Kinetic resolution is a common method to obtain enantioenriched material from a racemic mixture. This process will always deliver enantiopure unreacted material if the reactions are allowed to proceed to sufficient conversion and the selectivity is not unity (s > 1). However, the scalemic reaction product often is discarded, meaning, that the yield of this process seldom exceeds 40-45%. Parallel kinetic resolution can grant access to two distinct, highly enantioenriched products from a single racemic starting material. Here we describe the development of a flow-based system that enables practical parallel kinetic resolution (PKR) of a broad range of racemic saturated N-heterocycles. This process provides access to both enantiomers of the racemic starting material in good yield and high enantiopurity; similar results with classical kinetic resolution would require selectivities 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 were obtained in good yields and high enantiopurities and could be readily separated and hydrolyzed to the corresponding amines without detectable epimerization.

The catalytic kinetic resolution of cyclic amines with achiral N-heterocyclic carbenes (NHC) and chiral hydroxamic acids has emerged as a promising method to obtain enantioenriched amines with high selectivity factors. In this report, we describe the catalytic kinetic resolution of disubstituted piperdines with practical selectivity factors (s up to 52) in which we uncovered an unexpected and pronounced conformational effect resulting in disparate reactivity and selectivity between the cis and trans-substituted piperidine isomers. Detailed experimental and computational (DFT) studies of the kinetic resolution of various disubstituted piperidines revealed a strong preference for the acylation of conformers in which the α-substituent occupies the axial position. This work provides further experimental and computational support for the concerted 7-member transition state model for acyl transfer reagents and expands the scope and functional group tolerance of the secondary amine kinetic resolution.

The scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved by a new catalyst structure and a more environmentally friendly reaction protocol. In addition to increasing selectivity across all substrates, these conditions make possible the resolution of N-heterocycles containing lactams or other basic functional groups that can inhibit the catalyst.

The preparation of enantioenriched chiral compounds by kinetic resolution dates back to the laboratories of Louis Pasteur in the middle of the 19th century. Unlike asymmetric synthesis, this process can always deliver enantiopure material (ee > 99%) if the reactions are allowed to proceed to sufficient conversion and the selectivity of the process is not unity (s > 1). One of the most appealing and practical variants is acylative kinetic resolution, which affords easily separable reaction products, and several highly efficient enzymatic and small molecule catalysts are available. Unfortunately, this method is applicable to limited substrate classes such as alcohols and primary benzylamines. This Account focuses on our work in catalytic acylative kinetic resolution of saturated N-heterocycles, a class of molecules that has been notoriously difficult to access via asymmetric synthesis. We document the development of hydroxamic acids as suitable catalysts for enantioselective acylation of amines through relay catalysis. Alongside catalyst optimization and reaction development, we present mechanistic studies and theoretical calculation accounting for the origins of selectivity and revealing the concerted nature of many amide-bond forming reactions. Immobilization of the hydroxamic acid to form a polymer supported reagent allows simplification of the experimental setup, improvement in product purification, and extension of the substrate scope. The kinetic resolutions are operationally straight forward: reactions proceed at room temperature and open to air conditions, without generation of difficult-to-remove side products. This was utilized to achieve decagram scale resolution of antimalarial drug mefloquine to prepare more than 50 g of (+)-erythro-meflqouine (er > 99:1) from the racemate. The immobilized quasienantiomeric acyl hydroxamic acid reagents were also exploited for a rare practical implementation of parallel kinetic resolution that affords both enantiomers of the amine products in high enantiopurity. The success of this process relied on identification of two cleavable acyl groups alongside implementation of flow-chemistry techniques to ensure reusability of the resolving agents. The work discussed in this Account has laid foundations for new catalyst design as well as development of desymmetrization and dynamic kinetic resolution processes. In the meantime, as all the requisite reagents are commercially available, we hope that hydroxamic acid promoted acylative kinetic resolution will become a method of choice for preparation of saturated N-heterocycles in enantiopure form.

Decagram quantities of enantiopure (+)‐mefloquine have been produced via kinetic resolution of racemic mefloquine using a ROMP‐gel supported chiral acyl hydroxamic acid resolving agent. The requisite monomer was prepared in a few synthetic steps without chromatography and polymerization was safely performed on a >30 gram scale under ambient conditions. The reagent was readily regenerated and reused multiple times for the resolution of 150 grams of (±)‐mefloquine and other chiral N‐heterocylces.