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. 2022 Nov 8;58(89):12439-12442.
doi: 10.1039/d2cc04967h.

A phosphine-based redox method for direct conjugation of disulfides

Yong Lu  1 , Lin You  1 , Chuo Chen  1
Affiliations

A phosphine-based redox method for direct conjugation of disulfides

Yong Lu et al. Chem Commun (Camb). .

Abstract

Technologies for cysteine disulfide detection and conjugation are pivotal to understanding protein functions and developing disulfide-derived therapeutic agents. Currently, disulfide modification requires reductive cleavage prior to functionalization, posing challenges to differentiating disulfides from free thiols. We describe herein Redox-assisted Disulfide Direct Conjugation (RDDC) as a new method to enable disulfide rebridging without cross-reacting with free thiols.

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Conflict of interest statement

Conflicts of interest

The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Strategies for disulfide bioconjugation and the design of RDDC.
A) Traditional reduction-conjugation methods do not differentiate disulfides from free thiols. B) To achieve selective disulfide conjugation, free thiols are masked prior to disulfide reduction and conjugation. C) Redox-assisted Direct Disulfide Conjugation (RDDC) allows for selective disulfide conjugation in one-step. D) Mechanistic rationale for RDDC. Oxidation of phosphine 1 by a disulfide would activate itsaldehyde group. Trapping the released thiolate by 2 would generate 3 that rearranges through oxonium 4 to form dithioacetal 5.
Figure 2.
Figure 2.. The efficiencies of different phosphines in promoting disulfide–aldehyde condensation in benzene.
Small, electron-rich phosphines are generally more reactive. Reaction conditions: 6:7:PR3=1:1:1, substrate concentration: 0.1 M.
Figure 3.
Figure 3.. Scope of the trimethylphosphine-promoted bisthioacetal formation.
RCHO 1.0 mmol, 1.0 equiv, RSSR: 1.5 equiv, PMe3: 1.5 equiv. For aliphatic aldehyde/dialkyl disulfide: RSSR: 3.0 equiv, PMe3: 3.0 equiv. The reported yields are after isolation.
Figure 4.
Figure 4.. Synthesis of the RDDC reagent.
11 are air-stable tetrafluoroborate salts.
Figure 5.
Figure 5.. RDDC proceeds smoothly in water.
11b inserted into the disulfide of lipoic acid effectively in pH 8.2 HEPES buffer under aerobic conditions. Reaction conditions: 0.1 mmol lipoic acid, 0.02M, 10 equiv 11b.
Figure 6.
Figure 6.. RDDC in peptide stapling.
11b inserted into the disulfide of salmon calcitonin (13) under physiologically relevant conditions.
See this image and copyright information in PMC

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