Synthesis and applications of optically pure trans-2-(3,5-dimethylphenoxy)cyclohexan-1-ol as chiral auxiliary for preparation of α-substituted carboxylic acid derivatives

Abstract

In the present work, trans-2-(3,5-dimethylphenoxy)cyclohexan-1-ol was synthesized and its enantiomers were separated by Enzymatic Kinetic Resolution (EKR). The absolute configuration was established by converting to diastereomer with esters of known chiral description. Chiral alcohol was then used as an auxiliary for the preparation of esters by coupling with racemic α-halo acids in presence of DCC and a suitable base. We observed an efficient Dynamic Kinetic Resolution as the product esters were obtained in enriched diastereomeric forms. Effect of several parameters like base, temperature and reaction time was studied. The relative energy profile of the diastereomers was studied by computational analysis and the energy difference of diastereomeric products were in accordance with the observed diastereoselectivity. The chirally pure α-halo acid could be separated from the auxiliary, without any loss of optical purity of both components.