, pages 8286 (2015) | Download Citation

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.

  • Compound C20H28O2

    (3S,7R,9S,9aR)-3,6,9-Trimethyl-7-(2-methylprop-1-en-1-yl)-2,3,7,8,9,9a-hexahydro-1H-phenalene-4,5-diol

  • Compound C20H28O2

    (3S,7S,9S,9aR)-3,6,9-Trimethyl-7-(2-methylprop-1-en-1-yl)-2,3,7,8,9,9a-hexahydro-1H-phenalene-4,5-diol

  • Compound C20H28O2

    (3R,7S,9R,9aS)-3,6,9-Trimethyl-7-(2-methylprop-1-en-1-yl)-2,3,7,8,9,9a-hexahydro-1H-phenalene-4,5-diol

  • Compound C20H28O2

    (3R,7R,9R,9aS)-3,6,9-Trimethyl-7-(2-methylprop-1-en-1-yl)-2,3,7,8,9,9a-hexahydro-1H-phenalene-4,5-diol

  • Compound C20H28O2

    (4R,6R,6aS,9R)-3,6,9-Trimethyl-4-(2-methylprop-1-en-1-yl)-4,5,6,6a,7,8,9,9a-octahydro-1H-phenalene-1,2(3H)-dione

  • Compound C18H28

    (2R,4R,4aS,7R,E)-1-Ethylidene-4,7-dimethyl-2-(2-methylprop-1-en-1-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene

  • Compound C2O2

    Ethene-1,2-dione

  • Compound C16H24

    (3R,5R,E)-6-Ehylidene-3-methyl-5-(2-methylprop-1-en-1-yl)-1-((Z)-prop-1-en-1-yl)cyclohex-1-ene

  • Compound C6H10

    4-Methyl-1,3-pentadiene

  • Compound C10H14

    (R,Z)-4-((E)-Prop-1-en-1-yl)hepta-2,3,5-triene

  • Compound C4H6O

    (E)-But-2-enal

  • Compound C5H6

    (E)-Pent-3-en-1-yne

  • Compound C7H8O

    (E)-Hept-5-en-3-yn-2-one

  • Compound C7H10O

    (S,E)-Hept-5-en-3-yn-2-ol

  • Compound C4H6O

    (S)-3-Butyn-2-ol

  • Compound C3H5Br

    (E)-1-Bromoprop-1-ene

  • Compound C8H12O3S

    (S,E)-Hept-5-en-3-yn-2-yl methanesulfonate

  • Compound C3H5BrMg

    (Z)-Prop-1-en-1-ylmagnesium bromide

  • Compound C6H8O3

    Ethyl (E)-4-oxobut-2-enoate

  • Compound C16H22O3

    Ethyl (1S,5S,6R,Z)-2-ethylidene-6-formyl-5-methyl-3-((Z)-prop-1-en-1-yl)cyclohex-3-ene-1-carboxylate

  • Compound C19H26O4

    Ethyl (2S,3R,4S,4aS,7S,Z)-1-ethylidene-3,6-diformyl-4,7-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalene-2-carboxylate

  • Compound C17H26O2

    Ethyl (2S,4R,4aS,7R,Z)-1-ethylidene-4,7-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalene-2-carboxylate

  • Compound C18H28

    (2R,4R,4aS,7R,Z)-1-Ethylidene-4,7-dimethyl-2-(2-methylprop-1-en-1-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene

  • Compound C20H31NO2

    (1R,3R,3aS,4R,6aS,7R,9R)-1,4,7-Trimethyl-9-(2-methylprop-1-en-1-yl)-3-nitro-2,3,3a,4,5,6,6a,7,8,9-decahydro-1H-phenalene

  • Compound C20H30O

    (3R,4R,6R,6aS,9R,9aS)-3,6,9-Trimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4,5,6,6a,7,8,9,9a-decahydro-1H-phenalen-1-one

  • Compound C20H30O2

    (3S,4R,6R,6aS,9R,9aS)-2-Hydroxy-3,6,9-trimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4,5,6,6a,7,8,9,9a-decahydro-1H-phenalen-1-one

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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.

Author information

Author notes

    • Andrew L. Lawrence

    Present address: School of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ, UK

Affiliations

  1. Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia

    • Christopher G. Newton
    • , Samuel L. Drew
    • , Andrew L. Lawrence
    • , Anthony C. Willis
    •  & Michael S. Sherburn
  2. School of Chemistry, The University of New South Wales, Sydney, New South Wales 2052, Australia

    • Michael N. Paddon-Row

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

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    Crystallographic data for compound 20

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DOI

https://doi.org/10.1038/nchem.2112

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