Versatile Ru‐Photoredox‐Catalyzed Functionalization of Dehydro‐Amino Acids and Peptides

Abstract

A versatile photoredox‐catalyzed synthesis of unnatural amino acids and peptides is presented. Commercially available Ru(bpy)3(PF6)2 was efficiently used as visible light photocatalyst in combination with a broad number of different types of radical precursors in the coupling with several dehydrogenated amino acid residues. This method provides new entries to the mild, selective and direct modification of both simple and complex peptide‐like compounds towards novel structures with improved or unusual properties. Hence, (fluorinated)alkyl halides, arylsulfonyl chlorides or various N‐(acyloxy)phthalimides (NHPI esters) were effectively reacted with a series of natural and unnatural α,β‐dehydroamino acids and dipeptides. Moreover, the applicability of the process was also proved by the late stage functionalization of the naturally occurring peptide thiostrepton.

Synthesis of complex unnatural fluorine-containing amino acids

“…In addition, it was also utilised in the late-stage functionalisation of an oligopeptide (thiostrepton) including the incorporation of fluorine atoms.

Scheme 42 Photocatalysis to functionalise dehydroamino acids, Brandhofer et al [ 160 ].

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Advances in Asymmetric Amino Acid Synthesis Enabled by Radical Chemistry

“…Dehydroalanine (ΔAla) are naturally occurring non‐coded amino acid, found primarily in peptides. In this context, ΔAla appendage is a useful synthetic tool for simple modification of peptides or proteins by different reactions such as Michael addition, Diels‐Alder cycloaddition and radical coupling under mild conditions . Dehydroalanine derivatives are also widely applied as electrophilic partners in the range of ionic reactions for the asymmetric synthesis of unusual AAs .…”

Radikal‐basierte Synthese und Modifikation von Aminosäuren

“…García Mancheño berichtete 2019 über eine einfache lichtvermittelte Methode zur Funktionalisierung von Dha‐Derivaten (Abbildung 21 B). [63a] Obwohl der Großteil des Anwendungsspektrums mit fluorierten Alkylhalogeniden durchgeführt wurde, sind auch Arylsulfonylchloride oder NHP‐abgeleitete RAE geeignete Vorläufer in diesem Ru‐katalysierten Prozess. Um die Vielseitigkeit der Methodik hervorzuheben, wurden Modifikationen an Peptiden, welche Dha‐Reste enthielten, durchgeführt.…”