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

Abstract

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.

Recent Advances in Asymmetric Organomulticatalysis

“…However, Int‐52 was unable to react with the racemic amine 72 . A smooth trans‐aclyation between Int‐52 and chiral hydroxamic acids Cat‐29 [41c] was further conducted and led to the formation of NHC Cat‐28 and acylated intermediate Int‐53 , which could be confirmed by 1 H NMR spectroscopy. Int‐53 selectively reacted with the amine to afford the amide 74 and recovered 73 .…”

N‐Heterocyclic Carbene (NHC)‐Organocatalyzed Kinetic Resolutions, Dynamic Kinetic Resolutions, and Desymmetrizations

“…Although numerous catalytic activation modes have been established over the last decadei nN HC organocatalysis, [10] their applications in KRs are limited. [11] Enantioselective acylation reactions with chiral acylazoliums generated from various startingm aterials have been the dominant ones in NHC-catalyzed KR processes. Currently,r acemic functional molecules such as alcohols, amines,a mides, and aldehydesa re able to be efficientlyr esolved with good s and ee values through asymmetric NHCcatalytic reactions.…”

“…However,c ompared to the tremendous development in asymmetricc atalytic reactions enabled by NHCs, their applications in KR and desymmetrization processes have been relatively less reported. [11] Limited reactionm odes have been involvedi nt he KR and desymmetrization processes enabled by NHC organic catalystsa nd, in addition to this, the synthesis of chiral molecules that bear one or more heteroatom stereogenic centers is challenging and therefore interesting. [12] NHC-catalytic KR and desymmetrization processes couldprovide promising strategies for the generation of heteroatom-based chiral centers.C learly,t here is plenty of room for growth in this highly active research field.…”

Highly selective acylation of polyamines and aminoglycosides by 5-acyl-5-phenyl-1,5-dihydro-4H-pyrazol-4-ones

“…The formation of an amide bond by acyl transfer is a classic chemical reaction 1 that has been extensively studied 2 and widely applied. 3 Over the years numerous acyl transfer agents have been investigated; their activities have been dependent on the leaving group, which has ranged from those of the highly reactive acyl chlorides and anhydrides to those that are conjugate bases of relatively weak acids. The linkage to the acyl group has included N -imidazolyl 4a – g and N -benzotriazolyl, 4h – m succinimidyloxy, 5 cyanide, 6 sulfonamide, 7 trichloromethyl, 8 enolates, 9 and, most recently, boron trifluoride.…”