Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Abstract

Kinetic resolution is a common method to obtain enantioenriched material from a racemic mixture. This process will deliver enantiopure unreacted material when the selectivity factor of the process, s, is greater than 1; however, the scalemic reaction product is often discarded. Parallel kinetic resolution, on the other hand, provides access to two enantioenriched products from a single racemic starting material, but suffers from a variety of practical challenges regarding experimental design that limit its applications. Here, we describe the development of a flow-based system that enables practical parallel kinetic resolution of saturated N-heterocycles. This process provides access to both enantiomers of the starting material in good yield and high enantiopurity; similar results with classical kinetic resolution would require selectivity factors in the range of s = 100. To achieve this, two immobilized quasienantiomeric acylating agents were designed for the asymmetric acylation of racemic saturated N-heterocycles. Using the flow-based system we could efficiently separate, recover and reuse the polymer-supported reagents. The amide products could be readily separated and hydrolysed to the corresponding amines without detectable epimerization. Parallel kinetic resolution (PKR) of N-heterocycles via asymmetric acylation has been achieved using quasienantiomers of polymer supported hydroxamic acid reagents. Flow techniques provide physical separation of the reagents, establishing a practical implementation of PKR. The enantioenriched amide products can be readily deprotected to reveal the desired amine without detectable epimerization.