A Modular and Diastereoselective 5 + 1 Cyclization Approach to N-(Hetero)Aryl Piperidines

Abstract

A new general de novo synthesis of pharmaceutically important N-(hetero)­aryl piperidines is reported. This protocol uses a robustly diastereoselective reductive amination/aza-Michael reaction sequence to achieve rapid construction of complex polysubstituted ring systems starting from widely available heterocyclic amine nucleophiles and carbonyl electrophiles. Notably, the diastereoselectivity of this process is enhanced by the presence of water, and DFT calculations support a stereochemical model involving a facially selective protonation of a water-coordinated enol intermediate.

Regiodivergent synthesis of sulfone-tethered lactam–lactones bearing four contiguous stereocenters

“…N -arylated γ-lactam-tethered alkenoic acids underwent productive 6- exo -cyclization (see 2c/d ), which is noteworthy since N -aryl γ-lactams are embedded in several pharmacologically pertinent targets. 17 Lactam-tethered alkenoic acids harboring electronically diverse N -benzyl substituents undergo satisfactory cyclization (see 2e–g ). The successful construction of sulfonylated lactam–lactones harboring the N -phenethyl group (see 2h–i ) is noteworthy given that the latter is often employed as a precursor to the indolizidine/quinolizidine scaffold.…”

Leveraging the 1,3-azadiene-anhydride reaction for the synthesis of functionalized piperidines bearing up to five contiguous stereocenters

“…N -Aryl piperidines and 2-oxopiperidines are embedded in several pharmacologically pertinent targets, including Factor Xa inhibitors and phosphodiesterase-10 inhibitors. 15 N -aryl imines are typically reluctant substrates for the CCR, 16 presumably due to the hydrolytic instability (and subsequent proneness of the resulting amine to undergo acylation with the anhydride) as well as the relatively reduced nucleophilicity of the nitrogen atom. The reluctance is further exacerbated when electron-withdrawing anilines are employed.…”

Tunable [3+2] and [4+2] annulations for pyrrolidine and piperidine synthesis

“…Using 2 equivalents of NIS, we were excited that the piperidine product 3 was formed in 37% yield as a single diastereomer (Scheme 2, entry 1). 18 Although increasing solvent concentration raised the yield to 49%, we could not improve upon this level regardless of condition changes based on NIS loading (Scheme 2, entries 2 and 3). Our stoichiometry screening of NIS found that instead of piperidine 3 , the pyrrolidine 4a was formed exclusively when the NIS stoichiometry was lowered to 1 equivalent (Scheme 2, entries 3–5).…”