Induced folding by chiral nonplanar aromatics.

Area of Science:

• Organic Chemistry
• Supramolecular Chemistry
• Stereochemistry

Background:

• Development of chiral, bowl-shaped molecular architectures is crucial for advanced materials and catalysis.
• Controlling regioselectivity in complex organic synthesis remains a significant challenge.
• Trioxatricornan serves as a versatile scaffold for creating C(3)-symmetric structures.

Purpose of the Study:

• To synthesize and characterize novel C(3)-symmetric folded structures based on a trioxatricornan core.
• To control the regioselectivity of substitution reactions on the trioxatricornan scaffold.
• To investigate the conformational behavior of peripheral amino acid substituents.

Main Methods:

• Synthesis of C(3)-symmetric trioxatricornan isomers via ortho-lithiation and nucleophilic substitution.
• Derivatization with amino acids and menthol to form diastereomers.
• Separation of diastereomers using preparative chromatography.
• Characterization using vibrational circular dichroism (VCD), electronic circular dichroism (ECD), density functional theory (DFT), 2D NMR, and molecular dynamics.

Main Results:

• Successful synthesis of predominantly C(3)-symmetric trioxatricornan isomers by reversing statistical regioselectivity.
• Formation of diastereomers with amino acids or menthol, exhibiting distinct folded and spread-out conformations.
• Determination of absolute configurations and detailed structural analysis of folded and spread-out diastereomers.

Conclusions:

• A novel method for regioselective C-H activation and functionalization of trioxatricornan enables controlled synthesis of C(3)-symmetric structures.
• The synthesized chiral folded structures exhibit tunable peripheral conformations (folded vs. spread-out) of appended amino acids.
• This work provides a foundation for designing complex chiral molecules with predictable structural and conformational properties.