The Synthesis of Ruthenium and Rhodium Complexes with Functionalized N‐Heterocyclic Carbenes and Their Use in Solid Phase Peptide Synthesis

Abstract

AbstractWhile N‐heterocyclic carbenes (NHCs) are ubiquitous ligands in catalysts for organic or industrial synthesis, their potential to form stable transition metal complexes has hardly been exploited in metal bioconjugates. In this work, we describe a straightforward synthesis of carboxylato‐functionalized imidazolium salts for covalent binding to peptides. Carbene complexes of Ru and Rh were prepared from these imidazolium salts using Ag2O, followed by transmetallation. The neuropeptide [Leu5]‐enkephalin (Tyr‐Gly‐Gly‐Phe‐Leu) was chosen as a model peptide. Exploratory NMR experiments identified the Ru(p‐cymene)Cl2 complex of the asymmetrically substituted imidazol‐2‐ylidene 3b as the most suitable metal carbene precursor for solid phase peptide synthesis (SPPS). After optimization of the conditions for SPPS, a ruthenium‐NHC pseudoenkephalin (dichloro(η6‐p‐cymene)[1‐methyl‐3‐(methyl‐p‐benzoyl‐Gly‐Gly‐Phe‐Leu‐OH)imidazol‐2‐ylidene]ruthenium(II), 12) was synthesized from 3b on solid phase using the 2‐Cl‐Trt resin and cleavage by 2 % TFA to yield the free carboxylic acid. Peptide 12 was fully characterized by HPLC, 1H and 13C NMR and ESI‐MS. Characteristic NMR signals, as well as the isotope pattern of Ru in the ESI‐MS, unequivocally confirm the formation of this metal‐carbene peptide bioconjugate.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)