Reductive amination of (alpha) - amino acids: Solution - Phase synthesis

Preparation of a small library of secondary amino acids was achieved by solution-phase organic synthesis using reductive amination reactions with selected cc-amino acids and aromatic aldehydes. Reductive amination employing sodium triacetoxyborohydride instead of sodium cyanoborohydride was found to give shorter reaction times and much safer byproducts. With less sterically hindered a-amino acids, direct reductive amination generally yielded the bisalkylated product. However, monoalkylation was achieved by adopting an indirect reductive amination route. Reaction mixtures were characterized by HPLC and LC-MS, resulting in the synthesis of a 21 compound library

Charge-Transfer Complexes for Amine Synthesis

A method to generate α-amino radicals, via a photoinduced charge-transfer complex, is reported. A multicomponent radical fragmentation-cyclization reaction was developed, combining secondary amines, cyclopropyl carboxaldehydes and alkenes, to generate cyclopentyl methylamines. To initiate the fragmentation step, single-electron reduction of alkyliminium ions to α-amino radicals was achieved, using an aromatic thiol and visible light irradiation. Mechanistic and computational studies supported the formation of a transient, ion-pair charge-transfer complex between iminium and thiolate ions. DFT calculations indicated that irradiation of the complex with visible light could promote intra-complex electron transfer from the thiolate HOMO to the iminium LUMO. This method of α-amino radical formation was extended to acyclic aldehydes, by development of a radical reductive amination, using thiol as the single-electron reductant and hydrogen atom source. Subsequently, the chemoselective reductive amination of secondary amines over primary amines was attempted. Preliminary studies on a di-amine drug indicated that the radical reductive amination had high selectivity for primary aminothiazoles over secondary amines, contrasting with existing polar reductive amination techniques

A consecutive process for C–C and C–N bond formation with high enantio-and diastereocontrol : direct reductive amination of chiral ketones using hydrogenation catalysts

Authors thank the University of St Andrews, and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT) for financial support [PhD studentship to SG; Grant code: EP/L016419/1].High diastereoselectivity was observed in the Rh-catalysed reductive amination of 3-arylcyclohexanones to form tertiary amines. This was incorporated into a one-pot enantioselective conjugate addition and diastereoselective reductive amination, including an example of assisted tandem catalysis.PostprintPeer reviewe

Highly Selective Hydroformylation of the Cinchona Alkaloids

The four naturally occurring cinchona alkaloids were subjected to hydroformylation to create an extra functional group that allows immobilization. Cinchonidine, quinine, and quinidine, could be hydroformylated with virtually complete terminal selectivity, using a rhodium/tetraphosphite catalyst. The cinchonidine aldehyde was reduced to the alcohol and subjected to reductive amination with benzylamine.

One Pot Silane Mediated Reductive Amination using Methyl Esters as Nominal Electrophiles

Reductive aminations are a commonly employed method of C−N bond formation with a quarter of C−N bond formations in pharmaceutical synthesis performed via a reductive amination. Conventional reductive amination reactions rely on aldehydes as electrophiles which can be difficult to handle as a result of aldol dimerisation and autooxidation. This poster describes a new class of reductive amination reaction in which readily available carboxylic acid esters are used as nominal electrophiles in place of aldehydes. The amination process involves organocatalytic amide formation followed by silane-mediated reduction of the derived amide. The thesis describes the optimisation, scope, and mechanism of this novel amination protocol

Cross-Linked Cyclodextrins Bimetallic Nanocatalysts: Applications in Microwave-Assisted Reductive Aminations

The optimization of sustainable protocols for reductive amination has been a lingering challenge in green synthesis. In this context, a comparative study of different metal-loaded cross-linked cyclodextrins (CDs) were examined for the microwave (MW)-assisted reductive amination of aldehydes and ketones using either H2 or formic acid as a hydrogen source. The Pd/Cu heterogeneous nanocatalyst based on Pd (II) and Cu (I) salts embedded in a β-CD network was the most efficient in terms of yield and selectivity attained. In addition, the polymeric cross-linking avoided metal leaching, thus enhancing the process sustainability; good yields were realized using benzylamine under H2. These interesting findings were then applied to the MW-assisted one-pot synthesis of secondary amines via a tandem reductive amination of benzaldehyde with nitroaromatics under H2 pressure. The formation of a CuxPdy alloy under reaction conditions was discerned, and a synergic effect due to the cooperation between Cu and Pd has been hypothesized. During the reaction, the system worked as a bifunctional nanocatalyst wherein the Pd sites facilitate the reduction of nitro compounds, while the Cu species promote the subsequent imine hydrogenation affording structurally diverse secondary amines with high yields

One Pot Silane Mediated Reductive Amination using Methyl Esters as Nominal Electrophiles

Reductive aminations are a commonly employed method of C−N bond formation with a quarter of C−N bond formations in pharmaceutical synthesis performed via a reductive amination. Conventional reductive amination reactions rely on aldehydes as electrophiles which can be difficult to handle as a result of aldol dimerisation and autooxidation. This poster describes a new class of reductive amination reaction in which readily available carboxylic acid esters are used as nominal electrophiles in place of aldehydes. The amination process involves organocatalytic amide formation followed by silane-mediated reduction of the derived amide. The thesis describes the optimisation, scope, and mechanism of this novel amination protocol

Cross-linked cyclodextrins bimetallic nanocatalysts: Applications in microwave-assisted reductive aminations

The optimization of sustainable protocols for reductive amination has been a lingering challenge in green synthesis. In this context, a comparative study of different metal-loaded cross-linked cyclodextrins (CDs) were examined for the microwave (MW)-assisted reductive amination of aldehydes and ketones using either H2 or formic acid as a hydrogen source. The Pd/Cu heterogeneous nanocatalyst based on Pd (II) and Cu (I) salts embedded in a β-CD network was the most efficient in terms of yield and selectivity attained. In addition, the polymeric cross-linking avoided metal leaching, thus enhancing the process sustainability; good yields were realized using benzylamine under H2. These interesting findings were then applied to the MW-assisted one-pot synthesis of secondary amines via a tandem reductive amination of benzaldehyde with nitroaromatics under H2 pressure. The formation of a CuxPdy alloy under reaction conditions was discerned, and a synergic effect due to the cooperation between Cu and Pd has been hypothesized. During the reaction, the system worked as a bifunctional nanocatalyst wherein the Pd sites facilitate the reduction of nitro compounds, while the Cu species promote the subsequent imine hydrogenation affording structurally diverse secondary amines with high yields

Reductive Aminations by Imine Reductases: From Milligrams to Tons

The synthesis of secondary and tertiary amines through the reductive amination of carbonyl compounds is one of the most significant reactions in synthetic chemistry. Asymmetric reductive amination for the formation of chiral amines, which are required for the synthesis of pharmaceuticals and other bioactive molecules, is often achieved through transition metal catalysis, but biocatalytic methods of chiral amine production have also been a focus of interest owing to their selectivity and sustainability. The discovery of asymmetric reductive amination by imine reductase (IRED) and reductive aminase (RedAm) enzymes has served as the starting point for a new industrial approach to the production of chiral amines, leading from laboratory-scale milligram transformations to ton-scale reactions that are now described in the public domain. In this perspective we trace the development of the IRED-catalyzed reductive amination reaction from its discovery to its industrial application on kg-ton scale. In addition to surveying examples of the synthetic chemistry that has been achieved with the enzymes, the contribution of structure and protein engineering to the understanding of IRED-catalyzed reductive amination is described, and the consequent benefits for activity, selectivity and stability in the design of process suitable catalysts