Methods for the chemoselective modification of amino acids and peptides are powerful techniques in biomolecular chemistry. Among other applications, they enable the total synthesis of artificial peptides. In recent years, significant momentum has been gained by exploiting palladium-catalyzed cross-coupling for peptide modification. Despite major advances, the prefunctionalization elements on the coupling partners translate into undesired byproduct formation and lengthy synthetic operations. In sharp contrast, we herein illustrate the unprecedented use of versatile ruthenium(II)carboxylate catalysis for the step-economical late-stage diversification of α- and β-amino acids, as well as peptides, through chemo-selective C-H arylation under racemization-free reaction conditions. The ligand-accelerated C-H activation strategy proved water-tolerant and set the stage for direct fluorescence labelling as well as various modes of peptide ligation with excellent levels of positional selectivity in a bioorthogonal fashion. The synthetic utility of our approach is further demonstrated by twofold C-H arylations for the complexity-increasing assembly of artificial peptides within a multicatalytic C-H activation manifold.
The C-C bond forming catalytic hydroaminoalkylation of terminal alkenes, 1,3-dienes, or styrenes allows a direct and highly atom efficient (100 %) synthesis of amines which can result in the formation of two regioisomers, the linear and the branched product. We present a new titanium catalyst with 2,6-bis(phenylamino)pyridinato ligands for intermolecular hydroaminoalkylation reactions of styrenes and 1-phenyl-1,3-butadienes that delivers the corresponding linear hydroaminoalkylation products with excellent regioselectivities.
Methods for the late-stage diversification of structurally complex peptides hold enormous potential for advances in drug discovery, agrochemistry and pharmaceutical industries. While C–H arylations emerged for peptide modifications, they are largely limited to highly reactive, expensive and/or toxic reagents, such as silver(I) salts, in superstoichiometric quantities. In sharp contrast, we herein establish the ruthenium(II)-catalyzed C–H alkylation on structurally complex peptides. The additive-free ruthenium(II)carboxylate C–H activation manifold is characterized by ample substrate scope, racemization-free conditions and the chemo-selective tolerance of otherwise reactive functional groups, such as electrophilic ketone, bromo, ester, amide and nitro substituents. Mechanistic studies by experiment and computation feature an acid-enabled C–H ruthenation, along with a notable protodemetalation step. The transformative peptide C–H activation regime sets the stage for peptide ligation in solution and proves viable in a bioorthogonal fashion for C–H alkylations on user-friendly supports by means of solid phase peptide syntheses.
Methods for the chemoselective modification of amino acids and peptides are powerfult echniques in biomolecular chemistry.A mong other applications,t hey enable the total synthesis of artificial peptides.Inrecent years,significant momentum has been gained by exploiting palladium-catalyzed cross-coupling for peptide modification. Despite major advances,the prefunctionalization elements on the coupling partners translate into undesired byproduct formation and lengthy synthetic operations.Insharp contrast, we herein illustrate the unprecedented use of versatile ruthenium(II)carboxylate catalysis for the step-economical late-stage diversification of aand b-amino acids,aswell as peptides,through chemo-selective C À Ha rylation under racemization-free reaction conditions. The ligand-accelerated C À Ha ctivation strategy proved watertolerant and set the stage for direct fluorescence labelling as well as various modes of peptide ligation with excellent levels of positional selectivity in ab ioorthogonal fashion. The synthetic utility of our approach is further demonstrated by twofold C À Ha rylations for the complexity-increasing assembly of artificial peptides within amulticatalytic C À Hactivation manifold.Scheme 2. Expedient ruthenium(II)-catalyzeda mino acid CÀHarylation. a) Versatile CÀHarylation of a-amino acid 1.b )Fluorescent properties of CÀHa rylated products 3 versus substrate 1,and a3D excitation/emission graph for 3m.c )Unprecedentedruthenium(II)catalyzed CÀHactivation of b 3 -amino acid 4.
Angewandte Chemie
CommunicationsScheme 3. Ruthenium(II)-catalyzed CÀHactivation for the fluorescence labeling and late-stage modification of peptides 6.Scheme 4. Peptide ligation by means of ruthenium(II)-catalyzed CÀH activation. a) At wofold CÀHa rylation/ligation strategy.b )Chemical ligation of peptides 6 by CÀHarylation.c )Peptide ligation by using asequential palladium(II)-and ruthenium(II)-catalyzed CÀHfunctionalization strategy.
Die über eine C‐C‐Bindungsknüpfung verlaufende katalytische Hydroaminoalkylierung von terminalen Alkenen, 1,3‐Dienen und Styrolen ermöglicht eine direkte und zu 100 % atomökonomische Synthese von Aminen, bei der zwei Regioisomere (linear und verzweigt) gebildet werden können. Hier berichten wir über einen neuen Titan‐Katalysator mit 2,6‐Bis(phenylamino)pyridinato‐Liganden, in dessen Gegenwart die intermolekulare Hydroaminoalkylierung von Styrolen und 1‐Phenyl‐1,3‐butadienen mit exzellenten Regioselektivitäten zugunsten des linearen Produktes erreicht werden kann.
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