Pd(II)‐Mediated C−H Activation for Cysteine Bioconjugation

Abstract

Selective bioconjugation remains a significant challenge for the synthetic chemist due to the stringent reaction conditions required by biomolecules coupled with their high degree of functionality. The current trailblazer of transition‐metal mediated bioconjugation chemistry involves the use of Pd(II) complexes prepared via an oxidative addition process. Herein, the preparation of Pd(II) complexes for cysteine bioconjugation via a facile C−H activation process is reported. These complexes show bioconjugation efficiency competitive with what is seen in the current literature, with a user‐friendly synthesis, common Pd(II) sources, and a more cost‐effective ligand. Furthermore, these complexes need not be isolated, and still achieve high conversion efficiency and selectivity of a model peptide. These complexes also demonstrate the ability to selectively arylate a single surface cysteine residue on a model protein substrate, further demonstrating their utility.

Isoindolium‐Based Allenes: Reactivity Studies and Applications in Fluorescence Temperature Sensing and Cysteine Bioconjugation

“…The low abundance (ca. 1.7 %), unique reactivity of the sulfhydryl group and ease of incorporation by site‐directed mutagenesis allow cysteine to serve as an ideal residue for peptide/protein labeling [31–50] . In our previous studies on the modification of cysteine‐containing peptides and proteins, we found that electron‐deficient alkynones [36a] and isoxazoliniums [37c] were excellent reagents owing to their outstanding electrophilicity.…”

“…1.7 %), unique reactivity of the sulfhydryl group and ease of incorporation by site-directed mutagenesis allow cysteine to serve as an ideal residue for peptide/protein labeling. [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] In our previous studies on the modification of cysteine-containing peptides and proteins, we found that electron-deficient alkynones [36a] and isoxazoliniums [37c] were excellent reagents owing to their outstanding electrophilicity. Along with our ongoing interest in the development of selective bioconjugation reactions, [36, 37, 51, we envisioned that the isoindolium-based allene 1, which exhibited excellent electrophilicity towards the sulfhydryl group, would be a useful handle for chemoselective modification of cysteine-containing peptides.…”

Organometallic S-arylation Reagents for Rapid PEGylation of Biomolecules

“…This strategy could allow for conjugation of polymers to proteins with limited stability at room temperature or which are only stable or soluble at non-neutral pH for the exploration of new biologics for therapeutic applications. Overall, this work represents an expansion of the growing organometallic reagent toolkit available for bioconjugation chemistry. ,,− …”

Chemical modification of proteins – challenges and trends at the start of the 2020s

“…Frost and coworkers have shown that Pd complexes for Cys arylation can be generated in situ from widely available Pd precursors, a method they have used for arylation of the free Cys34 of BSA, with 92–99% conversion. 119…”

“…Frost and coworkers have shown that Pd complexes for Cys arylation can be generated in situ from widely available Pd precursors, a method they have used for arylation of the free Cys34 of BSA, with 92-99% conversion. 119 The Pd-catalyzed Tsuji-Trost allylation reaction 120,121 has been used to introduce prenyl units on ubiquitin-like protein 3 (UBL3) and heat shock protein 27 (Hsp27) with a Pd/ BIPHEPHOS catalyst system. 122 Visible-light induced thiol-ene reactions.…”