Reductive Amination Research Articles

Biosynthesis of Diverse Ephedra-Type Alkaloids via a Newly Identified Enzymatic Cascade.

Ephedra-type alkaloids represent a large class of natural and synthetic phenylpropanolamine molecules with great pharmaceutical values. However, the existing methods typically rely on chemical approaches to diversify the N-group modification of Ephedra-type alkaloids. Herein, we report a 2-step enzymatic assembly line for creating structurally diverse Ephedra-type alkaloids to replace the conventional chemical modification steps. We first identified a new carboligase from Bacillus subtilis (BsAlsS, acetolactate synthase) as a robust catalyst to yield different phenylacetylcarbinol (PAC) analogs from diverse aromatic aldehydes with near 100% conversions. Subsequently, we screened imine reductases (IREDs) for the reductive amination of PAC analogs. It was found that IRG02 from Streptomyces albidoflavus had good activities with conversions ranging from 37% to 84% for the reductive alkylamination with diverse amine partners such as allylamine, propargylamine, and cyclopropylamine. Overall, 3 new bio-modifications at the N-group of Ephedra-type alkaloids were established. Taken together, our work lays a foundation for the future implementation of biocatalysis for synthesizing structurally diverse Ephedra-type alkaloids with potential new pharmaceutical applications.

Synthesis of a sustainable and robust heterogeneous TEMPO catalyst utilizing activated carbon for aerobic alcohol oxidation

Ozone-induced surface-carbonylation and reductive amination to construct stable TEMPO grafting on activated carbon with prominent durability and prolonged lifetime.

Orthogonal assisted tandem reactions for the upgrading of bio-based aromatic alcohols using chitin derived mono and bimetallic catalysts

The upgrading of a benzyl-type alcohols was explored via an orthogonal tandem sequence comprised of a first oxidative step producing the corresponding aldehydes, and a subsequent reductive amination to achieve both secondary and tertiary amines.

External [1 1 1] facets on nanorod gamma alumina boosts catalytic reductive amination of carbonyl compound to primary amine

Hydrogen spillover had played a significant role in catalytic processes involving reducible oxide supported metal catalyst and hydrogen molecule. Herein, crystal plane regulative hydrogen spillover strategy for the effective reductive amination on Ni/Al2O3 was developed. A rod-like alumina supported Ni catalyst with primarily external (111) facets was prepared. In the presence of NH3 and H2, Ni/Al2O3 (111) exhibited a turnover number of 30.4 h−1, which was 136-fold higher than that of Ni/Al2O3 (110) in the reductive amination of furfural to furfuryl amine. For the Ni/Al2O3 (111) catalyst, Al2O3 (111) facets exhibited strong Lewis acidity, resulting in an enhanced H affinity of Al2O3 (111) and a positively charged of Ni through electronic interaction. It was revealed that strong H affinity of Al2O3 (111) and positively charged Ni sites significantly promoted hydrogen migration from Ni surface to Al2O3 (111) facets, which effectively prevented the Ni sites from hydrogen poisoning and enhanced the adsorption and activation of NH3 and intermediates for reductive amination. Consequently, the activation energy of Schiff base reductive ammonolysis was obviously reduced, resulting in high inherent activity for furfural reductive amination to furfuryl amine. This work developed a new strategy for high efficiency reductive amination catalyst in terms of hydrogen spillover effect.

Sterically controllable adsorption on nickel surface for selective reductive amination

Sterically controllable adsorption on nickel surface for selective reductive amination

Highly active Co1-N3-O1 single-atom catalyst for boosting catalytic synthesis of unsaturated benzylamines and arylamines

Unsaturated benzylamines and arylamines are the key building blocks for the synthesis of organic pharmaceutical molecules, but their synthetic processes always suffer from low selectivity as a result of the excessive hydrogenation of unsaturated groups. Herein, the cobalt single-atom catalyst with an asymmetric Co1-N3-O1 structure was designed and constructed on porous carbon nanospheres. It is found that the Co1-N3-O1 catalyst showed excellent catalytic activity toward the synthesis of unsaturated benzylamines and arylamines. The results of characterization analysis and density functional theory (DFT) calculation further clarify that introducing oxygen into the Co single-atom coordination environment of Co1-N3-O1 increased hydrogenation energy barrier of the terminal C=C double bond, which is beneficial to suppress competing hydrogenation reactions. Meanwhile, the Co1-N3-O1 catalyst had the lower energy barrier for reduction of the C=N bond to amino group, boosting the yields of unsaturated benzylamines and arylamines. This study offers an attracting strategy for efficient and selective reductive amination reaction by making use of the asymmetrically structured Co single-atom catalyst.

Rational Design, Synthesis, and Anti-Proliferative Evaluation of Novel 4-Aryl-3,4-Dihydro-2H-1,4-Benzoxazines.

A synthetic pathway to a novel 4-aryl-3,4-dihydro-2H-1,4-benzoxazine scaffold was developed and a series of compounds based on the scaffold were synthesised as potential anticancer agents. The 4-aryl-substituted compounds were prepared via Buchwald-Hartwig cross-coupling between substituted bromobenzenes and various 1,4-benzoxazines, which in turn were generated from a cascade hydrogenation and reductive amination one-pot reaction. These analogues exhibited moderate to good potency against various cancer cell lines. Structure-activity relationship analysis indicated that the inclusion of hydroxyl groups on ring A and ring B was beneficial to biological activity, while having a para-amino group on ring C significantly enhanced potency. Molecule 14f displayed the most potent anticancer activity (IC50 = 7.84-16.2 µM against PC-3, NHDF, MDA-MB-231, MIA PaCa-2, and U-87 MG cancer cell lines), indicating its potential as a lead compound for further structural optimisation. All the synthesised compounds were fully characterised with NMR, HMRS, and IR. The novel benzoxazine scaffold described in this study holds promise and deserves further in-depth studies.

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.

Highly efficient and stable Ni-based catalyst for selective conversion of biomass-derived aldehydes and ketones to primary amines

Here We report a yolk-shell structured Zr-assisted Ni-based catalyst, which could catalyze the reductive amination of a variety of biomass-derived aldehydes and ketones with high activity and robust stability. The novel LDH-derived Zr assisted-NiAl catalyst exhibits superior stability (>200 h) than traditional supported Ni/Al2O3 catalyst (<75 h) due to strong interaction between Ni0 yolk and NiAl2O4 shell. Outstanding yield of fufurylamine at 99 % is achieved under mild conditions at low temperature of 70 °C with 1 MPa H2. Other aldehydes and ketones are also transformed into primary amines with high yield above 90 % generally under mild conditions. Our study reveals that strong acidity favors the activation of imines, while strengthened hydrogen activation capability of catalyst promotes the dissociation of intermediate secondary amine to primary amine. The appropriate hydrogen activation capability regulated by Zr introduction into LDH-derived NiAl catalyst avoids over-hydrogenation of furyl-, hydroxyl- and imide-groups, which accounts for the high selectivity of mono-primary amine. Importantly, the dependence of mono-primary amine production on appropriate hydrogen activation capability of catalyst proved by this work provides ideas for tailored catalysts in the production of renewable primary amines from biomass.

Photocatalytic Production of Ethanolamines and Ethylenediamines from Bio‐Polyols over a Cu/TiO2 Catalyst

AbstractValorization of biomass‐derived polyols into high‐value‐added ethanolamines and ethylenediamines is highly attractive. Herein, we report a one‐step photocatalytic protocol to convert bio‐polyols into a 60 % yield of ethanolamines and ethylenediamines over a multifunctional Cu/TiO2 catalyst. This catalyst enables a tandem process of photocatalytic polyol C−C bond cleavage and reductive amination in one pot at room temperature, and also allows the selective conversion of various bio‐polyols and amines. Mechanistic studies revealed that photogenerated holes in TiO2 promote the retro‐aldol C−C bond cleavage or oxidative dehydrogenation of polyols, and photogenerated electrons accumulate on small‐sized Cu clusters, which facilitate the reductive amination via hydrogen transfer and prevent the H2 generation. This strategy provides new opportunities for the development of non‐noble metal photocatalysts and methods of biomass conversion under mild conditions.

Photocatalytic Production of Ethanolamines and Ethylenediamines from Bio-Polyols over a Cu/TiO2 Catalyst.

Valorization of biomass-derived polyols into high-value-added ethanolamines and ethylenediamines is highly attractive. Herein, we report a one-step photocatalytic protocol to convert bio-polyols into a 60 % yield of ethanolamines and ethylenediamines over a multifunctional Cu/TiO2 catalyst. This catalyst enables a tandem process of photocatalytic polyol C-C bond cleavage and reductive amination in one pot at room temperature, and also allows the selective conversion of various bio-polyols and amines. Mechanistic studies revealed that photogenerated holes in TiO2 promote the retro-aldol C-C bond cleavage or oxidative dehydrogenation of polyols, and photogenerated electrons accumulate on small-sized Cu clusters, which facilitate the reductive amination via hydrogen transfer and prevent the H2 generation. This strategy provides new opportunities for the development of non-noble metal photocatalysts and methods of biomass conversion under mild conditions.

Divergent syntheses of (−)-carvone-derived dimers

A series of diterpene-type compounds were synthesized starting from commercially available (−)-carvone. The Michael reaction of (−)-carvone itself delivered four diastereomeric dimers divergently. Following in parallel transformations of reduction, condensation and reductive amination, the corresponding alcohol, oxime and amine were obtained respectively. Particularly, several cage-like structures were obtained via late-stage olefin functionalization. The absolute configurations of the aforementioned compounds were unambiguously determined by NMR spectral, X-ray crystallographic and conformational analysis. Finally, the in-vitro anti-cancer and anti-inflammatory activities of these dimers were tested preliminarily.

Diazonium salt as a versatile, efficient and mild catalyst for reductive aminations of carbonyls and syntheses of bis(indolyl)methanes

This study used aryl diazonium salts as catalysts to catalyze reductive aminations of carbonyls and the synthesis of bis (3-indolyl)methane derivatives. The catalytic system showed good tolerance to substituents in the substrate in these two reactions. The separation yields of reductive aminations range from moderate to excellent. The separation yield of the reaction for synthesizing bis(3-indolyl)methane derivatives ranges from good to excellent. Finally, we also explored the catalytic behavior of aryl diazonium salts in amination reduction reactions.

Batch and Flow Green Microwave-Assisted Catalytic Conversion Of Levulinic Acid to Pyrrolidones.

This paper reports a new sustainable protocol for the microwave-assisted catalytic conversion of levulinic acid into N-substituted pyrrolidones over tailor-made mono (Pd, Au) or bimetallic (PdAu) catalysts supported on either highly mesoporous silica (HMS) or titania-doped HMS, exploiting the advantages of dielectric heating. MW-assisted reductive aminations of levulinic acid with several amines were first optimized in batch mode under hydrogen pressure (5 bar) in solvent-free conditions. Good-to-excellent yields were recorded at 150 °C in 90 min over the PdTiHMS and PdAuTiHMS, that proved recyclable and almost completely stable after six reaction cycles. Aiming to scale-up this protocol, a MW-assisted flow reactor was used in combination with different green solvents. Cyclopentyl methyl ether (CPME) provided a 99 % yield of N-(4-methoxyphenyl) pyrrolidin-2-one at 150 °C over PdTiHMS. The described MW-assisted flow synthesis proves to be a safe procedure suitable for further industrial applications, while averting the use of toxic organic solvents.

Reductive amination of oxidized hydroxypropyl cellulose with ω-aminoalkanoic acids as an efficient route to zwitterionic derivatives

Zwitterionic polymers, with their equal amounts of cationic and anionic functional groups, have found widespread utility including as non-fouling coatings, hydrogel materials, stabilizers, antifreeze materials, and drug carriers. Polysaccharide-derived zwitterionic polymers are attractive because of their sustainable origin, potential for lower toxicity, and possible biodegradability, but previous methods for synthesis of zwitterionic polysaccharide derivatives have been limited in terms of flexibility and attainable degree of substitution (DS) of charged entities. We report herein successful design and synthesis of zwitterionic polysaccharide derivatives, in this case based on cellulose, by reductive amination of oxidized 2-hydroxypropyl cellulose (Ox-HPC) with ω-aminoalkanoic acids. Reductive amination products could be readily obtained with DS(cation) (= DS(anion)) up to 1.6. Adduct hydrophilic/hydrophobic balance (amphiphilicity) can be influenced by selecting the appropriate chain length of the ω-aminoalkanoic acid. This strategy is shown to produce a range of amphiphilic, water-soluble, moderately high glass transition temperature (Tg) polysaccharide derivatives in just a couple of efficient steps from commercially available building blocks. The adducts were evaluated as crystallization inhibitors. They are strong inhibitors of crystallization even for the challenging, poorly soluble, fast-crystallizing prostate cancer drug enzalutamide, as supported by surface tension and Flory–Huggins interaction parameter results.

I2/CAN as a Mild and Efficient Reagent for Oxidative Csp3‐Csp2 Cleavage of 3,3′‐Bis‐7‐azaindolylmethane: A Rapid One‐Pot Access to 3‐Formyl and 3‐Iodo‐7‐azaindoles

AbstractThe combination of I2/CAN has emerged as a mild and powerful reagent for the oxidative Csp3‐Csp2 cleavage of 3,3′‐bis‐7‐azaindolylmethane to provide a quantitative combined yield of 3‐formyl and 3‐iodo‐7‐azaindole in a one‐pot reaction at RT. A plausible mechanism and characterization, including XRD, has been described. The synthetic transformations of title compounds were explored by reduction, Click, reductive amination, and Suzuki coupling reaction.

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.

Isomeric Separation of α2,3/α2,6-Linked 2-Aminobenzamide (2AB)-Labeled Sialoglycopeptides by C18-LC-MS/MS.

Determination of the relative expression levels of the α2,3/α2,6-sialic acid linkage isomers on glycoproteins is critical to the analysis of various human diseases such as cancer, inflammation, and viral infection. However, it remains a challenge to separate and differentiate site-specific linkage isomers at the glycopeptide level. Some derivatization methods on the carboxyl group of sialic acid have been developed to generate mass differences between linkage isomers. In this study, we utilized chemical derivatization that occurred on the vicinal diol of sialic acid to separate linkage isomers on a reverse-phase column using a relatively short time. 2-Aminobenzamide (2AB) labeling derivatization, including periodate oxidation and reductive amination, took only ∼3 h and achieved high labeling efficiency (>90%). Within a 66 min gradient, the sialic acid linkage isomers of 2AB-labeled glycopeptides from model glycoproteins can be efficiently resolved compared to native glycopeptides. Two different methods, neuraminidase digestion and higher-energy collision dissociation tandem mass spectrometry (HCD-MS2) fragmentation, were utilized to differentiate those isomeric peaks. By calculating the diagnostic oxonium ion ratio of Gal2ABNeuAc and 2ABNeuAc fragments, significant differences in chromatographic retention times and in mass spectral peak abundances were observed between linkage isomers. Their corresponding MS2 PCA plots also helped to elucidate the linkage information. This method was successfully applied to human blood serum. A total of 514 2AB-labeled glycopeptide structures, including 152 sets of isomers, were identified, proving the applicability of this method in linkage-specific structural characterization and relative quantification of sialic acid isomers.

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).

Cover Picture: Optimized Stereoselective and Scalable Synthesis of Five‐Membered Cyclic trans‐β‐Amino Acid Building Blocks via Reductive Amination (BKCS 12/2023) Jungwoo Hong, Wonchul Lee, Hee‐Seung Lee

Unnatural β‐amino acids play pivotal roles in organic synthesis, drug development, and peptide chemistry. Highlighting their significance, the study by Jungwoo Hong, Wonchul Lee, and Hee‐Seung Lee presents an optimized, scalable method for producing enantiopure five‐membered cyclic trans‐β‐amino acid building blocks. More details are available in the article by Jungwoo Hong, Wonchul Lee, Hee‐Seung Lee image