Selective Photoredox Trifluoromethylation of Tryptophan‐Containing Peptides

Abstract

For application in drug discovery and biomedicine, it is crucial to develop new biocompatible methods to modify polypeptides. Herein, a visible-light-induced photoredox trifluoromethylation of tryptophan-containing peptides is reported. Under a mild, biocompatible, and straightforward condition, this strategy could incorporate the trifluoromethyl group into tryptophan residue with excellent chemo-and site-selectivity. The use of lower photocatalyst loading in 2 mol-% and cheap CF 3 SO 2 Na salt represents a great catalytic activity and [a] Methyl N-Acetyl-S-trifluoromethyl-L-cysteinate (2e): [15a] White solid. 1 H NMR (400 MHz, CDCl 3 ) δ = 6.84 (d, General Procedure for Trifluoromethylation of Di-, Tri-and Tetrapeptides: A solution of peptide 3 (0.20 mmol), CF 3 SO 2 Na (0.40 mmol) and Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (2 mol-%) in CH 3 CN (2 mL) was stirred under air atmosphere and irradiated by 3 W blue LEDs for 4 h. When the reaction finished, the solvent was removed under reduced pressure by an aspirator. Then, the product was obtained by flash column chromatography on silica gel (dichloromethane/ethyl acetate) to afford corresponding trifluoromethylation of peptide 4. Ac-Trp(CF 3 )-Gly-OMe (4a): [15b] White solid. 1 H NMR (400 MHz, CD 3 CN) δ = 10.18 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.2 Hz, ]DMSO) δ = 11.91 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.05 (d, J = 8.9 Hz, 0.54H) & 7.99 (d, J = 9.0 Hz, 0.12H), 7.83 (d, J = 8.1 Hz, 0.82H) & 7.77 (d, J = 8.3 Hz, 0.15H), 7.41 (d, J = 8.2 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 4.75-4.57 (m, 0.88H) & 4.57-4.47 (m, 0.15H), 4.42-4.25 (m, 1H), 3.61 (s, 0.44H) & 3.55 (s, 2.

Site‐Selective Trifluoromethylation Reactions of Oligopeptides

“…Driven by their experience in photoredox catalysis, Lei and co‐workers have recently reported a visible‐light induced Ir‐catalyzed radical C2‐trifluoromethylation of a variety of Trp‐containing short peptides with Langlois reagent . Unlike previous examples, the method was found applicable for the selective modification of a number of di‐, tri‐ and tetrapeptides bearing amino acids with unprotected alcohols such as Tyr, Thr and Ser, or the carboxyl group such as Asp, among others (Scheme ).…”

Single electron transfer-based peptide/protein bioconjugations driven by biocompatible energy input

“…On the other hand, since the thiol (thiolate) group of cysteine can readily react in SET reactions, the use of cysteine in conjunction with visible-light-induced photoredox bioconjugation 45 ). c Photoredox tryptophan bioconjugation with at the β-position of tryptophan, reported by Shi in 2018 (ref.…”

Recent Advances in Rapid Synthesis of Non-proteinogenic Amino Acids from Proteinogenic Amino Acids Derivatives via Direct Photo-Mediated C–H Functionalization

“…Trifluoromethanesulfonyl chloride, 2-(trifluoromethylsulfonyl)ethanone, and Umemoto reagent II have been used in the trifluoromethylation reactions independently by Blechert's group [60], Li's group [61], Hamashima and Egami's group [62], since 2015. NaSO 2 CF 3 as a stable, inexpensive, and easy-handling trifluoromethyl synthon has been applied in the trifluoromethylation of tryptophans catalyzed by the mesoporous graphitic carbon nitride (mpg-CN) [63] and iridium complex [64], respectively. Notably, electrochemistry was merged with photochemistry to catalyze the trifluoromethylation of tryptophan with NaSO 2 CF 3 [65].…”

“…Gem-difluoromythylation was realized using triaryl phosphine as an electron donor to combine with 2,2-difluoro-2-iodoacetate for the formation of an EDA complex facilitating the reaction by Zhang's group in 2020 (Scheme 29b) [67]. Particularly, Chiang's group has expended the scope of the visible-light-induced photoredox trifluoromethylation to the tryptophan-containing peptides with excellent chemo-and site-selectivity under mild and biocompatible conditions (Scheme 28) [64]. Trifluoromethylation of tryptophans from plentiful trifluoromethyl synthons in photochemistry has been widely investigated (Scheme 27).…”

“…C(sp 2 )-H trifluoromethylation of Trp derivatives.Particularly, Chiang's group has expended the scope of the visible-light-induced photoredox trifluoromethylation to the tryptophan-containing peptides with excellent chemo-and site-selectivity under mild and biocompatible conditions (Scheme 28)[64].…”