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Synthesis 2019; 51(09): 1961-1968
DOI: 10.1055/s-0037-1612084
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© Georg Thieme Verlag Stuttgart · New York

Transformation of the Carboxyl Group of an Amino Acid to Variously Substituted Imidazoles through a Davidson-Type Heterocyclization

Jim Küppers
a   Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany   Email: guetschow@uni-bonn.de
,
Michaela Hympánová
a   Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany   Email: guetschow@uni-bonn.de
,
Tim Keuler
a   Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany   Email: guetschow@uni-bonn.de
,
Andreas J. Schneider
b   Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
,
Gregor Schnakenburg
c   Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
,
Michael Gütschow*
a   Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany   Email: guetschow@uni-bonn.de
› Author AffiliationsJ.K. and M.G. acknowledge financial support by the DFG Forschergruppe under grant number FOR2372.
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Publication History

Received: 06 November 2018

Accepted after revision: 17 December 2018

Publication Date:
18 February 2019 (online)

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Abstract

The modification of amino acids leads to valuable building blocks for the synthesis of bioactive compounds. By keeping the amino group protected, the carboxylic acid functionality can be converted in two steps into an imidazole moiety via a Davidson-like heterocyclization. This reaction allows for a combinatorial approach, in which two positions at the heterocycle can be modified. Herein, we report the synthesis of such imidazole derivatives by employing N-protected cyclohexylalanine as the starting material. Different α-halo ketones were used and two points of diversity, positions 4 and 5, were examined. The structure of the final imidazole derivatives was confirmed by three X-ray crystal structure analyses and their protease inhibiting activities were evaluated.

Key words

amino acids - Davidson synthesis - heterocycles - imidazoles - X-ray crystal structure analysis

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    Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1612084.
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