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
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Inspect source passages
Protecting-group-free peptide CF3 labeling
These passages occur verbatim in the stored paper text. They support the points listed below; they do not verify every statement in the explanation.
15 mol% Ir and 20 equivalents of sulfinate gave 90% conversion of Asp–Tyr
The use of 15 mol% Ir catalyst and 20 equivalents of sulfinate salt gave the highest overall conversion (90%).
Insulin A19-CF3 product 18 was isolated in 12% yield
The insulin modified at tyrosine A19 ( 18 ) was isolated in 12% yield by preparative HPLC.
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.
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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.
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