An Iron‐Catalyzed Protein Desulfurization Method Reminiscent of Aquatic Chemistry

Abstract

One pillar of protein chemical synthesis based on the application of ligation chemistries to cysteine is the group of reactions enabling the selective desulfurization of cysteine residues into alanines. Modern desulfurization reactions use a phosphine as a sink for sulfur under activation conditions involving the generation of sulfur-centered radicals. Here we show that cysteine desulfurization by a phosphine can be effected efficiently by micromolar concentrations of iron under aerobic conditions in hydrogen carbonate buffer, that is using conditions that are reminiscent of iron-catalyzed oxidation phenomena occurring in natural waters. Therefore, our work shows that chemical processes taking place in aquatic systems can be adapted to a chemical reactor for triggering a complex chemoselective transformation at the protein level, while minimizing the resort to harmful chemicals.

Iron-catalyzed selective construction of indole derivatives via oxidative C(sp3)–H functionalization of indolin-2-ones

“…[1][2][3][4][5][6][7][8][9][10][11] Inspired by iron-containing enzyme catalysis, 12,13 the iron-catalyzed C(sp 3 )-H bond oxidation, coupled with the utilization of molecular oxygen, has emerged as a highly promising reaction over the past decade. [14][15][16][17][18][19][20][21][22][23][24] In 2015, Li's group pioneered the utilization of cross-dehydrogenative coupling (CDC) to develop an iron saltcatalyzed cross-dehydrogenative arylation between 3-substituted indolin-2-ones generating a series of 3,3′-disubstituted oxindole compounds. 25 Subsequently, Xu's group achieved significant progress by expanding the scope of the iron-catalyzed CDC reaction to include indolin-2-ones and various X-H bonds (X = C, N, or S), enabling the construction of functionalized indole derivatives by employing air as the sole oxidant (Scheme 1(I)).…”

Peptide and Protein Desulfurization with Diboron Reagents

“…9 Over the past two decades, desulfurization reactions based on radical mechanisms have been reported. 9−26 Numerous additives and special setups were devised including transition metal catalysts, 9,11,14,20,22 water-soluble radical initiators, 12,15,16,18,19 borohydride reagents, 10,17 and UV light. 13,21−24 All these studies not only widened the range from bioactive oligopeptides to more complicated protein substrates but also extended the ligation sites of NCL from cysteine to other unnatural mercapto amino acids.…”

“…In order to expand the utility of the NCL reaction, various desulfurization methods, which convert cysteine into alaninea more prevalent amino acidhave been investigated . Over the past two decades, desulfurization reactions based on radical mechanisms have been reported. − Numerous additives and special setups were devised including transition metal catalysts, ,,,, water-soluble radical initiators, ,,,, borohydride reagents, , and UV light. ,− All these studies not only widened the range from bioactive oligopeptides to more complicated protein substrates but also extended the ligation sites of NCL from cysteine to other unnatural mercapto amino acids. − ,, However, existing methods commonly involve either long reaction times, specialized laboratory equipment, or unstable additives to activate/stabilize the radical chains. As the common following step of NCL, desulfurization also requires a purified substrate from HPLC and a change of buffer to remove excess 4-mercaptophenylacetic acid (MPAA).…”