Chiral Calix[3]pyrrole Derivatives: Synthesis, Racemization Kinetics, and Ring Expansion to Calix[9]- and...

Area of Science:

• Supramolecular Chemistry
• Organic Synthesis
• Macrocyclic Chemistry

Background:

• Chiral pyrrolic macrocycles are of significant interest but challenging to design.
• Calixpyrroles are a versatile class of macrocyclic compounds.

Purpose of the Study:

• To synthesize and characterize a novel calixpyrrole-based chiral macrocyclic system.
• To investigate the racemization mechanism and explore methods for chiral resolution.
• To evaluate the synthetic utility of the new macrocycle.

Main Methods:

• Synthesis of the calix[1]furan[1]pyrrole[1]thiophene macrocycle from an oligoketone.
• Solid-state structural analysis using X-ray crystallography.
• Racemization studies and molecular dynamics simulations.
• Pyrrole N-methylation for stabilization and chiral resolution.
• Synthesis of larger calix[n]furan[n]pyrrole[n]thiophene analogues.

Main Results:

• A novel chiral macrocycle, calix[1]furan[1]pyrrole[1]thiophene (1), was successfully synthesized.
• Macrocycle 1 exhibits a partial cone conformation and undergoes racemization via ring inversion, with thiophene inversion being rate-limiting.
• Pyrrole N-methylation effectively suppressed racemization and enabled chiral resolution.
• Enantioselective N-methylation was achieved with modest stereoselectivity using a chiral ammonium salt.
• Compound 1 served as a precursor to various calix[n]furan[n]pyrrole[n]thiophene products (n=2-4), including a record-sized calix[12]pyrrole analogue.

Conclusions:

• The developed calixpyrrole-based system provides a new avenue for chiral macrocycle design.
• Understanding the racemization mechanism is crucial for controlling chirality in these systems.
• N-methylation offers a viable strategy for stabilizing chiral macrocycles and achieving resolution.
• The synthesized macrocycle is a versatile building block for constructing larger and more complex macrocyclic structures.