Pathway selection between click and acyl transfer reactions driven by aminoacyl phosphates

Area of Science:

• Chemical Synthesis
• Supramolecular Chemistry
• Biomimetic Chemistry

Background:

• Biological covalent transformations exhibit precise temporal control, crucial for regulating cellular processes.
• Achieving similar temporal regulation in synthetic chemical systems remains a significant challenge.

Purpose of the Study:

• To develop an abiotic aqueous reaction network with programmable temporal control over covalent transformations.
• To investigate the role of peptide-based nucleophiles in governing reaction sequences.

Main Methods:

• Utilized aminoacyl phosphate esters with alkyne groups as substrates.
• Employed phenolic and cysteine-containing peptides as nucleophiles to modulate copper-catalyzed azide-alkyne cycloaddition (CuAAC) and thioester formation.
• Performed kinetic analysis to understand pathway selection and intermediate lifetime effects.

Main Results:

• Phenolic nucleophiles accelerated CuAAC, while cysteine peptides delayed it, favoring thioester formation via transient copper coordination.
• Thiol-copper coordination was identified as a key factor in early pathway selection.
• Self-assembly of intermediates was shown to prolong their lifetimes, enabling subsequent transformations.
• A three-step cascade reaction (thioester formation, diester generation, CuAAC) was achieved by combining nucleophiles within a single peptide.
• Product selectivity was further tuned by varying the azide structure.

Conclusions:

• The interplay between chemical reactivity and supramolecular organization can encode intrinsic temporal order into reaction networks.
• This work provides a framework for designing synthetic systems with programmed temporal control, inspired by biological processes.