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Atropselective syntheses of (−) and (+) rugulotrosin A utilizing point-to-axial chirality transfer

Nature Chemistry volume 7, pages 234–240 (2015)Cite this article

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Abstract

Chiral, dimeric natural products containing complex structures and interesting biological properties have inspired chemists and biologists for decades. A seven-step total synthesis of the axially chiral, dimeric tetrahydroxanthone natural product rugulotrosin A is described. The synthesis employs a one-pot Suzuki coupling/dimerization to generate the requisite 2,2′-biaryl linkage. Highly selective point-to-axial chirality transfer was achieved using palladium catalysis with achiral phosphine ligands. Single X-ray crystal diffraction data were obtained to confirm both the atropisomeric configuration and absolute stereochemistry of rugulotrosin A. Computational studies are described to rationalize the atropselectivity observed in the key dimerization step. Comparison of the crude fungal extract with synthetic rugulotrosin A and its atropisomer verified that nature generates a single atropisomer of the natural product.

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Figure 1: Axially chiral, dimeric tetrahydroxanthone natural products and point-to-axial chirality transfer strategy.
Figure 2: Scalable syntheses of enantiopure tetrahydroxanthone monomers.
Figure 3: One-pot Suzuki dimerization of chiral tetrahydroxanthone monomers (+)-18.
Figure 4: Syntheses of (−) and (+)-rugulotrosin A and atrop-rugulotrosin A.
Figure 5: Computational studies for atropselective Suzuki dimerization.

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Acknowledgements

Financial support from the National Institutes of Health (NIH, GM-099920) and Vertex Pharmaceuticals, Inc. (graduate fellowship to T.Q.) is gratefully acknowledged. The authors thank J. Bacon for crystal structure determination, B. Qu and C. Senanayake for providing both (R) and (S)-BI-DIME ligands and E. Lacey for supplying extracts of Penicillium nov. sp. (MST-F8741). Research at the BU-CMD was supported by the NIH (grant GM-067041). This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (grant OCI-1053575).

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Authors and Affiliations

  1. Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, 02215, Massachusetts, USA

    Tian Qin & John A. Porco Jr

  2. Department of Chemistry, University of New Hampshire, Durham, 03824, New Hampshire, USA

    Sarah L. Skraba-Joiner & Richard P. Johnson

  3. The University of Queensland, Institute of Molecular Bioscience, 306 Carmody Road, St Lucia, 4072, Queensland, Australia

    Zeinab G. Khalil & Robert J. Capon

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Contributions

T.Q. and J.A.P. conceived of the project, designed and carried out the experiments, analysed the data and wrote most of the paper. S.L.S-J. and R.P.J. performed computational studies. Z.G.K. and R.J.C. performed natural extract comparisons and biological studies. All authors discussed the results and commented on the manuscript.

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Correspondence to John A. Porco Jr.

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Supplementary information

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Supplementary information (PDF 7041 kb)

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Crystallographic data for compound (-)-19. (CIF 118 kb)

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Crystallographic data for compound (-)-22. (CIF 242 kb)

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Qin, T., Skraba-Joiner, S., Khalil, Z. et al. Atropselective syntheses of (−) and (+) rugulotrosin A utilizing point-to-axial chirality transfer. Nature Chem 7, 234–240 (2015). https://doi.org/10.1038/nchem.2173

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