Selective radical-chain epimerisation at electron-rich chiral tertiary C–H centres using thiols as protic polarity-reversal catalysts

Cysteine residues as catalysts for covalent peptide and protein modification: a role for thiyl radicals?

“…In this sequence, the thiol is restored, and has functioned as a catalyst for the reaction of the carbon-centered radical with the amino acid. An analogous catalytic function of thiols has been described before for synthetic organic reactions with alcohols and ethers, referred to as “polarity-reversal catalysis” [10]. $$\text{-}{}^{•}\mathrm{CH}\text{-}+\mathrm{RSH}\to \text{-}{\mathrm{CH}}_2\text{-}+{\mathrm{RS}}^{•}$$$${\mathrm{RS}}^{•}+\text{-}\mathrm{NH}\text{-}\mathrm{CH}\left(\mathrm{normalR}’\right)\text{-}\mathrm{CO}\text{-}\rightleftharpoons \mathrm{RSH}+\text{-}\mathrm{NH}\text{-}{}^{•}\mathrm{normalC}\left(\mathrm{normalR}’\right)\text{-}\mathrm{CO}\text{-}$$…”

“…Considering the significantly lower BDEs of the α C-H bonds of amino acid residues compared to the C-H bonds of alcohols and ethers, the similar rate constants suggest that hydrogen transfer reactions by thiyl radicals are not controlled by thermodynamics alone. In fact, polar effects promote the reactions of thiyl radicals with alcohols and ethers [10, 24], but may be of lower significance for the reactions of thiyl radicals with amino acid residues in peptides. It has been concluded that the α C-H bonds of amino acid residues are deactivated by inductive effects, especially in reactions with highly oxidizing radicals such as the hydroxyl radical (HO • ) and chlorine radical (Cl • ), but such inductive effects are less likely to control the reactions of less oxidizing radicals (such as thiyl radicals) [25].…”

“…In radiation biology, and the biology of oxidative stress, in general, hydrogen transfer processes of thiols had been referred to as “repair reactions”, for example “repairing” radicals located on DNA strands [8]. Only later was the reverse reaction, hydrogen abstraction by thiyl radicals, recognized when thiyl radicals were utilized for the inversion at chiral centers in organic molecules [9, 10]. Time-resolved pulse radiolysis experiments provided rate constants for hydrogen abstraction by thiyl radicals (reaction 7) from aliphatic alcohols and ethers, which are on the order of 10 3 -10 4 M -1 s -1 [11, 12].…”

Hydrogen Atom Transfer in Model Reactions

“…In contrast, Roberts and coworkers have devised the concept of ''polarity reversal catalysis'' (PRC), where polar transition states are dominant features explaining the catalytic affect of thiols and thiyl radicals on hydrogen transfer reactions between carbon-centered radicals and several hydrogen donors [68][69][70]. They conclude that polar transition state structures are not necessary to rationalize experimental re-sults (and may even lead to predictions of reactivity which strongly deviate from experimental results).…”

Biomimetic Modeling of the Nitrogen-centered Radical Postulated to occur during the Inhibition of Ribonucleotide Reductases by 2'-Azido-2'-deoxynucleotides.

“…For these reasons, this methodology is more appealing than γ-radiolysis 139 and experiments that require di-tert-butyl hyponitrite as the radical initiator in organic solvents. [140][141][142] Generation of thiyl radicals employing stannyl radicals 143 is inapplicable because azides undergo reduction to amines with tin radicals. 144 However, silane radicals [with exception of (Me 3 Si) 3 Si•] 145 might provide an alternative approach for generation of thiyl radicals since they do not affect reduction of azido groups.…”