Cross-Coupling Approach to an Array of Macrocyclic Receptors Functioning as Chiral Solvating Agents

Area of Science:

• Organic Chemistry
• Analytical Chemistry
• Supramolecular Chemistry

Background:

• Chiral macrocyclic receptors are crucial for enantioselective recognition.
• NMR chiral solvating agents (CSAs) are vital tools for determining enantiomeric purity.
• Developing novel CSAs with enhanced enantioselectivity is an ongoing challenge.

Purpose of the Study:

• To synthesize novel chiral macrocyclic receptors with multiple hydrogen-bonding sites.
• To evaluate their efficacy as NMR chiral solvating agents (CSAs) for enantiomeric analysis.
• To elucidate the structural basis for enhanced enantioselectivity.

Main Methods:

• Suzuki-Miyaura cross-coupling reactions for synthesizing receptor variants.
• NMR titration experiments to determine binding constants (Ka).
• X-ray crystallography and DFT calculations to analyze intermolecular interactions.

Main Results:

• A series of chiral macrocyclic receptors (1b-p) were synthesized, with compound 1d showing the highest efficacy.
• Compound 1d effectively resolved 2-chloropropionic acid (CPA) enantiomers, indicated by significant signal splitting in NMR.
• Binding studies revealed (R)-1d as the most enantioselective CSA (Ka(S)/Ka(R) = 5.4), with a notable interaction with (S)-CPA.
• Computational and crystallographic analyses suggested a C-H···Cl-C hydrogen bond between the 4-cyanophenyl group of (R)-1d and (S)-CPA.

Conclusions:

• The synthesized chiral macrocyclic receptors, particularly 1d, are effective NMR CSAs for enantiomeric analysis.
• The 4-cyanophenyl substituent in 1d plays a key role in enhancing enantioselectivity through specific C-H···Cl-C hydrogen bonding.
• This study provides insights into the design principles for developing advanced chiral recognition agents.