Exocyclic Olefinic Maleimides: Synthesis and Application for Stable and Thiol-Selective Bioconjugation

Area of Science:

• Organic Chemistry
• Bioconjugation Chemistry
• Medicinal Chemistry

Background:

• Michael addition reactions with endocyclic maleimides are common for site-specific bioconjugation.
• The resulting thio-succinimidyl linkages are unstable and prone to thiol exchange under physiological conditions.

Purpose of the Study:

• To develop a novel bioconjugation strategy using exocyclic olefinic maleimides for enhanced linkage stability.
• To establish a facile and high-yielding synthesis for various exocyclic olefinic maleimides.
• To investigate the catalytic role of phenolic compounds in the synthesis of these maleimides.

Main Methods:

• Synthesis of exocyclic olefinic maleimides via solvent-free Wittig reactions.
• 4-Nitrophenol was employed as a catalyst for the Wittig reaction.
• Mechanistic studies to elucidate the role of the catalyst in ylide formation.

Main Results:

• Exocyclic olefinic maleimides form highly stable thio-Michael adducts that resist thiol exchange.
• A high-yielding Wittig reaction approach for synthesizing diverse exocyclic olefinic maleimides was developed.
• Phenolic compounds, specifically 4-nitrophenol, were shown to effectively catalyze Wittig ylide formation.

Conclusions:

• Exocyclic olefinic maleimides represent a superior alternative to endocyclic counterparts for robust thiol bioconjugation.
• The reported Wittig reaction provides an efficient method for accessing these valuable bioconjugation reagents.
• Phenol-catalyzed Wittig reactions offer a new avenue for synthesizing functionalized olefins.