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.

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What C–H site is functionalized on peptides?

Tyrosine aromatic C–H, installing CF3 without protecting groups.

First stoichiometric oxidant system?

Baran’s ZnTFMS plus TBHP in aqueous acid.

Photoredox catalyst that worked?

Ir[dF(CF3)ppy]2(dtbbpy)PF6 with NaSO2CF3, not the zinc salt.

Best model-Tyr photoredox yield?

78% mono-CF3 in 1:1 MeCN / 10% aqueous AcOH.

Asp–Tyr screen optimum?

15 mol% Ir and 20 equiv sulfinate, 90% combined conversion.

Does Trp compete with Tyr?

Yes; CF3 also adds at indole C2 (Trp:Tyr up to 3.5:1).

Are longer peptides site-selective for Tyr?

Deltorphin, angiotensins, and β-casomorphin label Tyr whether N-terminal or internal.

How many insulin tyrosines can react?

All four (A14, A19, B16, B26); His and Phe were not labeled.

Isolated yield of A19-CF3 insulin?

12% after preparative HPLC.

Does A19-CF3 insulin keep function?

Yes; IC50 1.4 nM vs 0.8 nM native; fold retained by methyl HMQC.

Why is a 19F tag useful?

19F chemical shift reports local environment for bio-NMR without adding polar handles.