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Direct and highly regioselective and enantioselective allylation of β-diketones

Nature volume 487, pages 86–89 (2012)Cite this article

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Abstract

The enantioselective allylation of ketones is a problem of fundamental importance in asymmetric reaction design, especially given that only a very small number of methods can generate tertiary carbinols. Despite the vast amount of attention that synthetic chemists have given to this problem1,2,3,4,5,6,7,8, success has generally been limited to just a few simple ketone types. A method for the selective allylation of functionally complex ketones would greatly increase the utility of ketone allylation methods in the chemical synthesis of important targets. Here we describe the operationally simple, direct, regioselective and enantioselective allylation of β-diketones. The strong tendency of β-diketones to act as nucleophilic species was overcome by using their enol form to provide the necessary Brønsted-acid activation. This reaction significantly expands the pool of enantiomerically enriched and functionally complex tertiary carbinols that may be easily accessed. It also overturns more than a century of received wisdom regarding the reactivity of β-diketones.

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Figure 1: Origin and evolution of a proposal for a direct, enantioselective and regioselective allylation of β-diketones.
Figure 2: Reaction design and proof of concept.
Figure 3: Scope of the regio- and enantioselective allylation of β-diketones.
Figure 4: Regio-, diastereo- and enantioselective crotylation of β-diketones.
Figure 5: General mechanism and origin of regioselectivity.

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Data deposits

X-ray crystallographic data have been deposited in the Cambridge Crystallographic Data Centre database (http://www.ccdc.cam.ac.uk/) under accession code CCDC 874744.

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Acknowledgements

This work was supported by a grant from the National Institute of General Medical Sciences (GM58133). W.A.C. was supported by a Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship. We thank the US National Science Foundation (CRIF-0840451) for acquisition of a 400 MHz NMR spectrometer. We thank our colleagues G. Parkin and W. Sattler for an X-ray structure analysis (see the Supplementary Information), and the US National Science Foundation (CHE-0619638) for acquisition of an X-ray diffractometer.

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Authors and Affiliations

  1. Department of Chemistry, Columbia University, New York, 10027, New York, USA

    Wesley A. Chalifoux, Samuel K. Reznik & James L. Leighton

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  1. Wesley A. Chalifoux
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  2. Samuel K. Reznik
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  3. James L. Leighton
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Contributions

W.A.C. planned and did the vast majority of the experimental work. S.K.R. did the experiments that established the validity of the idea and optimized the allylation of acetylacetone. J.L.L. conceived and directed the project and wrote the manuscript.

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Correspondence to James L. Leighton.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Figures 1-80, Supplementary Methods, Supplementary Table 1, and Supplementary References. (PDF 14180 kb)

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Chalifoux, W., Reznik, S. & Leighton, J. Direct and highly regioselective and enantioselective allylation of β-diketones. Nature 487, 86–89 (2012). https://doi.org/10.1038/nature11189

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