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Forming all-carbon quaternary stereogenic centres in acyclic systems from alkynes

Nature volume 490, pages 522–526 (2012)Cite this article

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Abstract

The formation of all-carbon quaternary stereocentres in acyclic systems is one of the most difficult contemporary challenges in modern synthetic organic chemistry1,2. Particularly challenging is the preparation of all-carbon quaternary stereocentres in aldol adducts3; this difficulty is problematic because the aldol reaction represents one of the most valuable chemical transformations in organic synthesis4. The main problem that limits the formation of these stereocentres is the absence of an efficient method of preparing stereodefined trisubstituted enolates in acyclic systems5,6,7,8. Here we describe a different approach that involves the formation of two new stereogenic centres—including the all-carbon quaternary one—via a combined carbometalation–oxidation reaction of an organocuprate to give a stereodefined trisubstituted enolate. We use this method to generate a series of aldol and Mannich products from ynamides with excellent diastereomeric and enantiomeric ratios and moderate yields.

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Figure 1: General strategies for the formation of stereodefined enolates.
Figure 2: Proposed approach.
Figure 3: Combined carbometalation-oxidation sequence.
Figure 4: Application to the aldol and Mannich reactions.
Figure 5: Cleavage of the auxiliaries.

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Data deposits

Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, accession numbers CCDC 881250 (8), CCDC 881248 (5a) and CCDC 881249 (6a).

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Acknowledgements

This research was supported by the Israel Science Foundation administrated by the Israel Academy of Sciences and Humanities (140/12), and by the Fund for Promotion of Research at the Technion. L.L. thanks the Bayer-Stiftung for financial support. I.M. is holder of the Sir Michael and Lady Sobell Academic Chair.

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Authors and Affiliations

  1. The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry, and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, Technion-Israel Institute of Technology, Haifa 32000, Israel,

    Yury Minko, Morgane Pasco, Lukas Lercher & Ilan Marek

  2. Laboratory for X-ray Analysis, Technion-Israel Institute of Technology, Haifa 32000, Israel,

    Mark Botoshansky

Authors
  1. Yury Minko
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Contributions

Y.M., M.P. and L.L. planned, conducted and analysed experiments. I.M. conceived and directed the project and wrote the manuscript with contributions from Y.M. and M.P. X-ray structures were resolved by M.B. All authors contributed to discussions.

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Correspondence to Ilan Marek.

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The authors declare no competing financial interests.

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This file contains Supplementary Methods, Supplementary Text and Data and additional references – see Contents for details. (PDF 10000 kb)

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Minko, Y., Pasco, M., Lercher, L. et al. Forming all-carbon quaternary stereogenic centres in acyclic systems from alkynes. Nature 490, 522–526 (2012). https://doi.org/10.1038/nature11569

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