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

doi:10.1002/ejoc.201900399

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 language	English
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	https://doi.org/10.1002/ejoc.201900399
Publication status	Published - 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.

Funders	Funder number
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/ejoc.201900399

Efficient Diastereoselective Three-Component Synthesis of Pipecolic AmidesFinal published version, 2.57 MBLicence: Article 25fa Dutch Copyright Act

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title = "Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides",

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.",

keywords = "Argatroban, Multicomponent reactions, Pharmaceuticals, Pipecolic amides, Stereoselectivity",

author = "{van der Heijden}, Gydo and {van Schaik}, {Timo B.} and Valentinos Mouarrawis and {de Wit}, {Martin J.M.} and Velde, {Christophe M.L.Vande} and Eelco Ruijter and Orru, {Romano V.A.}",

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AU - van der Heijden, Gydo

AU - van Schaik, Timo B.

AU - Mouarrawis, Valentinos

AU - de Wit, Martin J.M.

AU - Velde, Christophe M.L.Vande

AU - Ruijter, Eelco

AU - Orru, Romano V.A.

N1 - Special Issue: Heterocyclic Chemistry

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

KW - Argatroban

KW - Multicomponent reactions

KW - Pharmaceuticals

KW - Pipecolic amides

KW - Stereoselectivity

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JO - European Journal of Organic Chemistry

JF - European Journal of Organic Chemistry

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ER -

Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Persistent URL (handle)

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Fingerprint

CCDC 1910686: Experimental Crystal Structure Determination

Cite this

Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Datasets

CCDC 1910686: Experimental Crystal Structure Determination

Cite this