Resolution of a Chiral β-Aminoketone via Diastereomeric Salt Formation: From Experimental Evidence to Molecular-Level Insights Into Solution-Phase Clusters

Abstract

The classical diastereomeric salt resolution approach was employed to separate (±)-1,3-diphenyl-3-(phenylamino)propan-1-one using both enantiomers of 10-camphorsulfonic acid (CSA) as resolving agents. Gentle stirring at room temperature resulted in the stereoselective precipitation of a single diastereomeric salt, yielding a solid phase highly enriched in one enantiomer of the target compound. Control experiments confirmed the crucial role of the chiral counterion in directing the selectivity of the process. Molecular Dynamics simulations and subsequent Principal Component Analysis revealed slight but significant differences in the pre-nucleation size distribution of ionic clusters and in the dynamics of their mutual interconversion, hence suggesting that these differences could play a role in the racemic resolution.