N-Heterocyclic Carbene-Stabilized Palladium Complexes as Organometallic Catalysts for Bioorthogonal Cross-Coupling Reactions

Abstract

A small library of water-soluble N-heterocyclic carbene (NHC)-stabilized palladium complexes was prepared and applied for cross-couplings of biomolecules under mild conditions in water. Pd-NHC complexes bearing hydrophilic groups were demonstrated to be efficient catalysts for the Suzuki-Miyaura coupling of various unnatural amino acids and proteins bearing p-iodophenyl functional groups. We further utilized this catalytic system for the rapid bioorthogonal labeling of proteins on the surfaces of mammalian cells. These results demonstrated that NHC-stabilized metal complexes have potential utility in cellular systems.

Advances in Chemical Protein Modification

“…Cross-couplings with either a fluorophore or a sugar boronic acid/fluorescent lectin reporter were visualized by fluorescence microscopy, demonstrating a reduced toxicity at the catalyst loadings required for efficient labeling. Although Pd(OAc) 2 ·(ADHP) 2 catalysts have proved efficient in both Suzuki−Miyaura and copper-free Sonogashira cross-couplings, the use of alternative catalytic systems (e.g., N-heterocyclic carbene (NHC)−Pd catalysts for the cell surface labeling of mammalian cells) (Scheme 22d) 188 or the development of ligandless protocols such as the site-selective protein PEGylation by Suzuki−Miyaura cross-coupling recently (Scheme 22e) will be of enlarged value in particularly important biotechnology applications such as the development of therapeutic proteins with improved properties. 189 …”

The Suzuki–Miyaura Cross-Coupling as a Versatile Tool for Peptide Diversification and Cyclization

“…Incubation of the iodine-bearing protein pIPM-BSA with 100 eq of this Pd-NHC complex and 100 eq of biotin-B(OH) 2 yielded the desired derivatives ( Figure 17E). Similarly, a lysozyme containing p-iodobenzoate (pIBZ-lyso) also underwent efficient cross-coupling with a PEG-bearing boronic acid (not shown) [135]. The utility of this catalytic system was even demonstrated to work on the cell-surface of live mammalian cells.…”

“…One solution was found in designing more hydrophilic analogues of traditional ligands [11,62]. For example, 3,3′,3″-phosphanetriyltris(benzene sulfonic acid) trisodium salt (TPPTS 77a, Figure 12) [18,64], its xylene analogue TXPTS 77b [64,133], sodium 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl-3'-sulfonate (SSPhos 78) [10,96], and water-soluble NHC-ligands (N-heterocyclic carbene), such as 79 [134][135][136][137], have been proposed for Pd-catalysis in aqueous media (Figure 12). Suzuki-Miyaura reactions encompassing other water soluble ligands [11,12,138], or additives such as polyethyleneglycol and surfactants were also applied [11,34,139] Notably for Suzuki-Miyaura reaction in aqueous conditions, ligands containing the guanidine functionality, such as 2-aminopyrimidine-4,6-diol disodium salt (ADHP 80a) [63,140], its dimethylated analogue (N,N-diMeADHP 80b) [34], and (methyl)guanidines 81 and 82 [34,141,142], have been reported.…”

“…With 1,1-dimethylguanidine 82 as a ligand, the first Pd-catalyzed introduction of 18 F, the most common radionuclide in PET imaging, was exemplified on SBL-156Pic ( Figure 17D) with 250 eq of Pd-catalyst solution and 250 eq of labeled 4-fluorophenylboronic acid. Moreover, Ma and coworkers have shown that water-soluble NHCs, such as 79 (Figure 12), can be applied for protein derivatizations ( Figure 17E) [135]. Pd-complexes with NHC-ligands bearing hydrophilic groups were first verified on N-Boc-4-iodophenylalanine under mild conditions (37 • C, 2-6 h).…”

Arylierungschemie für die Biokonjugation

“…Erste Arbeiten mit Phosphanliganden (Abbildung 43; L1 und L2), [218,220] Na 2 PdCl 4 [221] oder Pd-DBA [224] zeitigten allerdings wegen der geringen Effizienz der Katalysatoren und der harschen Reaktionsbedingungen nur moderate Erfolge.M it Nicht-Phosphan-Liganden (Abbildung 43; L3-L8) [227,229,230] oder Pd(NO 3 ) 2 [228] wurde dagegen eine hocheffiziente Arylierung nichtnatürlicher Aminosäuren von Proteinen beobachtet, sowohl in vitro als auch in vivo. Erste Arbeiten mit Phosphanliganden (Abbildung 43; L1 und L2), [218,220] Na 2 PdCl 4 [221] oder Pd-DBA [224] zeitigten allerdings wegen der geringen Effizienz der Katalysatoren und der harschen Reaktionsbedingungen nur moderate Erfolge.M it Nicht-Phosphan-Liganden (Abbildung 43; L3-L8) [227,229,230] oder Pd(NO 3 ) 2 [228] wurde dagegen eine hocheffiziente Arylierung nichtnatürlicher Aminosäuren von Proteinen beobachtet, sowohl in vitro als auch in vivo.…”