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Multifunctional organoboron compounds for scalable natural product synthesis

Abstract

Efficient catalytic reactions that can generate C–C bonds enantioselectively, and ones that can produce trisubstituted alkenes diastereoselectively, are central to research in organic chemistry. Transformations that accomplish these two tasks simultaneously are in high demand, particularly if the catalysts, substrates and reagents are inexpensive and if the reaction conditions are mild. Here we report a facile multicomponent catalytic process that begins with a chemoselective, site-selective and diastereoselective copper–boron addition to a monosubstituted allene; the resulting boron-substituted organocopper intermediates then participate in a similarly selective allylic substitution. The products, which contain a stereogenic carbon centre, a monosubstituted alkene and an easily functionalizable Z-trisubstituted alkenylboron group, are obtained in up to 89 per cent yield, with more than 98 per cent branch-selectivity and stereoselectivity and an enantiomeric ratio greater than 99:1. The copper-based catalyst is derived from a robust heterocyclic salt that can be prepared in multigram quantities from inexpensive starting materials and without costly purification procedures. The utility of the approach is demonstrated through enantioselective synthesis of gram quantities of two natural products, namely rottnestol and herboxidiene (also known as GEX1A).

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Figure 1: Multicomponent catalytic enantioselective generation of alkenylboron compounds.
Figure 2: Catalytic chemo-, site- and enantioselective multicomponent reactions.
Figure 3: Origins of high efficiency and selectivity.
Figure 4: Enantioselective gram-scale synthesis of rottnestol.
Figure 5: Enantioselective gram-scale synthesis of herboxidiene.

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Acknowledgements

This research was supported by grants from the National Institutes of Health, Institute of General Medical Sciences (GM-47480) and the National Science Foundation (CHE-1111074 and CHE-1362763). F.M. acknowledges a LaMattina graduate fellowship in organic synthesis. We thank M. J. Koh, D. L. Silverio and F. Haeffner for discussions, Boston College for access to computational facilities and Frontier Scientific, Inc., for gifts of B2(pin)2.

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F.M. performed the catalyst studies and method development studies, as well as the total syntheses of rottnestol and herboxidiene. K.P.M. carried out the computational studies. A.H.H. and F.M. conceived the project. A.H.H. designed and directed the investigations and composed the manuscript with revisions provided by the other authors.

Corresponding author

Correspondence to Amir H. Hoveyda.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Information parts 1 and 2. Part 1 contains data regarding catalyst and method development and Part 2 contains spectra data for catalyst and method development. (PDF 22354 kb)

Supplementary Information

This file contains Supplementary Information Part 3, containing spectra data for the total syntheses. (PDF 23626 kb)

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Meng, F., McGrath, K. & Hoveyda, A. Multifunctional organoboron compounds for scalable natural product synthesis. Nature 513, 367–374 (2014). https://doi.org/10.1038/nature13735

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