The energy-transfer-enabled biocompatible disulfide-ene reaction

Area of Science:

• Organic Chemistry
• Biochemistry
• Photochemistry

Background:

• Sulfur-containing molecules are vital for biological processes.
• The methylthioether moiety is essential, found in methionine and installed via radical-S-adenosylmethionine methylthiotransferases.
• Existing thiol-ene reactions lack biocompatibility and regioselectivity for unactivated substrates.

Purpose of the Study:

• To develop a general, biocompatible, chemo-, and regioselective hydrothiolation method for unactivated alkenes and alkynes.
• To enable the formation of carbon-sulfur bonds, including the biologically important hydromethylthiolation.
• To utilize triplet-triplet energy transfer for disulfide activation.

Main Methods:

• Activation of disulfides via triplet-triplet energy transfer.
• Development of a photosensitized disulfide-ene reaction.
• Utilizing transient absorption spectroscopy to study the sensitization mechanism.
• Optimization of the catalytic system based on mechanistic insights.

Main Results:

• A general, chemoselective anti-Markovnikov hydroalkylation/arylation of alkenes and alkynes was achieved.
• The reaction demonstrated high functional group tolerance and biocompatibility.
• Successful hydromethylthiolation, crucial for biological contexts, was accomplished.
• Mechanistic studies using transient absorption spectroscopy informed catalytic system optimization.

Conclusions:

• The developed photosensitized disulfide-ene reaction provides a novel route for carbon-sulfur bond formation.
• This method offers a biocompatible and efficient alternative for hydrothiolation, applicable to unactivated substrates.
• The reaction is poised to advance bioimaging and late-stage functionalization in chemical biology, particularly for metabolic labeling.