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Remodelling of the natural product fumagillol employing a reaction discovery approach

Nature Chemistry volume 3, pages 969–973 (2011)Cite this article

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Abstract

In the search for new biologically active molecules, diversity-oriented synthetic strategies break through the limitation of traditional library synthesis by sampling new chemical space. Many natural products can be regarded as intriguing starting points for diversity-oriented synthesis, wherein stereochemically rich core structures may be reorganized into chemotypes that are distinctly different from the parent structure. Ideally, to be suited to library applications, such transformations should be general and involve few steps. With this objective in mind, the highly oxygenated natural product fumagillol has been successfully remodelled in several ways using a reaction-discovery-based approach. In reactions with amines, excellent regiocontrol in a bis-epoxide opening/cyclization sequence can be obtained by size-dependent interaction of an appropriate catalyst with the parent molecule, forming either perhydroisoindole or perhydroisoquinoline products. Perhydroisoindoles can be further remodelled by cascade processes to afford either morpholinone or bridged 4,1-benzoxazepine-containing structures.

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Figure 1: Natural product remodelling using fumagillol.
Figure 2: Mechanistic studies of bis-epoxide ring opening.
Figure 3: Use of amino-acid esters as reaction partners.
Figure 4: Metal triflate catalysed reactions of fumagillol with 2-ethynylaniline.

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Acknowledgements

The authors acknowledge the NIGMS CMLD initiative (P50 GM067041) for financial support, the National Science Foundation for supporting the purchase of NMR (CHE 0619339) and high-resolution mass spectrometry (CHE 0443618) spectrometers, and the Boston University Undergraduate Research Opportunities Program for support to M.C.M. The authors also thank Jia-He Li of Sinova Inc. for the generous donation of fumagillin.

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  1. Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, 590 Commonwealth Avenue, Boston, 02215, Massachusetts, USA

    Bradley R. Balthaser, Meghan C. Maloney, Aaron B. Beeler, John A. Porco Jr & John K. Snyder

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  1. Bradley R. Balthaser
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  2. Meghan C. Maloney
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Contributions

B.R.B. and M.C.M. carried out the experimental work. A.B.B., J.A.P. and J.S.K. provided oversight. B.R.B, J.A.P. and J.S.K. conceived the experiments and wrote the manuscript.

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Correspondence to John A. Porco Jr or John K. Snyder.

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Balthaser, B., Maloney, M., Beeler, A. et al. Remodelling of the natural product fumagillol employing a reaction discovery approach. Nature Chem 3, 969–973 (2011). https://doi.org/10.1038/nchem.1178

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