Catalytic Kinetic Resolution of Saturated N-Heterocycles by Enantioselective Amidation with Chiral Hydroxamic Acids.

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.

Synthesis of Tetrahydronaphthyridines from Aldehydes and HARP Reagents via Radical Pictet-Spengler Reactions.

The combination of aldehydes with newly designed HARP (halogen amine radical protocol) reagents gives access to α-substituted tetrahydronaphthyridines. By using different HARP reagents, various regioisomeric structures can be prepared in a single operation. These products, which are of high value in medicinal chemistry, are formed in a predictable manner via a formal Pictet-Spengler reaction of electron-poor pyridines that would not participate in the corresponding polar reactions.

A Robust, Recyclable Resin for Decagram Scale Resolution of (±)-Mefloquine and Other Chiral N-Heterocycles.

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.

Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights.

The catalytic kinetic resolution of cyclic amines with achiral N-heterocyclic carbenes and chiral hydroxamic acids has emerged as a promising method to obtain enantio-enriched 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 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.

Kinetic resolution of nitrogen heterocycles with a reusable polymer-supported reagent.

Shake it up baby! Simply shaking a polymer-supported reagent and the racemic amine at room temperature kinetically resolves a broad range of N-heterocycles with good selectivity. The polymer-supported reagents are robust, easy to regenerate, and can be reused dozens of times. Cleavable acyl groups can be used to give access to both amine enantiomers in a single resolution.

Expanded substrate scope and catalyst optimization for the catalytic kinetic resolution of N-heterocycles.

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.