Enantioselective Synthesis of α-Secondary and α-Tertiary Piperazin-2-ones and Piperazines by Catalytic Asymmetric Allylic Alkylation

Authors

  • Katerina M. Korch,

    1. The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, MC 101-20, Pasadena, CA 91125 (USA)
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  • Dr. Christian Eidamshaus,

    1. The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, MC 101-20, Pasadena, CA 91125 (USA)
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  • Dr. Douglas C. Behenna,

    1. The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, MC 101-20, Pasadena, CA 91125 (USA)
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  • Dr. Sangkil Nam,

    1. Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010 (USA)
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  • Prof. Dr. David Horne,

    1. Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010 (USA)
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  • Prof. Dr. Brian M. Stoltz

    Corresponding author
    1. The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, MC 101-20, Pasadena, CA 91125 (USA)
    • The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, MC 101-20, Pasadena, CA 91125 (USA)

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  • We wish to thank the NIH-NIGMS (R01GM080269) for financial support. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1144469 (fellowship to K.M.K.). We also wish to thank the Deutsche Forschungsgemeinschaft (DFG postdoctoral fellowship to C.E.), Amgen, Abbott, Boehringer Ingelheim, and Caltech for financial support. Corey Reeves is acknowledged for providing allyl cyanoformate and for insightful discussions. Douglas Duquette is acknowledged for providing allyl 1H-imidazole-1-carboxylate reagents and for insightful discussions. Scott Virgil is acknowledged for assistance with instrumentation and insightful discussions.

Abstract

The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2-ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.

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