Enantiocontrolled Azetidine Library Synthesis via Strain-Release Functionalization of 1-Azabicyclobutanes.

Area of Science:

• Organic Chemistry
• Chemical Biology
• Medicinal Chemistry

Background:

• Azetidines are valuable heterocyclic compounds with broad applications in medicinal chemistry.
• Accessing complex stereopure azetidines remains a synthetic challenge.
• Strain-release functionalization offers a potential route to overcome these synthetic hurdles.

Purpose of the Study:

• To develop a simple, modular, and programmable synthetic strategy for stereopure azetidines.
• To enable the efficient parallel synthesis of diverse azetidine derivatives.
• To apply these azetidines in activity-based protein profiling to identify biological targets.

Main Methods:

• Utilized strain-release functionalization for azetidine synthesis.
• Employed parallel synthesis techniques for rapid analogue generation.
• Designed and synthesized stereoprobes based on the azetidine scaffolds.
• Performed activity-based protein profiling in human cancer cells.

Main Results:

• A straightforward and programmable method for accessing complex stereopure azetidines was established.
• The synthetic strategy allowed for the parallel production of stereodefined azetidines.
• Stereoprobes successfully identified specific protein targets in human cancer cells.
• Ligand binding demonstrated clear stereo- and chemo-selectivity.

Conclusions:

• The developed synthetic approach provides efficient access to valuable stereopure azetidines.
• This methodology facilitates the creation of chemical probes for biological investigations.
• The study highlights the utility of azetidine-based probes in cancer cell biology and target identification.