Hypervalent Iodine-Mediated Late-Stage Peptide and Protein Functionalization

Abstract

Hypervalent iodine compounds are powerful reagents for the development of novel transformations. As they exhibit low toxicity, high functional group tolerance, and stability in biocompatible media, they have been used for the functionalization of biomolecules. Herein, we report recent advances up to June 2021 in peptide and protein modification using hypervalent iodine reagents. Their use as group transfer or oxidizing reagents is discussed in this Minireview, including methods targeting polar, aromatic, or aliphatic amino acids and peptide termini.

Keywords: bioconjugation; hypervalent iodine; late-stage functionalization; peptides; proteins.

Figure 1

General representation of hypervalent iodine reagents used for peptide and protein functionalization.

Scheme 1

Selected examples of the trifluoromethylation of Cys‐containing peptides. Amino acids in italic are β‐amino acids. Amino acids in bold are d‐amino acids.

Scheme 2

Most plausible mechanism for the trifluoromethylation of thiols.

Scheme 3

Selected examples of perfluoroethyl‐substituted reagents and application to glutathione labeling. The yield of the isolated product as a trifluoroacetate salt is given in brackets.

Scheme 4

Selected examples of the derivatization of reagent 1 e.

Scheme 5

The functionalization of RA‐CM (14). Labeling efficiency: average percentage of chromophores attached to one protein.

Scheme 6

Noncyclic hypervalent iodine reagents 1 i–k and fluoroalkylation of 17. * Area under the curve (AUC×10²) determined by the integration of mass ion chromatograms measured on the crude mixture. By‐products result from sulfur oxidation.

Scheme 7

Trifluoromethylthiolation of dipeptides.

Scheme 8

a) Alkynylation of Cys‐containing dipeptides. b) Functionalization of the thioalkyne product 29 by CuAAC.

Scheme 9

Proposed mechanistic pathways for thioalkynylation using R‐EBX reagents. R²=OMe, Me, SiMe₃, SiiPr₃, Ph, CO₂Me.

Scheme 10

Proteomic target profiling using EBX reagents a) 3 c and b) 3 e in HeLa cell lysates. Hyperreactive Cys is noted with *.

Scheme 11

Use of TMS‐EBX (3 f) for the functionalization of antibody 34.

Scheme 12

Lipidation of hexapeptides using reagents 3 g and 3 h. M=Na or K.

Scheme 13

Lipidation of longer peptides and a protein using 3 g and 3 h.

Scheme 14

Selected examples of a) Cyc‐Cys stapling, b) Cys‐Lys stapling and the subsequent click reaction. c) One‐pot Cys‐Lys stapling followed by a click reaction. Yields of isolated products are given in brackets.

Scheme 15

VBX formation on a peptide and proteins using 3 c.

Scheme 16

Double functionalization of VBX product 60.

Scheme 17

Met‐selective bioconjugation of peptides and proteins.

Scheme 18

Photoredox‐mediated a) reduction of sulfonium conjugates and b) radical cross‐coupling. * Determined by ¹H NMR spectroscopy.

Scheme 19

a) Fluoroalkylation of Trp‐containing peptides using conditions A or B. b) Labeling of myoglobin.

Scheme 20

Selected examples of Trp‐alkynylation using TIPS‐EBX (3 a).

Scheme 21

C−H arylation of Trp‐containing peptides using diaryliodonium salts 4 d–i.

Scheme 22

a) Tyr oxidation using PhI(OAc)₂ (5) and functionalization using a hydrazine. b) CuAAC functionalization of 99.

Scheme 23

C(sp³)−H a) azidation and b) chlorination of dipeptides. c) Plausible mechanism.

Scheme 24

C(sp³)−H hydroxylation of a Leu‐containing a) dipeptide and b) tripeptide. CFL=household compact fluorescent lamp.

Scheme 25

Photoinduced alkynylation by HAT.

Scheme 26

C(sp³)−H acetoxylation of tripeptides.

Scheme 27

Decarboxylative cyanation using CBX (8).

Scheme 28

a) General catalytic cycle. Proposed mechanisms for b) alkynylation and c) cyanation.

Scheme 29

Decarboxylative alkynylation using R‐EBX reagents 3 k–m.

Scheme 30

Selected examples of decarboxylative introduction of proteinogenic a) indoles and b) phenols on the C‐terminus of various peptides.

Scheme 31

Synthesis of cis‐β‐N‐MeO‐amide‐VBX dipeptides.

Scheme 32

N‐terminus alkynylation of dipeptides using 3 n and 3 a.