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Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues

Nature Chemistry volume 5, pages 886–893 (2013)Cite this article

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Abstract

The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells. Here we describe syntheses of trioxacarcin A, DC-45-A1 and structural analogues by late-stage stereoselective glycosylation reactions of fully functionalized, differentially protected aglycon substrates. Key issues addressed in this work include the identification of an appropriate means to activate and protect each of the two 2-deoxysugar components, trioxacarcinose A and trioxacarcinose B, as well as a viable sequencing of the glycosidic couplings. The convergent, component-based sequence we present allows for rapid construction of structurally diverse, synthetic analogues that would be inaccessible by any other means, in amounts required to support biological evaluation. Analogues that arise from the modification of four of five modular components are assembled in 11 steps or fewer. The majority of these are found to be active in antiproliferative assays using cultured human cancer cells.

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Figure 1: Trioxacarcin A and structural relatives.
Figure 2: Syntheses of DC-45-A1 and the trioxacarcinose B-containing monoglycoside 9.
Figure 3: Model studies led to selection of O-acetyl for protection of the 3-hydroxyl group of trioxacarcinose B.
Figure 4: Modular synthesis of trioxacarcin A.
Figure 5: Fully synthetic trioxacarcin analogues.
Figure 6: Rationalizations of the stereochemical outcome of glycosylation reactions with trioxacarcinose A and B donors.

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Acknowledgements

T.M. acknowledges the Austrian Science Fund for a Schrödinger postdoctoral fellowship (FWF J3000-B11). D.J.S. acknowledges the Department of Defense for a National Defense Science and Engineering Graduate Fellowship. Financial support from the National Institutes of Health (Grant CA047148) is acknowledged. We thank M. Shair for discussions. We thank A. Schumacher for assistance in the preparation of compounds 27 and 28, as detailed in the Supplementary Information. We acknowledge a gift of authentic samples of trioxacarcin A and DC-45-A1 from research scientists at Pfizer Research and Development in Groton, Connecticut, as well as a gift of an authentic sample of trioxacarcin A from G. Sheldrick at Universität Göttingen.

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  1. Thomas Magauer and Daniel J. Smaltz: These authors contributed equally to this work

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  1. Harvard Department of Chemistry and Chemical Biology, Cambridge, 02138, 12 Oxford Street, Massachusetts, USA

    Thomas Magauer, Daniel J. Smaltz & Andrew G. Myers

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Contributions

T.M., D.J.S. and A.G.M. conceived the synthetic route. T.M. and D.J.S. conducted all experimental work and analysed the results. T.M., D.J.S. and A.G.M. wrote the manuscript.

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Correspondence to Andrew G. Myers.

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The authors declare no competing financial interests.

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Magauer, T., Smaltz, D. & Myers, A. Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues. Nature Chem 5, 886–893 (2013). https://doi.org/10.1038/nchem.1746

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