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Synergy of synthesis, computation and NMR reveals correct baulamycin structures

Nature volume 547, pages 436–440 (2017)Cite this article

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Abstract

Small-molecule, biologically active natural products continue to be our most rewarding source of, and inspiration for, new medicines1. Sometimes we happen upon such molecules in minute quantities in unique, difficult-to-reach, and often fleeting environments, perhaps never to be discovered again. In these cases, determining the structure of a molecule—including assigning its relative and absolute configurations—is paramount, enabling one to understand its biological activity. Molecules that comprise stereochemically complex acyclic and conformationally flexible carbon chains make such a task extremely challenging2. The baulamycins (A and B) serve as a contemporary example. Isolated in small quantities and shown to have promising antimicrobial activity, the structure of the conformationally flexible molecules was determined largely through J-based configurational analysis3,4, but has been found to be incorrect. Our subsequent campaign to identify the true structures of the baulamycins has revealed a powerful method for the rapid structural elucidation of such molecules. Specifically, the prediction of nuclear magnetic resonance (NMR) parameters through density functional theory—combined with an efficient sequence of boron-based synthetic transformations, which allowed an encoded (labelled) mixture of natural-product diastereomers to be prepared—enabled us rapidly to pinpoint and synthesize the correct structures.

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Figure 1: Retrosynthetic analysis and synthesis of the originally proposed structures of baulamycin A and B.
Figure 2: Stereochemical analysis and synthesis of fragment A.
Figure 3: Stereochemical analysis and synthesis of fragment B.
Figure 4: Determination of the relative and absolute configurations of baulamycins A and B.

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Acknowledgements

We thank the UK Engineering and Physical Sciences Research Council (EPSRC; grant EP/I038071/1) and the European Research Council (ERC; funding programme FP7; grant 670668) for financial support; and the UK Biotechnology and Biological Sciences Research Council (BBSRC)/EPSRC-funded BrisSynBio Research Centre (L01386X) for providing the 700 MHz NMR spectrometer used. Parts of this work were carried out using the computational facilities of the Advanced Computing Research Centre at the University of Bristol (http://www.bris.ac.uk/acrc/). P.L. thanks Xunta de Galicia, M.A. thanks HEC Pakistan, and J.W. thanks the Shanghai Institute of Organic Chemistry for postdoctoral fellowships. S.Z. thanks the EPSRC Bristol Chemical Synthesis Doctoral Training Centre for a studentship (EP/L015366/1). We thank D. Sherman for providing the raw NMR (free induction decay) data for baulamycin A.

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Author notes

  1. Jingjing Wu, Paula Lorenzo and Siying Zhong: These authors contributed equally to this work.

  2. Muhammad Ali: Department of Chemistry, COMSATS Institute of Information Technology (CIIT), Abbottabad-22060, Pakistan.

Authors and Affiliations

  1. School of Chemistry, University of Bristol, Cantock’s Close, BS8 1TS, Bristol, UK

    Jingjing Wu, Paula Lorenzo, Siying Zhong, Muhammad Ali, Craig P. Butts, Eddie L. Myers & Varinder K. Aggarwal

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Contributions

V.K.A., E.L.M. and C.P.B. designed and led the project. P.L., J.W. and M.A. designed and conducted the synthesis experiments and analysed the data. S.Z. performed computational and NMR studies and analysed the data. All authors contributed to the writing of the manuscript.

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Correspondence to Craig P. Butts, Eddie L. Myers or Varinder K. Aggarwal.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks K.J. Szabó and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Wu, J., Lorenzo, P., Zhong, S. et al. Synergy of synthesis, computation and NMR reveals correct baulamycin structures. Nature 547, 436–440 (2017). https://doi.org/10.1038/nature23265

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