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Cross-aldol reactions of ketones catalyzed by leucinol: a mechanistic investigation

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posted on 04.09.2015 by Andrei Malkov, Mikhail A. Kabeshov, Ondrej Kysilka, Lubomir Rulisek, Y.V. Suleimanov, M. Bella, Pavel Kocovsky
Comprehensive mechanistic studies on the enantioselective aldol reaction between isatin (1 a) and acetone, catalyzed by L-leucinol (3 a), unraveled that isatin, apart from being a substrate, also plays an active catalytic role. Conversion of the intermediate oxazolidine 4 into the reactive syn-enamine 6, catalyzed by isatin, was identified as the rate-determining step by both the calculations (ΔG≠=26.1 kcal mol−1 for the analogous L-alaninol, 3 b) and the kinetic isotope effect (kH/kD=2.7 observed for the reaction using [D6]acetone). The subsequent reaction of the syn-enamine 6 with isatin produces (S)-2 a (calculated ΔG≠=11.6 kcal mol−1). The calculations suggest that the overall stereochemistry is controlled by two key events: 1) the isatin-catalyzed formation of the syn-enamine 6, which is thermodynamically favored over its anti-rotamer 7 by 2.3 kcal mol−1; and 2) the high preference of the syn-enamine 6 to produce (S)-2 a on reaction with isatin (1 a) rather than its enantiomer (ΔΔG≠=2.6 kcal mol−1).

Funding

We thank Loughborough University, the University of Cambridge and EPSRC (EP/K009494/1) for supporting this research. Further support was obtained from the Axel Wenner-Gren Foundation, the Grant Agency of the Czech Republic (grant No. 14-31419S), and the COST office via the ORCA action CM905. An allocation of computer time on the Western Canada Research Grid (WestGrid) is also gratefully acknowledged. Y. V. S. acknowledges the support via the Newton International Alumni Scheme from the Royal Society.

History

School

  • Science

Department

  • Chemistry

Published in

Chemistry - A European Journal

Volume

21

Citation

MALKOV, A.V. ...et al., 2015. Cross-aldol reactions of ketones catalyzed by leucinol: a mechanistic investigation. Chemistry - A European Journal, 21 (34), pp. 12026-12033

Publisher

© Wiley

Version

AM (Accepted Manuscript)

Publisher statement

This work is made available according to the conditions of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) licence. Full details of this licence are available at: https://creativecommons.org/licenses/by-nc-nd/4.0/

Publication date

2015

Notes

This is the peer reviewed version of the following article: MALKOV, A.V. ...et al., 2015. Cross-aldol reactions of ketones catalyzed by leucinol: a mechanistic investigation. Chemistry - A European Journal, 21 (34), pp. 12026-12033, which has been published in final form at http://dx.doi.org/10.1002/chem.201500536. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."

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en

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