Direct Asymmetric Amination of α-Branched Cyclic Ketones Catalyzed by a Chiral Phosphoric Acid

Abstract

Here we report the direct asymmetric amination of α-substituted cyclic ketones catalyzed by a chiral phosphoric acid, yielding products with a N-containing quaternary stereocenter in high yields and excellent enantioselectivities. Kinetic resolution of the starting ketone was also found to occur on some of the substrates under milder conditions, providing enantio-enriched α-branched ketones, another important building block in organic synthesis. The utility of this methodology was demonstrated in the short synthesis of (S)-ketamine, the more active enantiomer of this versatile pharmaceutical.

Asymmetric addition of α-branched cyclic ketones to allenamides catalyzed by a chiral phosphoric acid

“…A heteroaryl-substituted analogue worked well, yielding the product ( 3j ) in excellent yield and enantioselectivity. In contrast to our previous work in the amination of the thiophenylketone, no kinetic resolution of the starting ketone was observed under these conditions 13. The cyclopentanone ( 3k ) and 4-pyranone ( 3l ) derived substrates were also well tolerated in this transformation.…”

“…Very recently, we reported on the direct asymmetric amination of α-branched cyclic ketones catalyzed by a chiral phosphoric acid to generate N-containing quaternary stereocenters from unactivated cyclic ketones 13. With our continuing interest in asymmetric functionalization of α-branched cyclic ketones,13,14 we turned our attention to potential Michael addition of these substrates to conjugated olefins.…”

“…With our continuing interest in asymmetric functionalization of α-branched cyclic ketones,13,14 we turned our attention to potential Michael addition of these substrates to conjugated olefins. Unfortunately, addition of 2-phenylcyclohexanone to acrolein or methyl acrylate using ( S )-TRIP as catalyst did not afford the desired addition product (Fig.…”

Synthesis of carbon‐14 labeled ketamine and norketamine

“…They have also been used as deuterated drugs for the optimization of metabolic and safety profiles of ketamine, leveraging the kinetic isotope effect of deuterium. Despite the existence of a number of cold synthetic approaches to ketamine and norketamine, [8][9][10][11][12][13][14][15][16] there appear to be no examples in the literature of radiolabeling at any metabolically stable positions, namely, the cyclohexyl or phenyl positions. 6,7 Ketamine itself undergoes N-demethylation in vivo as part of its biotransformation, making carbon-14 labeling at the N-methyl position unsuitable for longer duration studies.…”

Metal‐Free Nitration of the C(sp3)−H Bonds of 2‐Oxindoles through Radical Coupling Reaction at Room Temperature

“…[11] As shown in scheme 3a, when the reaction was carried out in nitrogen, the desired product 3 a was not obtained. In addition, the reduction of 3 a to 3-amino-3-phenylindolin-2-one 4 a was achieved (Scheme 2b).…”