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

Abstract

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.

Recent Advances in Asymmetric Organomulticatalysis

“…A catalytic kinetic resolution of cyclic amines was then disclosed by Bode [41] and coworkers who utilized the cooperative catalysis system involving carbene Cat‐24 and chiral hydroxamic acid Cat‐25 to afford the enantioenriched amines 73 with high selectivity factors (Scheme 23). [41a] The proposed cooperative catalytic cycle [41b] for the kinetic resolution of amines started with the generation of Int‐49 by the nucleophilic addition of the NHC Cat‐28 ’ to the substituted α ‐hydroxyenone 71 , followed by the liberation of acetone to form the Breslow intermediate Int‐50 . β ‐Protonation of Int‐50 resulted in the azolium intermediate Int‐51 , and Int‐52 after subsequent tautomerization.…”

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

“…In the case of trans-2,3-disubstituted piperidines, the two lowest energy transition states (2S,3R-α-axial and 2R,3S-α-equatorial), which give rise to enantiomeric products, are of similar energy thus accounting for the rather low selectivity. 19 To further probe these results,we prepared and resolved transdecahydroquinoline, a conformationally locked substrate with both substituents occupying equatorial position (Scheme 15). The recovered enantioenriched amine was obtained with an opposite sense of enantioinduction as suggested by a previously established stereochemical model.…”

“…Additionally, the calculations indicate rather large energy differences for the acylation of the (2 S ,3 S ) and (2 R ,3 R ) enantiomers, leading to an increased selectivity in the case of cis- 2,3-disubstituted piperidines. In the case of trans- 2,3-disubstituted piperidines, the two lowest energy transition states (2 S ,3 R -α-axial and 2 R ,3 S -α-equatorial), which give rise to enantiomeric products, are of similar energy thus accounting for the rather low selectivity …”

Novel (S)-Selective Hydrolase from Arthrobacter sp. K5 for Kinetic Resolution of Cyclic Amines

“…Optically active amines can be prepared from racemic amine by diastereomeric salt formation using chiral carboxylic acids [17] or by stereoselective bioconversion of racemic N-acyl amine using enzymes [18][19][20]. Several studies on chiral cyclic amines' preparation via chemical or enzymatic resolution have been reported (Scheme 1) [21][22][23][24][25][26][27][28][29][30][31][32][33]. In the enzy- Optically active amines can be prepared from racemic amine by diastereomeric salt formation using chiral carboxylic acids [17] or by stereoselective bioconversion of racemic N-acyl amine using enzymes [18][19][20].…”

“…In the enzymatic method, racemic piperidines are stereoselectively acylated or hydrolyzed by a lipase or protease to obtain the desired enantiomer [21][22][23][24]. Conversely, the racemates are chemically resolved by chiral acylating reagents to provide enantioenriched amines [25][26][27]. Other chemical resolutions have been reported [28][29][30]; however, these chemical processes require chiral reagents for kinetic resolution.…”