title: A sequential Ugi multicomponent/Cu-catalyzed azide-alkyne cycloaddition approach for the continuous flow generation of cyclic peptoids.
abstract: The development of a continuous flow multistep strategy for the synthesis of linear peptoids and their subsequent macrocyclization via Click chemistry is described. The central transformation of this process is an Ugi four-component reaction generating the peptidomimetic core structure. In order to avoid exposure to the often toxic and malodorous isocyanide building blocks, the continuous approach was telescoped by the dehydration of the corresponding formamide. In a concurrent operation, the highly energetic azide moiety required for the subsequent intramolecular copper-catalyzed azide-alkyne cycloaddition (Click reaction) was installed by nucleophilic substitution from a bromide precursor. All steps yielding to the linear core structures can be conveniently coupled without the need for purification steps resulting in a single process generating the desired peptidomimetics in good to excellent yields within a 25 min reaction time. The following macrocyclization was realized in a coil reactor made of copper without any additional additive. A careful process intensification study demonstrated that this transformation occurs quantitatively within 25 min at 140 °C. Depending on the resulting ring strain, either a dimeric or a monomeric form of the cyclic product was obtained.
authors.affiliation: †Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria.|‡Laboratório de Química Metodológica e Orgânica Sintética, Instituto de Química, Universidade de Brasília, Campus Universitário Darcy Ribeiro, C.P. 4478, 70904-970, Brasília-DF, Brazil.
authors.forename: Carlos Eduardo M
authors.initials: CE
authors.lastname: Salvador
authors.affiliation: †Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria.
authors.forename: Bartholomäus
authors.initials: B
authors.lastname: Pieber
authors.affiliation: †Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Neu
authors.affiliation: §Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
authors.forename: Ana
authors.initials: A
authors.lastname: Torvisco
authors.affiliation: ‡Laboratório de Química Metodológica e Orgânica Sintética, Instituto de Química, Universidade de Brasília, Campus Universitário Darcy Ribeiro, C.P. 4478, 70904-970, Brasília-DF, Brazil.
authors.forename: Carlos
authors.initials: C
authors.lastname: Kleber Z Andrade
authors.affiliation: †Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria.
authors.forename: C Oliver
authors.initials: CO
authors.lastname: Kappe
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D001386:Azides / Q000737:chemistry*; D002384:Catalysis; D003300:Copper / Q000737:chemistry*; D003500:Cyclization; D008872:Microwaves; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D057786:Peptidomimetics
chemical_list: D000480:Alkynes; D001386:Azides; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D003300:Copper