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 language | English |
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Pages (from-to) | 5313-5325 |
Number of pages | 13 |
Journal | European Journal of Organic Chemistry |
Volume | 2019 |
Issue number | 31-32 |
Early online date | 25 Apr 2019 |
DOIs | |
Publication status | Published - 1 Sept 2019 |
Bibliographical note
Special Issue: Heterocyclic ChemistryFunding
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.
Funders | Funder number |
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Mercachem B.V. | |
National Science Foundation | 0087210 |
Ohio Board of Regents | CAP-491 |
Youngstown State University | |
Seventh Framework Programme | |
European Federation of Pharmaceutical Industries and Associations | |
Seventh Framework Programme | FP7/ 2007–2013 |
Innovative Medicines Initiative | 115360 |
Keywords
- Argatroban
- Multicomponent reactions
- Pharmaceuticals
- Pipecolic amides
- Stereoselectivity
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CCDC 1910686: Experimental Crystal Structure Determination
van der Heijden, G. (Contributor), van Schaik, T. (Contributor), Mouarrawis, V. (Contributor), de Wit, M. (Contributor), Velde, C. V. (Contributor), Ruijter, E. (Contributor) & Orru, R. (Contributor), Unknown Publisher, 1 Jan 2019
DOI: 10.5517/ccdc.csd.cc22471j, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc22471j&sid=DataCite
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