Experimental and Computational Investigations into Trivalent Phosphorous-Mediated Radical Thiol Desulfurization

Abstract

Radical-mediated thiol desulfurization processes using tricoordinate phosphorous reagents are used in a range of applications from small molecule synthesis to peptide modification. A combined experimental and computational examination of the mechanism and kinetics of the radical desulfurization of alkyl thiyl radicals using trivalent phosphorus reagents was performed. Primary alkyl thiols undergo desulfurization between 10^6 to 10^9 M-1s-1 depending on the phosphorus component with either an H-atom transfer step or β-fragmentation of the thiophosphoranyl intermediate may be rate-controlling. While the desulfurization of primary aliphatic thiols showed a marked dependence on the identity of phosphorous reagent used with either a rate-controlling H-atom transfer or -fragmentation, thiols yielding stabilized C-centered radicals showed much less sensitivity. Support for a stepwise S-atom transfer process progressing via a distorted trigonal bipyramidal thiophosphoranyl radical intermediate was obtained from DFT calculated energetics and hyperfine splitting values.

Superfast desulfurization for protein chemical synthesis and modification

“…k obs of 6 3 10 À5 s À1 was obtained in the absence of thiol additives, although a nearly 12-times larger k obs (7 3 10 À4 s À1 ) was recorded in the presence of 10% tBuSH, (Figure 6A, entry 2-3; Figures S113-S115; Table S4). In addition, the propagation rate constant of VA-044 desulfurization with sacrificial thiols obtained in agreement with reported data 37,38 were 10 times larger than that of without thiol (Table S4). This may be rationalized by the less efficient chain propagation in peptide/protein with more complicated structures instead of simple organic thiol compounds, which demonstrates the crucial role of thiol additives to improve desulfurization efficiency in VA044 method.…”

Metal-free reductive desulfurization of C-sp3-substituted thiols using phosphite catalysis

“…12 b Both phosphines and phosphites are well established reagents for desulfurization reactions, 11,15 with the electronics of the R group on PR 3 being key to reactivity. 16 Phosphine sulfides react with super silyl hydride (TTMSS) 17 under free radical conditions to produce phosphines in good yields. 14 Unlike P( iii )/P( v ) = O redox cycles, which occur via polar pathways, the P( iii )/P( v ) = S reduction occurs via a radical mechanism.…”