Metal-Catalyzed C(sp2)−H Functionalization Processes of Phenylalanine- and Tyrosine-Containing Peptides

The site-selective chemical diversification of biomolecules constitutes an unmet challenge of capital importance within medicinal chemistry and chemical biology. The functionalization of otherwise unreactive C-H bonds holds great promise for reducing the reliance on existing functional groups, thereby streamlining chemical syntheses. Over the last years, a myriad of peptide labelling techniques featuring metal-catalyzed C-H functionalization reactions have been developed. Despite the wealth of reports in the field, the site-selective modification of both phenylalanine (Phe) and tyrosine (Tyr) compounds upon metal catalysis remain comparatively overlooked. This review highlights these promising tagging strategies, which generally occur through the formation of challenging 6-membered metallacycles and enable the late-stage diversification of peptides in a tailored fashion.A. Correa is grateful to Ministerio de Ciencia e Innovacion (RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and Basque Government (IT1033-16) for financial support. He also kindly acknowledges the GEQO group of the RSEQ for the GEQO Young Research Award 2019. Likewise, he sincerely thanks all co-workers for their dedication and invaluable contribution

Selective C(sp2)−H Halogenation of "click" 4-Aryl-1,2,3-triazoles

Selective bromination reactions of “click compounds” are described. Electron-neutral and electron-deficient arenes selectively undergo unprecedented Pd-catalyzed C–H ortho-halogenations assisted by simple triazoles as modular directing groups, whereas electron-rich arenes are regioselectively halogenated following an electrophilic aromatic substitution reaction pathway. These C–H halogenation procedures exhibit a wide group tolerance, complement existing bromination procedures, and represent versatile synthetic tools of utmost importance for the late-stage diversification of “click compounds”. The characterization of a triazole-containing palladacycle and density functional theory studies supported the mechanism proposal.We are grateful to Gobierno Vasco (ELKARTEK_KK-2015/0000101; IT_1033-16) and UPV/EHU (GIU15/31) for financial support. A. C. thanks MINECO for a Ramón y Cajal research contract (RYC-2012-09873). Cost-CHAOS action is also acknowledged

Site-Selective Trifluoromethylation Reactions of Oligopeptides

Site-selective chemical modifications that target proteinogenic amino acid residues complement the methods entailing genetic manipulation, thereby allowing straightforward and rapid access to engineered proteins. The incorporation of the trifluoromethyl group into amino acids within a peptide sequence results in relevant peptidomimetics with unique biomedicinal properties. As a result, the last decade has witnessed the development of a powerful set of protocols toward the selective trifluoromethylation of small-to-medium size peptides and proteins in a late-stage fashion. This minireview seeks to highlight those particularly compelling cases published in the last years.We are grateful to MINECO (RTI2018‐093721‐BI00) and Basque Government (IT1033‐16) for financial support. I. G. thanks Basque Government for a predoctoral fellowshi

Cu-Catalyzed Site-Selective C(sp2)–H Radical Trifluoromethylation of Tryptophan Containing Peptides

Site-selective functionalization of C–H bonds within a peptide framework poses a challenging task of paramount synthetic relevance. Herein, we report an operationally simple C(sp2)–H trifluoromethylation of tryptophan (Trp)-containing peptides. This fluorination technique is characterized by its chirality preservation, tolerance of functional groups, and scalability and exhibits chemoselectivity for Trp residues over other amino acid and heterocyclic units. As a result, it represents a sustainable tool toward the late-stage peptide modification and protein engineering.We are grateful to MINECO (RTI2018-093721-B-I00) and the Basque Government (IT1033-16) for financial support. I.G. thanks the Basque Government for a predoctoral fellowship. We are thankful for technical and human support provided by SGIker of UPV/EHU and European funding (ERDF and ESF). Cost-CHAOS action (CA15106) is also acknowledged

Triazole-Directed Pd-Catalyzed C(sp2)–H Oxygenation of Arenes and Alkenes

Selective Pd-catalyzed C(sp2)–H oxygenation of 4-substituted 1,2,3-triazoles is described. Unlike previous metal-catalyzed C–H functionalization events, which preferentially occur at the activated heterocyclic C–H bond, the regioselective oxygenation of the arene/alkene moiety is now achieved featuring the unconventional role of a simple triazole scaffold as a modular and selective directing group.MINECO for a Ramon y Cajal research contract (RYC-2012-09873)

Palladium-Catalyzed Site-Selective C(sp2)−H Acetoxylation of Tyrosine-Containing Peptides

A Pd-catalyzed C(sp2)−H acetoxylation of Tyr-containing peptides is described. The method relies on the use of a removable 2-pyridyloxy group as directing group and is distinguished by its reliable scalability and easily tuned regioselectivity to perform mono- and diacetoxylation reactions. Remarkably, the assembly of L–DOPA peptidomimetics is beyond reach upon cleavage of the directing group.We are grateful to Ministerio de Ciencia e Innovación (RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and Basque Government (IT-1741-22) for financial support. We thank for the technical and human support provided by Central Service of Analysis-SGIker of UPV/EHU and European funding (ERDF and ESF)

Late-Stage C-H Acylation of Tyrosine-Containing Oligopeptides with Alcohols

The selective tagging of amino acids within a peptide framework while using atom-economical C-H counterparts poses an unmet challenge within peptide chemistry. Herein, we report a novel Pd-catalyzed late-stage C-H acylation of a collection of Tyr-containing peptides with alcohols. This water-compatible labeling technique is distinguished by its reliable scalability and features the use of ethanol as a renewable feedstock for the assembly of a variety of peptidomimetics.The authors are grateful to the Ministerio de Ciencia e Innovacion (RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and the Basque Government (IT1033-16) for financial support. The authors thank the technical and human support provided by the Central Service of Analysis-SGIker of UPV/EHU and European funding (ERDF and ESF). In~aki Urruzuno thanks UPV/EHU for the postdoctoral research grant (EspDoc2020

Co-Catalyzed C(sp3)−H Oxidative Coupling of Glycine and Peptide Derivatives

obalt-catalyzed selectiveα-alkylation andα-heteroarylation processes ofα-amino esters and peptide derivativesare described. These cross-dehydrogenative reactions occur undermild conditions and allow for the rapid assembly of structurallydiverseα-amino carbonyl compounds. Unlike enolate chemistry,these methods are distinguished by their site-specificity, occurwithout racemization of the existing chiral centers, and exhibit totalselectivity for aryl glycine motifs over other amino acid units, hence providing ample opportunities for peptide modificationsWe acknowledge technical and human support provided by SGIker of UPV/EHU and European funding (ERDF and ESF). We are grateful to G. V. (ELKARTEK_KK-2015/0000101; IT_1033-16) and MINECO (CTQ2016-78395-P) for financial support. A.C. thanks MINECO for a Ramón y Cajal contract. Cost-CHAOS action is also acknowledged

On the Mechanism of Cross-Dehydrogenative Couplings between N-Aryl Glycinates and Indoles: A Computational Study

Despite the widespread use of cross-dehydrogenative couplings in modern organic synthesis, mechanistic studies are still rare in the literature and those applied to α-amino carbonyl compounds remain virtually unexplored. Herein, the mechanism of Co-catalyzed cross-dehydrogenative couplings of N-aryl glycinates with indoles is described. Density functional theory studies supported the formation of an imine-type intermediate as the more plausible transient electrophilic species. Likewise, key information regarding the role of the N-aryl group and free NH motif within the reaction outcome has been gained, which may set the stage for further developments in this field of expertise.Ministerio de Ciencia e Innovación (RTI2018-093721-B-I00) Eusko Jaurlaritza (IT1033-16; IT1254-19

Ru-Catalyzed C-H Hydroxylation of Tyrosine-Containing Di- and Tripeptides toward the Assembly of L-DOPA Derivatives

[EN] The development of catalytic tools for the late-stage modification of amino acids within a peptide framework is a challenging task of capital importance. Herein, we report a Ru-catalyzed C(sp(2))-H hydroxylation of a collection of Tyr-containing di- and tripeptides featuring the use of a carbamate as a removable directing group and PhI(OCOCF3)(2) (PIFA) as oxidant. This air-compatible tagging technique is reliable, scalable and provides access to L-DOPA (L-3,4-dihydroxyphenylalanine) peptidomimetics in a racemization-free fashion. Density Functional Theory calculations support a Ru(II)/Ru(IV) catalytic cycle.We are grateful to Ministerio de Ciencia e Innovacion (RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and Basque Government (IT1033-16 and IT1254-19) for financial support. We thank for technical and human support provided by SGIker of UPV/EHU and European funding (ERDF and ESF). P. A.-S. thanks DIPC for the research contract