Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides

Gydo van der Heijden, Timo B. van Schaik, Valentinos Mouarrawis, Martin J.M. de Wit, Christophe M.L.Vande Velde, Eelco Ruijter*, Romano V.A. Orru

*Corresponding author for this work

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Abstract

An efficient Ugi-type three-component reaction (U-3CR) for the synthesis of pipecolic amides is reported. The U-3CR between electronically diverse isocyanides, carboxylic acids and 4-substituted Δ1-piperideines proceeds in a highly diastereoselective fashion. The Δ1-piperideines are obtained by NCS-mediated oxidation of the corresponding 4-substituted piperidines, which in turn are generated by an efficient two-step procedure involving the alkylation of 4-picoline and subsequent catalytic hydrogenation of the pyridine ring. We demonstrate the utility of this U-3CR, in combination with the convertible isocyanide 2-bromo-6-isocyanopyridine, in the synthesis of the anticoagulant argatroban.

Original languageEnglish
Pages (from-to)5313-5325
Number of pages13
JournalEuropean Journal of Organic Chemistry
Volume2019
Issue number31-32
Early online date25 Apr 2019
DOIs
Publication statusPublished - 1 Sept 2019

Bibliographical note

Special Issue: Heterocyclic Chemistry

Funding

We thank Elwin Janssen for technical assistance, Jurriën Collet for HRMS measurements (both VU Amsterdam). We gratefully thank Mercachem B.V. for separation of the diastereomers of 9b. The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking project CHEM21 under Grant Agreement No. 115360, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/ 2007–2013) and EFPIA companies' in kind contribution. We thank Matthias Zeller (Youngstown State University) for collection of the X-ray diffraction data. The X-ray diffractometer was funded by NSF Grant 0087210, Ohio Board of Regents Grant CAP-491, and by Youngstown State University. We thank Elwin Janssen for technical assistance, Jurri?n Collet for HRMS measurements (both VU Amsterdam). We gratefully thank Mercachem B.V. for separation of the diastereomers of 9b. The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking project CHEM21 under Grant Agreement No. 115360, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/ 2007?2013) and EFPIA companies' in kind contribution. We thank Matthias Zeller (Youngstown State University) for collection of the X-ray diffraction data. The X-ray diffractometer was funded by NSF Grant 0087210, Ohio Board of Regents Grant CAP-491, and by Youngstown State University.

FundersFunder number
Mercachem B.V.
National Science Foundation0087210
Ohio Board of RegentsCAP-491
Youngstown State University
Seventh Framework Programme
European Federation of Pharmaceutical Industries and Associations
Seventh Framework ProgrammeFP7/ 2007–2013
Innovative Medicines Initiative115360

    Keywords

    • Argatroban
    • Multicomponent reactions
    • Pharmaceuticals
    • Pipecolic amides
    • Stereoselectivity

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