Protecting-group-free peptide CF3 labeling
ZnTFMS/TBHP or Ir photoredox trifluoromethylates tyrosine C–H on unprotected peptides, including insulin, without hitting polar side chains.
Source
Protecting group free radical C-H trifluoromethylation of peptides
Study at a glance
- Design
- Other — Radical CF3 labeling of unprotected peptides and insulin with photoredox or zinc sulfinate conditions
- N
- Peptide chemistry with secondary receptor-binding assays — no subject cohort N
- Population
- Model peptides, hormones, and insulin
- Outcome
- Site-selective tyrosine trifluoromethylation yields and retained insulin activity
Structured fields used in claim comparison tables when every cited study has a complete layer.
What they did
They optimized radical CF3 transfer to Ac-Tyr-NHMe, then dipeptides and longer hormones, using either Zn(SO2CF3)2/TBHP in aqueous acid or NaSO2CF3 plus Ir[dF(CF3)ppy]2(dtbbpy)PF6 under blue light. Insulin was labeled, HPLC-separated, and checked by LC-MS/MS, binding, and NMR.
What they found
Photoredox on the Tyr model gave 78% mono-CF3 in MeCN/aqueous AcOH. Asp–Tyr reached 90% combined conversion with 15 mol% Ir and 20 equiv sulfinate; the MSD photoreactor gave 61% combined isolated-scale yield. Insulin was labeled at all four tyrosines (~30% conversion); A19-CF3 insulin was isolated in 12% yield and kept nM insulin-receptor activity (IC50 1.4 vs 0.8 nM).
The limits
What it doesn't show
Isolated yields on long peptides are modest; Trp competes when present. The work is labeling chemistry, not an in-cell biological mechanism study. Photoredox scale-up is light-source dependent (Kessil 39% vs MSD 61%).
Key terms
- Langlois/Baran sulfinate
- CF3SO2– salts (Na or Zn) that generate •CF3 after oxidation.
- Protecting-group-free
- Native peptides with free side chains, not fully protected synthetic intermediates.
- Photoredox CF3 transfer
- An Ir(III) photocatalyst oxidizes sulfinate to •CF3 under blue light, milder than excess TBHP.
- 19F NMR handle
- A CF3 reporter whose chemical shift reports local structure without changing polarity much.
- SOFAST HMQC
- Proton-efficient 2D NMR used to compare methyl fingerprints of native vs A19-CF3 insulin.
Flashcards
Research intelligence for this paper
See its role on concept claims, tensions it is part of, placement history, and related discoveries.
Quiz yourself
The preferred aromatic residue for CF3 installation is
Common questions
Which residue is the main target?
Tyrosine aromatic C–H; His/Phe are less reactive, Trp competes if present.
Why photoredox instead of only TBHP?
Controlled oxidant generation cuts tyrosine dimerization and raises mono-CF3 selectivity (up to 78% on the model).
Does CF3-insulin still bind the receptor?
Yes—A19-CF3 insulin IC50 1.4 nM vs 0.8 nM native; overall fold is retained by NMR.
Need protecting groups?
No; conditions are aqueous-acid compatible with native side chains.
More on Chemical biology