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. 2014 Jul 30;136(30):10700-7.
doi: 10.1021/ja504532d. Epub 2014 Jul 16.

Transition state analysis of enantioselective Brønsted base catalysis by chiral cyclopropenimines

Jeffrey S Bandar  1 , Gregory S Sauer, William D Wulff, Tristan H Lambert, Mathew J Vetticatt
Affiliations

Transition state analysis of enantioselective Brønsted base catalysis by chiral cyclopropenimines

Jeffrey S Bandar et al. J Am Chem Soc. .

Abstract

Experimental (13)C kinetic isotope effects have been used to interrogate the rate-limiting step of the Michael addition of glycinate imines to benzyl acrylate catalyzed by a chiral 2,3-bis(dicyclohexylamino) cyclopropenimine catalyst. The reaction is found to proceed via rate-limiting carbon-carbon bond formation. The origins of enantioselectivity and a key noncovalent CH···O interaction responsible for transition state organization are identified on the basis of density functional theory calculations and probed using experimental labeling studies. The resulting high-resolution experimental picture of the enantioselectivity-determining transition state is expected to guide new catalyst design and reaction development.

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Figures

Scheme 1
Scheme 1. Chiral Brønsted Base-Catalyzed Michael Addition of Glycine Imine to Acrylates
Figure 1
Figure 1
Experimental 13C KIEs for reaction of 2 and 3b catalyzed by 1. The two sets of KIEs for each carbon represent two independent experiments and the numbers in parentheses represent the standard deviation in the last digit as determined from six measurements. KIEs for the bond-forming carbon atoms are shown in red.
Scheme 2
Scheme 2. Proposed Mechanism Based on Experimental KIEs
Figure 2
Figure 2
Division of layers for the ONIOM method used for initial exploration of transition structures.
Figure 3
Figure 3
Possible binding modes of the catalyst–enolate complex 5.
Figure 4
Figure 4
Transition structures leading to major (S) enantiomer of product 4a that utilize monocoordinated binding modes 5a and 5b. Most hydrogen atoms have been removed for clarity. All transition structures are oriented with the acrylate in the foreground and the enolate in the background.
Figure 5
Figure 5
Transition structures leading to minor (R) enantiomer of product 4a that utilize monocoordinated binding modes 5a and 5b. Most hydrogen atoms have been removed for clarity. All transition structures are oriented with the acrylate in the foreground and the enolate in the background.
Figure 6
Figure 6
Comparison of experimental (black) and predicted (red) 13C KIEs.
Figure 7
Figure 7
Labeling studies as an experimental probe of CH···O interaction.
See this image and copyright information in PMC

References

    1. Bandar J.; Lambert T. H. J. Am. Chem. Soc. 2012, 134, 5552–5555. - PubMed
    1. Bandar J. S.; Lambert T. H. J. Am. Chem. Soc. 2013, 135, 11799–11802. - PMC - PubMed
    1. Bandar J. S.; Mazori A. Y.; Lambert T. H. Manuscript in preparation.
    1. Ishikawa T.; Araki Y.; Kumamoto T.; Seki H.; Fukuda K.; Isobe T. Chem. Commun. 2001, 245.

    1. Several catalytic enantioselective Brønsted base catalyzed reactions are currently being developed using 1 and related catalysts. 1 is available as a salt from Sigma-Aldrich.

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