Advances on Asymmetric Reductive Amination with Ammonium Salts as Amine Sources

Abstract

α-Chiral primary amine subunits are widespread structural units in a large number of pharmaceutical molecules and are key intermediates toward the preparation of numerous amine-containing drugs. Versatile functionalizations on the NH2 group also supply a quick way to construct molecular complexity. Additionally, chiral primary amines can serve as ligands or organocatalysts which can be applied in organic synthesis. Therefore, efficient synthetic routes toward chiral primary amines have attracted tremendous attention. Asymmetric chemo-catalytic reactions that are capable of directly preparing chiral primary amines remain scarce. Transition-metal-catalyzed asymmetric reductive amination (ARA), a reaction type that transforms easily available ketones and amines into chiral amines in the presence of a chiral metal-catalyst and reductant, is among the most straightforward methods to access chiral amines. However, studies on ARA are still limited compared to that on imine hydrogenation, probably due to the presence of competitive ketone reduction as the side reaction. ARA using ammonium salts as the amine sources can directly yield chiral primary amines from prochiral ketones and are thus highly attractive and of great significance. In addition to competition with ketone reduction process, this reaction also faces some other challenges, including: (1) NH3 or the produced primary amines can coordinate to the metal center which results in catalyst poisoning effect; (2) the coordination of amine ligand to the metal center may lead to ligand exchange that enhances the challenge on asymmetric control; (3) the produced primary amines may undergo further alkylation process via double reductive amination, thus providing more complicated outcome. The existing problems and challenges in ARA require urgent development of applicable catalytic systems. Aiming to solve some challenges in the field of ARA with ammonium salts, we have carried out systematic studies and will present the latest progress achieved from our team in this account.

Synthesis of Chiral Primary Amines via Enantioselective Reductive Amination: From Academia to Industry

“…In comparison, ERA reactions of ketones with ammonium salts or ammonia gas, which are capable of producing valuable and versatile primary amines (NH2) in one step, are rarely studied until recently (Scheme 3c). 12 The reasons for the slow advance in this field might be ascribed to the following challenges. The first issue that needs to be solved is the in-situ formation of unstable NH imines.…”

“…were rarely studied until recently (Scheme 3c). 12 The reasons for the slow advance in this field might be due to the following challenges. The first issue that needs to be resolved is the in situ formation of unstable NH-imines.…”

Asymmetric Reductive Amination in Organocatalysis and Biocatalysis

“…In 2021, Zhang's team [10] and Bera's team [11] independently reviewed the recent progress on transition‐metal‐catalysed ARA. Shortly after, Zhang and his colleagues further evaluated the recent advancements in ARA which employed ammonium salts as amine sources [12] and discussed the historical development of enantioselective reductive amination reactions that utilized ammonium salts or ammonia gas [13] . We sensed a need to present a systematic discussion on organocatalytic and biocatalytic ARA.…”

Palladium nanocatalyst assisted in situ regeneration of amino donor in a one-enzyme cascade

“…These processes necessitate transition metal complexes which are costly and increasingly unsustainable. 5 In recent years, a range of chemical processes have been developed for the direct conversion of prochiral ketones to chiral amines [6][7][8][9][10][11] or asymmetric hydrogenation of oximes to produce chiral amines. 12 Nonetheless, most of these reactions call for harsh reaction conditions and have a low efficiency and high environmental impact, usually resulting in low product yields and ees.…”