Catalytic Kinetic Resolution of Cyclic Secondary Amines

Abstract

The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.

Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes

“…An ingenious approach to resolving chiral, racemic amines was reported in 2011 by Bode and co-workers. 228 The optimized catalytic system was composed of an achiral, bicyclic triazolium precatalyst G 20 and a chiral, aminoindanol-derived hydroxamic acid 209 . These conditions were used to resolve a range of chiral, racemic cyclic amines bearing a stereogenic carbon α to the nitrogen atom (Scheme 194).…”

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

“…10 Slightly higher reaction rates and selectivities are observed with this reagent and a recyclable, resin supported variant makes it an attractive option for practical amine resolution. 13 We first examined the kinetic resolution of the compounds in the 2,3-disubstitution series (Table 2).…”

6.11 N-Acylation Reactions of Amines

“…This novel catalytic protocol proved successful for the kinetic resolution of a range of racemic piperidines, piperazines, morpholines, tetrahydroisoquinolines, and azepanes with synthetically useful s values ranging 8-74 ( Figure 72). 423 There have been numerous reports of lipases employing esters and carbonates as acyl donors for the enantioselective N-acylation of ammonia, primary and secondary amines, anilines, and hydroxylamines. 253 Ester ammonolysis and aminolysis reactions are essentially irreversible in organic or ionic liquid solvents under anhydrous conditions that serve to minimize unwanted hydrolysis of enzyme-acyl intermediates.…”

“…253 Figure 72 Tandem organocatalytic N-acylation of (rac)-secondary cyclic amines using hydroxyenone as an acyl donor. 423 Ar R Figure 71 Tandem organocatalytic N-acylation of (rac)-secondary amines using DMAP and a chiral thiourea catalyst. 422 BcL, E >100 Figure 73 A representative range of chiral amides prepared in high enantioselectivity via lipase-catalyzed N-acylation of their parent (rac)-amines using esters or acids as acyl donors.…”