Site-Selective C - H Functionalization of Amino Acids and Peptides Upon Radical Chemistry

224 p.El objetivo de esta Tesis Doctoral ha sido desarrollar nuevas metodologías de modificación selectiva decompuestos peptídicos. Por un lado, hemos estudiado metales alternativos como el cobalto para lamodificación C-H selectiva de N-aril glicinas mediante procesos CDC (Cross-DehydrogenativeCoupling). Por otra parte, también hemos desarrollado nuevas metodologías para la diversificación deenlaces C ¿ H de aminoácidos con ramificaciones aromáticas como la fenilalanina (Phe) y tirosina (Tyr).Para ello se introdujeron grupos directores exógenos de tipo piridina en las estructuras peptídicas quepermitieron llevar a cabo la acilación selectiva de enlaces C-H con aldehídos mediante procesosradicalarios en presencia de catalizadores de paladio. Esta aproximación sintética ofrece múltiplesventajas frente a métodos más convencionales, donde generalmente se requieren sustratosprefuncionalizados y la generación de residuos halogenados es inevitable

Site-Selective C - H Functionalization of Amino Acids and Peptides Upon Radical Chemistry

224 p.El objetivo de esta Tesis Doctoral ha sido desarrollar nuevas metodologías de modificación selectiva decompuestos peptídicos. Por un lado, hemos estudiado metales alternativos como el cobalto para lamodificación C-H selectiva de N-aril glicinas mediante procesos CDC (Cross-DehydrogenativeCoupling). Por otra parte, también hemos desarrollado nuevas metodologías para la diversificación deenlaces C ¿ H de aminoácidos con ramificaciones aromáticas como la fenilalanina (Phe) y tirosina (Tyr).Para ello se introdujeron grupos directores exógenos de tipo piridina en las estructuras peptídicas quepermitieron llevar a cabo la acilación selectiva de enlaces C-H con aldehídos mediante procesosradicalarios en presencia de catalizadores de paladio. Esta aproximación sintética ofrece múltiplesventajas frente a métodos más convencionales, donde generalmente se requieren sustratosprefuncionalizados y la generación de residuos halogenados es inevitable

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

Site-Selective Aqueous C–H Acylation of Tyrosine-Containing Oligopeptides with Aldehydes

The development of useful synthetic tools to label amino acids within a peptide framework for the ultimate modification of proteins in a late-stage fashion is a challenging task of utmost importance within chemical biology. Herein, we report the first Pd-catalyzed C–H acylation of a collection of Tyr-containing peptides with aldehydes. This water-compatible tagging technique is distinguished by its site-specificity, scalability and full tolerance of sensitive functional groups. Remarkably, it provides straightforward access to a high number of oligopeptides with altered side-chain topology including mimetics of endomorphin-2 and neuromedin N, thus illustrating its promising perspectives toward the diversification of structurally complex peptides and chemical ligationWe are grateful to Ministerio de Ciencia e Innovación (RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and Basque Government (IT1033-16) for financial support. We thank for technical and human support provided by Central Service of Analysis-SGIker of UPV/EHU and European funding (ERDF and ESF)

Site-Selective Cu-Catalyzed Alkylation of α-Amino Acids and Peptides toward the Assembly of Quaternary Centers

The Cu(I)-catalyzed selective a-alkylation of a-amino acid and peptide derivatives with 2-alkyl-1,3-dioxolanes is reported. This oxidative coupling is distinguished by its site-specificity, high diastereoselectivity, and chirality preservation and exhibits absolute chemoselectivity for N-aryl glycine motifs over other amino acid units. Collectively, the method allows for the assembly of challenging quaternary centers, as well as compounds derived from natural products of high structural complexity, which may provide ample opportunities for late-stage functionalization of peptides.We are grateful to MINECO (CTQ2016‐78395‐P) and Basque Government (IT1033‐16) for financial support. A. C. thanks MINECO for a Ramón y Cajal research contract (RYC‐2012–09873). We thank for technical and human support provided by SGIker of UPV/EHU and European funding (ERDF and ESF). Cost‐CHAOS action (CA15106) is also acknowledged. M. Agirre is kindly acknowledged by her support on HPLC analysi

Cross-Dehydrogenative Coupling Reactions for the Functionalization of α-Amino Acid Derivatives and Peptides

The functionalization of typically unreactive C(sp3)–H bondsholds great promise for reducing the reliance on existing functionalgroups while improving atom-economy and energy efficiency. As a re-sult, this topic is a matter of genuine concern for scientists in order toachieve greener chemical processes. The site-specific modification of α-amino acid and peptides based upon C(sp3)–H functionalization stillrepresents a great challenge of utmost synthetic importance. This shortreview summarizes the most recent advances in ‘Cross-Dehydrogenative Couplings’ of α-amino carbonyl compounds and peptide derivativeswith a variety of nucleophilic coupling partners.We are grateful to MINECO (CTQ2016-78395-P) and Gobierno Vasco (IT_1033-16) for financial support. A. C. thanks MINECO for a Ramón y Cajal research contract (RYC-2012-09873). Cost-CHAOS action (CA15106) is also acknowledged

Pd-catalyzed site-selective C(sp(2))-H radical acylation of phenylalanine containing peptides with aldehydes

The site-selective functionalization of C-H bonds within a peptide framework remains a challenging task of prime synthetic importance. Herein, the first Pd-catalyzed delta-C(sp(2))-H acylation of Phe containing peptides with aldehydes is described. This oxidative coupling is distinguished by its site-specificity, tolerance of sensitive functional groups, scalability, and enantiospecificity and exhibits entire chemoselectivity for Phe motifs over other amino acid units. The compatibility of this dehydrogenative acylation platform with a number of oligopeptides of high structural complexity illustrates its ample opportunities for the late-stage peptide modification and bioconjugation.We are grateful to MINECO (CTQ2016-78395-P; RTI2018093721-B-I00) and Basque Government (IT1033-16) for. nancial support. A.C. thanks MINECO for a Ramon y Cajal research contract (RYC-2012-09873). We acknowledge technical and human support provided by SGIker of UPV/EHU and European funding (ERDF and ESF). Cost-CHAOS action (CA15106) is also acknowledged

Radical C–H Alkylation with Ethers and Unactivated Cycloalkanes toward the Assembly of Tetrasubstituted Amino Acid Derivatives

A radical α−C−H alkylation of a collection of N-picolinamide amino acid derivatives with ethers and cycloalkanes as chemical feedstock is described. This cross-dehydrogenative coupling is distinguished by its reliable scalability and removable auxiliary group, and enables the assembly of a variety of tri- and tetrasubstituted amino acid compoundsMinisterio de Ciencia e Innovación (RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and Basque Government (IT1033-16

Iron-Catalyzed C(sp3)−H Functionalization of N,N-Dimethylanilines with Isocyanides

An efficient ligand-free Fe-catalyzed oxidative Ugi-type reaction toward the assembly of α-amino amides and short peptides is described. The reaction proceeds through the α-C(sp3)−H oxidation of N,N-dimethylanilines and further nucleophilic attack of the resulting iminium species by isocyanides. Additive screening showed that judicious choice of the carboxylic acid could lead to the formation of α-amino imides via a 3-component reaction. The process occurs with operational simplicity and is compatible with a variety of sensitive functional groups.We thank for technical and human support provided by Central Service of Analysis de Alava–SGIker of UPV/EHU. We are grateful to Gobierno Vasco (IT_1033-16) and MINECO (CTQ2016-78395-P) for financial support. A. C. thanksMINECO for a Ramón y Cajal research contract (RYC-2012-09873). Cost-CHAOS action (CA15106) is also acknowledge

Iron-Catalyzed C(sp3)−H Functionalization of N,N-Dimethylanilines with Isocyanides

An efficient ligand-free Fe-catalyzed oxidative Ugi-type reaction toward the assembly of α-amino amides and short peptides is described. The reaction proceeds through the α-C(sp3)−H oxidation of N,N-dimethylanilines and further nucleophilic attack of the resulting iminium species by isocyanides. Additive screening showed that judicious choice of the carboxylic acid could lead to the formation of α-amino imides via a 3-component reaction. The process occurs with operational simplicity and is compatible with a variety of sensitive functional groups.We thank for technical and human support provided by Central Service of Analysis de Alava–SGIker of UPV/EHU. We are grateful to Gobierno Vasco (IT_1033-16) and MINECO (CTQ2016-78395-P) for financial support. A. C. thanksMINECO for a Ramón y Cajal research contract (RYC-2012-09873). Cost-CHAOS action (CA15106) is also acknowledge