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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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).
The authors declare no competing financial interests.
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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