Rhodium-Catalyzed Asymmetric Hydrogenation of N-(1-benzylpiperidin-3-yl)-enamides: An Efficient Access to Valuable Enantioenriched 3-Aminopiperidine Derivatives

Abstract

An efficient synthetic entry to enantioenriched 3-aminopiperidine derivatives using rhodium-catalyzed asymmetric hydrogenation of N-(1-benzylpiperidin-3-yl)enamides is described. This method provides an atom-economical and attractive route to both enantiomers of the valuable 3-aminopiperidine moiety, which is an important structural unit that can be found in many natural products and pharmaceutical drugs encompassing a broad range of biological activities. Under optimized reaction conditions, the targeted 3-aminopiperidine derivatives were obtained in high yields up to 92% and with enantiomeric excesses up to 96% after a single crystallization.

Rh-Catalyzed Enantioselective Hydrogenation of Di- and Tri-Substituted Enamides Enabled by Easily Tunable P-Stereogenic N-Phosphinyl Phosphoramidite Ligands

“…Frequently, the alkyl/aryl group at the amide part becomes an important factor that affects the enantioselective outcome in enamide hydrogenation. , Hence, we also screened two additional indanone-enamides with an alkyl and aryl (i-Pr, Ph) substituent at the amide functionality ( 1a-iPr and 1a-Ph ) to examine the effect on the ee. A quantitative yield was obtained in the hydrogenation of both 1a-iPr and 1a-Ph using Rh/ JoSoPhos - ( S P ) - L7 in dichloromethane (Scheme ) with a small reduction in enantioselectivity ( i-Pr : 94% and Ph : 92% ee).…”

Recent Advances in the Enantioselective Synthesis of Chiral Amines via Transition Metal-Catalyzed Asymmetric Hydrogenation

“…Despite that, the resulting chiral cyclic amines are very useful structural motifs that can be found in a range of bioactive molecules. 358 An example of this class of substrates are cyclic α-dehydro amino ketones (S94, Scheme 59). In 2016, W. Zhang and co-workers reported that P-stereogenic chiral ligand L18b, using Rh catalysis, efficiently hydrogenated S94 to chiral cyclic trans-β-amino alcohols P94a via a one-pot sequential AH with excellent enantioselectivities and diastereoselectivities.…”

“…In contrast to acyclic enamides, which have been extensively studied, the AH of cyclic enamides remained a challenge before the past decade. Despite that, the resulting chiral cyclic amines are very useful structural motifs that can be found in a range of bioactive molecules . An example of this class of substrates are cyclic α-dehydro amino ketones ( S94 , Scheme ).…”

Concise synthesis of Azilect via cobalt-catalyzed enantioselective hydrogenation in a bio-based solvent

“…It has been reported that the enantioselectivity dropped from 92% to 7% upon changing the phenyl group to iso-propyl along with a reduced conversion using Rh/SYNPHOS catalyst using N-(1-benzylpiperidin-3-yl)-enamides as substrates. 66 On the other hand, the ee could be improved with 56% upon changing the Me substituent (40% ee) to o-MeO-C 6 H 4 (96% ee) in the hydrogenation of 2-amido-acrylates using a Ni/BINAP catalyst. 67 Hence, we examined the amide substituent effect in the enantioselective hydrogenation of the enamides with two additional enamide derivatives (Fig.…”