The homo-PADAM Protocol: Stereoselective and Operationally Simple Synthesis of α-Oxo- or α-Hydroxy-γ-acylaminoamides and Chromanes

Authors

  • Dr. Fabio Morana,

    1. Department of Chemistry and Industrial Chemistry, University of Genova via Dodecaneso, 31, 16146 Genova (Italy), Fax: (+39) 010-3536118
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  • Dr. Andrea Basso,

    1. Department of Chemistry and Industrial Chemistry, University of Genova via Dodecaneso, 31, 16146 Genova (Italy), Fax: (+39) 010-3536118
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  • Prof. Dr. Renata Riva,

    1. Department of Chemistry and Industrial Chemistry, University of Genova via Dodecaneso, 31, 16146 Genova (Italy), Fax: (+39) 010-3536118
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  • Valeria Rocca,

    1. Department of Chemistry and Industrial Chemistry, University of Genova via Dodecaneso, 31, 16146 Genova (Italy), Fax: (+39) 010-3536118
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  • Prof. Luca Banfi

    Corresponding author
    1. Department of Chemistry and Industrial Chemistry, University of Genova via Dodecaneso, 31, 16146 Genova (Italy), Fax: (+39) 010-3536118
    • Department of Chemistry and Industrial Chemistry, University of Genova via Dodecaneso, 31, 16146 Genova (Italy), Fax: (+39) 010-3536118
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  • PADAM=Passerini–amine deprotection–acyl migration.

Abstract

A straightforward and fully stereoselective synthesis of a new class of peptidomimetics, that is α-oxo-γ-acylaminoamides, was achieved starting from various benzaldehydes by a sequence of 1) an asymmetric organocatalytic Mannich reaction, 2) a Passerini multicomponent reaction, 3) an amine deprotection–acyl migration protocol, and 4) a final oxidation. The whole sequence can be performed without purification of the intermediates and represents the first example of a homo-Passerini–amine deprotection–acyl migration (PADAM) strategy. Highly stereoselective reduction of the α-oxo-γ-acylaminoamides afforded α-hydroxy-γ-acylaminoamides as well. In some cases both diastereomers were obtained by simply changing the reducing agent. Finally, starting from protected salicylaldehyde, the same sequence, followed by a Mitsunobu cyclization, afforded highly substituted chromanes.

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