Chiral Amplification through the Interplay of Racemizing Conditions and Asymmetric Crystal Growth.

Area of Science:

• Chiral chemistry
• Crystallization science
• Asymmetric synthesis

Background:

• Enantiomeric excess (ee) amplification is typically achieved through combined crystal growth and dissolution.
• Crystal growth alone has been considered detrimental to enantiomeric purity, leading to erosion rather than amplification.
• Racemization in solution is a known phenomenon for conglomerate crystals.

Purpose of the Study:

• To demonstrate and explain enantiomeric amplification solely through crystal growth.
• To investigate the mechanistic basis for unexpected amplification during crystallization.
• To identify factors influencing asymmetric amplification for practical applications.

Main Methods:

• Experimental crystallization of clopidogrel and tert-leucine precursors.
• Analysis of enantiomeric excess in solid phases.
• Development of a mechanistic framework linking racemization and crystal growth rates.

Main Results:

• Striking enantiomeric amplification was observed during crystal growth for clopidogrel and tert-leucine.
• The interplay between racemization and crystal growth rates was identified as the key mechanism.
• Increasing the mass of grown material enhanced asymmetric amplification, enabling high ee from low ee seeds.

Conclusions:

• Crystal growth, when coupled with racemization, can be a powerful tool for enantiomeric amplification.
• This finding challenges the conventional view of crystal growth as a source of enantiomeric erosion.
• The study provides a practical basis for producing enantiopure molecules through optimized crystallization processes.