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A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials

Nature volume 525, pages 507–510 (2015)Cite this article

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Abstract

Alkaloids, secondary metabolites that contain basic nitrogen atoms, are some of the most well-known biologically active natural products in chemistry and medicine1. Although efficient laboratory synthesis of alkaloids would enable the study and optimization of their biological properties2, their preparation is often complicated by the basicity and nucleophilicity of nitrogen, its susceptibility to oxidation, and its ability to alter reaction outcomes in unexpected ways—for example, through stereochemical instability and neighbouring group participation. Efforts to address these issues have led to the invention of a large number of protecting groups that temper the reactivity of nitrogen3; however, the use of protecting groups typically introduces additional steps and obstacles into the synthetic route. Alternatively, the use of aromatic nitrogen heterocycles as synthetic precursors can attenuate the reactivity of nitrogen and streamline synthetic strategies4. Here we use such an approach to achieve a synthesis of the complex anti-HIV alkaloid (+)-batzelladine B in nine steps (longest linear sequence) from simple pyrrole-based starting materials. The route uses several key transformations that would be challenging or impossible to implement using saturated nitrogen heterocycles and highlights some of the advantages of beginning with aromatic reagents.

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Figure 1: Structure and synthetic analysis of (+)-batzelladine B (1).
Figure 2: Synthesis of the vessel fragment of (+)-batzelladine B (1) and determination of its stereochemistry.
Figure 3: Synthesis of the anchor fragment of (+)-batzelladine B (1).
Figure 4: Coupling of 17 and 27 and completion of the synthesis of (+)-batzelladine B (1).

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Acknowledgements

Financial support from the National Institutes of Health (NRSA fellowship GM110898-01A1 to B.T.P, Chemistry Biology Interface Training Program T32GM067543 to C.E.) and Yale University is acknowledged. We thank B. Mercado for X-ray crystallographic analysis of 19 and K.-p. Wang for assistance with HPLC purification of 1.

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Authors and Affiliations

  1. Department of Chemistry, Yale University, New Haven, 06520, Connecticut, USA

    Brendan T. Parr, Christos Economou & Seth B. Herzon

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  1. Brendan T. Parr
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  2. Christos Economou
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  3. Seth B. Herzon
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Contributions

B.T.P. and C.E. performed and analysed the experiments. All authors contributed to the design of experiments and composition of the manuscript.

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Correspondence to Seth B. Herzon.

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The authors declare no competing financial interests.

Additional information

Crystallographic data for 19 have been deposited at the Cambridge Crystallographic Data Centre as CCDC 1400311.

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Supplementary Information

This file contains Supplementary Tables 1-8, Supplementary Text and Data and a Supplementary Bibliography – see contents page for details. (PDF 8756 kb)

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Parr, B., Economou, C. & Herzon, S. A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials. Nature 525, 507–510 (2015). https://doi.org/10.1038/nature14902

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