Amination Of Ketones Research Articles

Biocatalytic Synthesis of Ruxolitinib Intermediate via Engineered Imine Reductase.

An enzyme catalyzed strategy for the synthesis of a chiral hydrazine from 3-cyclopentyl-3-oxopropanenitrile 5 and hydrazine hydrate 2 is presented. An imine reductase (IRED) from Streptosporangium roseum was identified to catalyze the reaction between 3-cyclopentyl-3-oxopropanenitrile 5 and hydrazine hydrate 2 to produce trace amounts of (R)-3-cyclopentyl-3-hydrazineylpropanenitrile 4. We employed a 2-fold approach to optimize the catalytic performance of this enzyme. First, a transition state analogue (TSA) model was constructed to illuminate the enzyme-substrate interactions. Subsequently, the Enzyme_design and Funclib methods were utilized to predict mutants for experimental evaluation. Through three rounds of site-directed mutagenesis, site saturation mutagenesis, and combinatorial mutagenesis, we obtained mutant M6 with a yield of 98% and an enantiomeric excess (ee) of 99%. This study presents an effective method for constructing a hydrazine derivative via IRED-catalyzed reductive amination of ketone and hydrazine. Furthermore, it provides a general approach for constructing suitable enzymes, starting from nonreactive enzymes and gradually enhancing their catalytic activity through active site modifications.

Ir/XuPhos-catalyzed direct asymmetric reductive amination of ketones with secondary amines

We herein report a novel iridium catalyst with XuPhos as a chiral monodentate phosphine ligand for the direct asymmetric reductive amination of ketones with secondary amines, providing a series of chiral tertiary amines efficiently.

Efficient synthesis of (R)-4-methoxyamphetamine and its analogues under low ammonium concentration using engineered amine dehydrogenase

Amphetamine and its analogues are widely used in various drugs because of its powerful and diverse effects on the nervous system of the brain, e.g., (R)-4-methoxyamphetamine is the key intermediate in formoterol for the treatment of asthma. Biocatalytic reductive amination of ketone by amine dehydrogenase (AmDH) is a potential method for the synthesis of chiral primary amines, but usually requires a high ammonium concentration to drive the amination reaction. In this study, iterative evolution was performed to generate a LsAmDH mutant W5–5 (T123G/S157T/S275G), which was able to catalyze the reductive amination of 200 mM 4-methoxypropiophenone at 500 mM ammonium concentration to afford (R)-4-methoxyamphetamine with >99% ee and 90% isolated yield. This variant also catalyzed the reductive amination of other phenylacetone analogues with high yields and excellent enantioselectivity at low ammonium concentration. This would greatly reduce the generation of ammonium-containing wastes and make the reaction more economic and greener, laying a foundation for the industrial application of AmDHs.

Direct Synthesis of N-formamides by Integrating Reductive Amination of Ketones and Aldehydes with CO2 Fixation in a Metal-Organic Framework.

Formamides are important feedstocks for the manufacture of many fine chemicals. State-of-the-art synthesis of formamides relies on the use of an excess amount of reagents, giving copious waste and thus poor atom-economy. Here, we report the first example of direct synthesis of N-formamides by coupling two challenging reactions, namely reductive amination of carbonyl compounds, particularly biomass-derived aldehydes and ketones, and fixation of CO2 in the presence of H2 over a metal-organic framework supported ruthenium catalyst, Ru/MFM-300(Cr). Highly selective production of N-formamides has been observed for a wide range of carbonyl compounds. Synchrotron X-ray powder diffraction reveals the presence of strong host-guest binding interactions via hydrogen bonding and parallel-displaced π⋅⋅⋅π interactions between the catalyst and adsorbed substrates facilitating the activation of substrates and promoting selectivity to formamides. The use of multifunctional porous catalysts to integrate CO2 utilisation in the synthesis of formamide products will have a significant impact in the sustainable synthesis of feedstock chemicals.

Cobalt-Catalyzed Enantioselective Reductive Amination of Ketones with Hydrazides.

An efficient cobalt-catalyzed asymmetric reductive amination of ketones with hydrazides has been realized, directly producing valuable chiral hydrazines in high yields and enantioselectivities (up to 98% enantiomeric excess).

In search for structural targets for engineering d-amino acid transaminase: modulation of pH optimum and substrate specificity.

The development of biocatalysts requires reorganization of the enzyme's active site to facilitate the productive binding of the target substrate and improve turnover number at desired conditions. Pyridoxal-5'-phosphate (PLP) - dependent transaminases are highly efficient biocatalysts for asymmetric amination of ketones and keto acids. However, transaminases, being stereoselective enzymes, have a narrow substrate specificity due to the ordered structure of the active site and work only in neutral-alkaline media. Here, we investigated the d-amino acid transaminase from Aminobacterium colombiense, with the active site organized differently from that of the canonical d-amino acid transaminase from Bacillus sp. YM-1. Using a combination of site-directed mutagenesis, kinetic analysis, molecular modeling, and structural analysis we determined the active site residues responsible for substrate binding, substrate differentiation, thermostability of a functional dimer, and affecting the pH optimum. We demonstrated that the high specificity toward d-glutamate/α-ketoglutarate is due to the interactions of a γ-carboxylate group with K237 residue, while binding of other substrates stems from the effectiveness of their accommodation in the active site optimized for d-glutamate/α-ketoglutarate binding. Furthermore, we showed that the K237A substitution shifts the catalytic activity optimum to acidic pH. Our findings are useful for achieving target substrate specificity and demonstrate the potential for developing and optimizing transaminases for various applications.

Relationships between the structure of spiro[[2]benzopyran-1,1′-cyclohexan]-4′-amines and their σ1 receptor affinity and selectivity

A set of 31 secondary and tertiary amines of type 5 was synthesized by reductive amination of ketones 6 and 22–24 with amines and NaBH(OAc)3. Usually, cis-configured amines display higher σ1 affinity than trans-configured analogs. Elongation of the distance between the amino moiety and the terminal phenyl ring from one to three CH2 moieties increased the σ1 affinity. Tertiary amines with one small N-substituent are well tolerated by the σ1 receptor. Within this class of compounds, the cyclohexylpiperazines trans-21a (Ki(σ1) = 6.3 nM) and cis-21b (Ki(σ1) = 4.4 nM) show very high σ1 affinity and selectivity over related receptors (σ2 receptor, MOR, DOR, KOR). On the other hand, the cis-configured p-fluorophenylpiperazine cis-20b was identified as high-affinity σ2 ligand (Ki(σ2) = 11 nM) with considerable selectivity over σ1 receptor, MOR, DOR and KOR. Very high MOR affinity (Ki = 2.3 nM), but only moderate affinity towards both σ receptor subtypes was detected for the cis-configured piperidine cis-17b without aryl moiety at the piperidine ring. Thus, cis-17b represents a novel MOR chemotype with high MOR affinity and high selectivity over both σ receptors, DOR and KOR.

Hexaazatrinaphthalene-Based Covalent Triazine Framework-Supported Rhodium(III) Complex: A Recyclable Heterogeneous Catalyst for the Reductive Amination of Ketones to Primary Amines.

The development of efficient and recyclable heterogeneous catalysts is an important topic. Herein, a rhodium(III) complex Cp*Rh@HATN-CTF was synthesized by the coordinative immobilization of [Cp*RhCl2]2 on a hexaazatrinaphthalene-based covalent triazine framework. In the presence of Cp*Rh@HATN-CTF (1 mo l% Rh), a series of primary amines could be obtained via the reductive amination of ketones in high yields. Moreover, catalytic activity of Cp*Rh@HATN-CTF is well maintained during six runs. The present catalytic system was also applied for the large scale preparation of a biologically active compound. It would facilitate the development of CTF-supported transition metal catalysts for sustainable chemistry.

Engineered Biocatalysts for Enantioselective Reductive Aminations of Cyclic Secondary Amines

AbstractReductive aminases (RedAms) have recently emerged as promising biocatalysts for the synthesis of chiral secondary amines by coupling primary amines with aldehydes/ketones. However, access to tertiary amines remains more problematic, particularly when coupling ketones with secondary amines. Here we show that the scope of these enzymes can be extended to allow selective reductive aminations of cyclic secondary amines, such as piperidines and morpholines, with both aldehydes and ketones. These biotransformations provide access to important motifs found in active pharmaceutical ingredients and other bioactive molecules. RedAm‐361, discovered from a metagenomic library, was engineered via directed evolution to allow efficient coupling of cyclic amines with carbonyl partners, including dynamic kinetic resolutions of α‐functionalized aldehydes and enantioselective amination of ketones. These RedAms now serve as valuable scaffolds for the engineering of industrial biocatalysts to produce key pharmaceutical intermediates.

Microwave-Assisted Reductive Amination of Aldehydes and Ketones Over Rhodium-Based Heterogeneous Catalysts.

Microwave (MW)-assisted reductive aminations of aldehydes and ketones were carried out in the presence of commercial and homemade heterogeneous Rh-based catalysts. Ultrasound (US) was used to improve dispersion and stability of metal nanoparticles, while commercial activated carbon and carbon nanofibers were used as supports. Moreover, various bio-derived molecules were selected as substrates, and aqueous ammonia was used as a cheap and non-toxic reagent. MW combined with heterogeneous Rh catalysts gave a 98.2 % yield in benzylamine at 80 °C with 10 bar H2 for 1 h; and a 43.3 % yield in phenylethylamine at 80 °C and 5 bar H2 for 2 h. Carbon nanofibers proved to be a better support for the metal active phase than simple activated carbon, since a limited yield in benzylamine (10.6 %) but a high selectivity for the reductive amination of ketones was obtained. Thus, raspberry ketone was converted to raspberry amine in a 63.0 % yield.

Turning thermostability of Aspergillus terreus (R)-selective transaminase At-ATA by synthetic shuffling

As versatile and green biocatalysts for the asymmetric amination of ketones, the insufficient thermostability of transaminases always limits its broad application in the pharmaceutical and fine chemical industries. Here, synthetic shuffling technology was used to enhance stability of (R)-selective transaminase from Aspergillus terreus. The results showed that 30 out of 5000 mutants had improved thermostability by color-based screening method, among which mutants with residual enzyme activity higher than 50% at 45 °C for 10 min were selected for further analysis. Especially, the half-inactivation temperature (T5010), half-life (t1/2), and melting temperature (Tm) of the best mutant M14 (M280C-H210N-M150C-F115L) were 13.7 °C, 165.8 min, and 13.9 °C higher than that of the wild type (WT), respectively. M14 also exhibited a significant biocatalytic efficiency toward acetophenone and 1-acetylnaphthalene, the yield of which were 265.6% and 117.5% higher than WT, respectively. Based on molecular dynamics simulation, improved catalytic efficiency of M14 could be attributed to its increased hydrogen bonds interaction around the mutation sites. Additionally, the introduction of disulfide bond combined with above mutations has a synergistic effect on the improved protein thermostability.

Integrated Uniformly Microporous C4 N/Multi-Walled Carbon Nanotubes Composite Toward Ultra-Stable and Ultralow-Temperature Proton Batteries.

Benefiting from the proton's small size and ultrahigh mobility in water, aqueous proton batteries are regarded as an attractive candidate for high-power and ultralow-temperature energy storage devices. Herein, a new-type C4 N polymer with uniform micropores and a large specific surface area is prepared by sulfuric acid-catalyzed ketone amine condensation reaction and employed as the electrode of proton batteries. Multi-walled carbon nanotubes (MWCNT) are introduced to induce the in situ growth of C4 N, and reaped significantly enhanced porosity and conductivity, and thus better both room- and low-temperature performance. When coupled with MnO2 @Carbon fiber (MnO2 @CF) cathode, MnO2 @CF//C4 N-50% MWCNT full battery shows unprecedented cycle stability with a capacity retention of 98% after 11000 cycles at 10 A g-1 and even 100% after 70000 cycles at 20 A g-1 . Additionally, a novel anti-freezing electrolyte (5 m H2 SO4 +0.5m MnSO4 ) is developed and showed a high ionic conductivity of 123.2 mScm-1 at -70°C. The resultant MnO2 @CF//C4 N-50% MWCNT battery delivers a specific capacity of 110.5mAhg-1 even at -70°C at 1Ag-1 , the highest in all reported proton batteries under the same conditions. This work is expected to offer a package solution for constructing high-performance ultralow-temperature aqueous proton batteries.

Ruthenium-catalyzed reductive amination of ketones with nitroarenes and nitriles.

The Ru(dppbsa)-catalyzed reductive amination of ketones with nitroarenes and nitriles using H2 as the environmentally benign hydrogen surrogate is developed in this study. Cross-experiments demonstrated that both reactions are initiated by the reduction of nitroarenes or nitriles to the corresponding amines, followed by condensation with ketones to give imines and thereafter hydrogenation. However, the route to the formation of an amino-ligated Ru complex during the reduction of nitroarenes or nitriles, followed by in situ nucleophilic C-N coupling, cannot be completely excluded. This newly developed versatile method features good functional group tolerance, which provides a novel design platform for homogeneous catalysts in constructing motifs of secondary amines.

Asymmetric Reductive Amination with Pinacolborane Catalyzed by Chiral SPINOL Borophosphates

The catalytic asymmetric reductive amination of ketones with pinacolborane employing chiral SPINOL-derived borophosphates as catalysts has been realized. A series of chiral amine derivatives bearing multiple functional groups were obtained in good to excellent yields and enantioselectivities (up to 97% yield, 98% ee) under mild reaction conditions. Moreover, the synthetic applicability of the established method has been demonstrated by the asymmetric synthesis of (R)-Fendiline.

Engineered Imine Reductase for Larotrectinib Intermediate Manufacture

Imine reductases (IREDs) are increasingly identified and characterized for the reduction of imines and reductive amination of ketones. However, their practical application is still limited due to the low activity and poor stability of native enzymes. Herein, we developed an engineered IRED through three rounds of evolution from wild-type Streptomyces clavuligerus. The specific activity of the engineered enzyme, ScIRED-R3-V4, was increased >100-fold, and stability was increased >270-fold. Using the more active and stable ScIRED-R3-V4, 80 g L–1 cyclic imine 2-(2,5-difluorophenyl)-pyrroline was completely reduced, producing kilogram quantities of a key chiral intermediate of larotrectinib in 82.5% yield, with >99.5% enantiomeric excess and a space–time yield of 352 g L–1 day–1. In addition, crystal structures of enzyme–substrate complexes and molecular dynamics simulations were conducted to gain insight into the molecular mechanism for improved enzyme performance. The significantly improved process demonstrated the potential of the engineered IRED in industrial applications.

Iridium-Catalyzed Direct Reductive Amination of Ketones and Secondary Amines: Breaking the Aliphatic Wall.

Invited for the cover of this issue are Matthieu Jouffroy from Discovery Process Research at Janssen Pharmaceutica N.V. and the group of Rafael Gramage-Doria at the University of Rennes. The image depicts an Ir-based catalytic system "fueled" by hydrogen for the direct reductive amination of ketones and secondary amines, allowing complex aliphatic tertiary amines to be prepared and, so, new chemical space to be reached. Read the full text of the article at 10.1002/chem.202201078.

Front Cover: Iridium‐Catalyzed Direct Reductive Amination of Ketones and Secondary Amines: Breaking the Aliphatic Wall (Chem. Eur. J. 36/2022)

An iridium-catalyzed methodology leads to fully aliphatic tertiary amines starting from readily available ketones and amines. This direct reductive amination transformation, fueled by hydrogen similar to a space rocket, enables access to an unprecedented chemical space with a functional group relevance compatible with active pharmaceutical ingredients. More information can be found in the Research Article by M. Jouffroy, R. Gramage-Doria et al. (DOI: 10.1002/chem.202201078).

Iridium-Catalyzed Direct Reductive Amination of Ketones and Secondary Amines: Breaking the Aliphatic Wall.

Direct reductive amination (DRA) is a ubiquitous reaction in organic chemistry. This transformation between a carbonyl group and an amine is most often achieved by using a super stoichiometric amount of hazardous hydride reagents, thus being incompatible with many sensitive functional groups. DRA could also be achieved by means of chemo- or biocatalysis, thereby attracting the interest of industry as well as academic laboratories due to the virtually perfect atom economy. Although DRAs are well-established for substrate pairs such as aldehydes with either 1° or 2° amines as well as ketones with 1° amines, the current methodologies are limited in the case of ketones with 2° amines. Herein, we present a general DRA protocol that overcomes this major limitation by means of iridium catalysis. The applicability of the methodology is demonstrated by accessing an unprecedented range of biologically relevant tertiary amines starting from both aliphatic ketones and aliphatic amines. The choice of a disphosphane ligand (Josiphos A or Xantphos) is essential for the success of the transformation.

Metal‐Free Reductive Amination of Ketones with Amines Using Formic Acid as the Reductant under BF3 ⋅ Et2O Catalysis

AbstractBF3 ⋅ Et2O has been found to effectively catalyze reductive amination of ketones with amines employing formic acid as the reductant under metal‐free conditions. This transformation tolerates a broad range of primary and secondary amines and differently decorated ketones, delivering N‐alkylated amines in good to excellent yields with high compatibility of functional groups. The synthetic potential of this protocol is demonstrated by its application in the preparation of biologically and pharmaceutically relevant compounds.

Hydroboration and reductive amination of ketones and aldehydes with HBpin by a bench stable Pd(II)-catalyst.

A palladium(II) complex [(κ4-{1,2-C6H4(NCH-C6H4O)2}Pd] (1) supported by a dianionic salen ligand [1,2-C6H4(NCH-C6H4O)2]2- (L) was synthesised and used as a molecular pre-catalyst in the hydroboration of aldehydes and ketones. The molecular structure of Pd(II) complex 1 was established by single-crystal X-ray diffraction analysis. Complex 1 was tested as a competent pre-catalyst in the hydroboration of aldehydes and ketones with pinacolborane (HBpin) to produce corresponding boronate esters in excellent yields at ambient temperature under solvent-free conditions. Further, the complex 1 proved to be a competent catalyst in the reductive amination of aldehydes with HBpin and primary amines under mild and solvent-free conditions to afford a high yield (up to 97%) of corresponding secondary amines. Both protocols provided high conversion, superior selectivity and broad substrate scope, from electron-withdrawing to electron-donating and heterocyclic substitutions. A computational study based on density functional theory (DFT) revealed a reaction mechanism for Pd-catalysed hydroboration of carbonyl species in the presence of HBpin. The protocols also uncovered the dual role of HBpin in achieving the hydroboration reaction.