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.

Micelle-Promoted Reductive Amination of DNA-Conjugated Amines for DNA-Encoded Library Synthesis.

DNA-encoded libraries (DELs) have become a leading technology for hit identification in drug discovery projects as large, diverse libraries can be generated. DELs are commonly synthesised via split-and-pool methodology; thus, chemical transformations utilised must be highly efficient, proceeding with high conversions. Reactions performed in DEL synthesis also require a broad substrate scope to produce diverse, drug-like libraries. Many pharmaceutical compounds incorporate multiple C-N bonds, over a quarter of which are synthesised via reductive aminations. However, few on-DNA reductive amination procedures have been developed. Herein is reported the application of the micelle-forming surfactant, TPGS-750-M, to the on-DNA reductive amination of DNA-conjugated amines, yielding highly efficient conversions with a broad range of aldehydes, including medicinally relevant heterocyclic and aliphatic substrates. The procedure is compatible with DNA amplification and sequencing, demonstrating its applicability to DEL synthesis.

Reductive amination of ω-conotoxin MVIIA: synthesis, determination of modification sites, and self-assembly.

Peptide drugs have disadvantages such as low stability, short half-life and side effects, which limit their widespread use in clinical practice. Therefore, peptide drugs can be modified to improve these disadvantages. Numerous studies have shown that alkyl-modified peptide drugs can self-assemble to prolong the duration of efficacy and/or reduce side effects. However, the commonly used solid-phase synthesis method for alkyl-modified peptides is time-consuming. To overcome this, a simple reductive amination reaction was employed, which can directly graft the alkyl chain to the peptide sequence and effectively avoid stepwise synthesis from C- to N-terminal with amino acids. In this study, ω-conotoxin MVIIA was used as the peptide drug, while myristic aldehyde was used as the alkylating agent. To obtain the maximum productivity of modified peptides, the molar ratio of peptide MVIIA to myristic aldehyde in the reductive amination reaction was optimized. Furthermore, the peptide modification sites in this reaction were confirmed by secondary mass spectrometry analysis. Besides, alkyl-modified peptide MVIIA was able to form micelles by self-assembly and improved stability in serum, which was related to our previous work where myristoylated peptide MVIIA micelles can improve the drug stability. Finally, this study was intended to provide a methodological basis for modifying the alkyl chain of peptide drugs.

Dissolved Organic Matter Contains Ketones Across a Wide Range of Molecular Formulas.

The carbonyl functionality of natural organic matter (NOM) is poorly constrained. Here, we treated Suwannee River NOM (SRNOM) with ammonium acetate and sodium cyanoborohydride to convert ketone-containing compounds by reductive amination to their corresponding primary amines. The total dissolved nitrogen content increased by up to 275% after amination. Up to 30% of the molecular formulas of SRNOM contained isomers with ketone functionalities as detected by ultrahigh-resolution mass spectrometry. Most of these isomers contained one or two keto groups. At least 3.5% of the oxygen in SRNOM was bound in ketone moieties. The conversion of reacted compounds increased linearly with O/H values of molecular formulas and was predictable from the elemental composition. The mean conversion rate of reacted compounds nearly followed a log-normal distribution. This distribution and the predictability of the proportion of ketone-containing isomers solely based on the molecular formula indicated a stochastic distribution of ketones across SRNOM compounds. We obtained isotopically labeled amines by using 15N-labeled ammonium acetate, facilitating the identification of reaction products and enabling NMR spectroscopic analysis. 1H,15N HSQC NMR experiments of derivatized samples containing less than 20 µg of nitrogen confirmed the predominant formation of primary amines, as expected from the reaction pathway.

Discovery and biocatalytic characterization of opine dehydrogenases by metagenome mining.

Enzymatic processes play an increasing role in synthetic organic chemistry which requires the access to a broad and diverse set of enzymes. Metagenome mining is a valuable and efficient way to discover novel enzymes with unique properties for biotechnological applications. Here, we report the discovery and biocatalytic characterization of six novel metagenomic opine dehydrogenases from a hot spring environment (mODHs) (EC 1.5.1.X). These enzymes catalyze the asymmetric reductive amination between an amino acid and a keto acid resulting in opines which have defined biochemical roles and represent promising building blocks for pharmaceutical applications. The newly identified enzymes exhibit unique substrate specificity and higher thermostability compared to known examples. The feature that they preferably utilize negatively charged polar amino acids is so far unprecedented for opine dehydrogenases. We have identified two spatially correlated positions in their active sites that govern this substrate specificity and demonstrated a switch of substrate preference by site-directed mutagenesis. While they still suffer from a relatively narrow substrate scope, their enhanced thermostability and the orthogonality of their substrate preference make them a valuable addition to the toolbox of enzymes for reductive aminations. Importantly, enzymatic reductive aminations with highly polar amines are very rare in the literature. Thus, the preparative-scale enzymatic production, purification, and characterization of three highly functionalized chiral secondary amines lend a special significance to our work in filling this gap. KEY POINTS: • Six new opine dehydrogenases have been discovered from a hot spring metagenome • The newly identified enzymes display a unique substrate scope • Substrate specificity is governed by two correlated active-site residues.

Synthesis of novel benzylamine antimycotics and evaluation of their antimycotic potency.

A series of 23 novel benzylamines was synthesized by reductive amination from halogen-substituted 3- and 4-benzyloxybenzaldehyde derivatives and 6-methylhept-2-yl amine or n-octylamine. The antimycotic activity of the resulting amines was evaluated in a microdilution assay against the apathogenic yeast Yarrowia lipolytica as test microorganism. Promising compounds were also tested against human pathogenic Candida species. The influence of halogen substituents at the benzyl ether side chain was studied in this screening, as well as the influence of the branched side chain of (±)-6-methylhept-2-yl amine in comparison with the n-octyl side chain.

Construction of N-Aryl-Substituted Pyrrolidines by Successive Reductive Amination of Diketones via Transfer Hydrogenation.

N-aryl-substituted pyrrolidines are important moieties widely found in bioactive substances and drugs. Herein, we present a practical reductive amination of diketones with anilines for the synthesis of N-aryl-substituted pyrrolidines in good to excellent yields. In this process, the N-aryl-substituted pyrrolidines were furnished via successive reductive amination of diketones via iridium-catalyzed transfer hydrogenation. The scale-up performance, water as a solvent, simple operation, as well as derivation of drug molecules showcased the potential application in organic synthesis.

Chemoenzymatic Synthesis of Selegiline: An Imine Reductase-Catalyzed Approach.

(R)-Homobenzylic amines are key structural motifs present in (R)-selegiline, a drug indicated for the treatment of early-stage Parkinson's disease. Herein, we report a new short chemoenzymatic approach (in 2 steps) towards the synthesis of (R)-selegiline via stereoselective biocatalytic reductive amination as the key step. The imine reductase IR36-M5 mutant showed high conversion (97%) and stereoselectivity (97%) toward the phenylacetone and propargyl amine substrates, offering valuable biocatalysts for synthesizing alkylated homobenzylic amines.

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.

Electrohydrogenation of Nitriles with Amines by Cobalt Catalysis.

Catalytic hydrogenation of nitriles represents an efficient and sustainable one-step synthesis of valuable bulk and fine chemicals. We report herein a molecular cobalt electrocatalyst for selective hydrogenative coupling of nitriles with amines using protons as the hydrogen source. The key to success for this reductive reaction is the use of an electrocatalytic approach for efficient cobalt-hydride generation through a sequence of cathodic reduction and protonation. As only electrons (e- ) and protons (H+ ) as the redox equivalent and hydrogen source, this general electrohydrogenation protocol is showcased by highly selective and straightforward synthesis of various functionalized and structurally diverse amines, as well as deuterium isotope labeling applications. Mechanistic studies reveal that the electrogenerated cobalt-hydride transfer to nitrile process is the rate-determining step.

Development of Iron-Based Single Atom Materials for General and Efficient Synthesis of Amines.

Earth abundant metal-based heterogeneous catalysts with highly active and at the same time stable isolated metal sites constitute a key factor for the advancement of sustainable and cost-effective chemical synthesis. In particular, the development of more practical, and durable iron-based materials is of central interest for organic synthesis, especially for the preparation of chemical products related to life science applications. Here, we report the preparation of Fe-single atom catalysts (Fe-SACs) entrapped in N-doped mesoporous carbon support with unprecedented potential in the preparation of different kinds of amines, which represent privileged class of organic compounds and find increasing application in daily life. The optimal Fe-SACs allow for the reductive amination of a broad range of aldehydes and ketones with ammonia and amines to produce diverse primary, secondary, and tertiary amines including N-methylated products as well as drugs, agrochemicals, and other biomolecules (amino acid esters and amides) utilizing green hydrogen.

sp3 -Rich Heterocycle Synthesis on DNA: Application to DNA-Encoded Library Production.

DNA encoded library (DEL) synthesis represents a convenient means to produce, annotate and store large collections of compounds in a small volume. While DELs are well suited for drug discovery campaigns, the chemistry used in their production must be compatible with the DNA tag, which can limit compound class accessibility. As a result, most DELs are heavily populated with peptidomimetic and sp2 -rich molecules. Herein, we show that sp3 -rich mono- and bicyclic heterocycles can be made on DNA from ketochlorohydrin aldol products through a reductive amination and cyclization process. The resulting hydroxypyrrolidines possess structural features that are desirable for DELs and target a distinct region of pharmaceutically relevant chemical space.

Comprehensive Study Addressing the Challenge of Efficient Electrocatalytic Biomass Upgrading of 5-(Hydroxymethyl)Furfural (HMF) with a CH3 NH2 Ionic Liquid on Metal-Embedded Mo2 B2 MBene Nanosheets.

Amine-containing derivatives are important intermediates in drug manufacturing; sustainable synthesis of amine compounds from green carbon-based biomass derivatives has attracted increasing attention, especially the reductive amination of biomass molecules via electrochemical upgrading. To achieve efficient reductive amination of 5-(hydroxymethyl)furfural (HMF) via electrocatalytic biomass upgrading, this work proposes a new HMF biomass upgrading strategy based on metal supported on Mo2 B2 MBene nanosheets using a density functional theory comprehensive study. HMF and methylamine (CH3 CH2 ) can be reduced to 5-(hydroxymethyl) aldiminefurfural (HMMAMF) via electrocatalytic biomass upgrading, which is identified as a promising technology to produce pharmaceutical intermediates. Based on the proposed reaction mechanisms of HMF reductive amination, this work performs a systematic study of HMF amination to HMMAMF using an atomic model simulation method. This study aims to design a high-efficiency catalyst based on Mo2 B2 @TM nanosheets via the reductive amination of 5-HMF and provide insights into the intrinsic relation between thermochemical and material electronic properties and the role of dopant metals. This work establishes the Gibbs free energy profiles of each reaction HMF Biomass Upgrading on Mo2 B2 systems and obtained the limiting potentials of the rate-determining step, which included the kinetic stability of dopants, HMF adsorbability, and the catalytic activity and selectivity of the hydrogen evolution reaction or surface oxidation. Furthermore, charge transfer, d-band center (εd ), and material property (φ) descriptors are applied to establish a linear correlation to determine promising candidate catalysts for reductive amination of HMF. The candidates Mo2 B2 @Cr, Mo2 B2 @Zr, Mo2 B2 @Nb, Mo2 B2 @Ru, Mo2 B2 @Rh, and Mo2 B2 @Os are suitable high-efficiency catalysts for HMF amination. This work may contribute to the experimental application of biomass upgrading catalysts for biomass energy and guide the future development of biomass conversion strategies and utilization.

On-capillary fluorescent labeling of saccharides for capillary electrophoresis.

The feasibility of on-capillary derivatization of saccharides by aromatic amine-based fluorescent labeling agents was tested. To avoid the problematic evolution of gaseous hydrogen cyanide, the Schiff base reduction by sodium cyanoborohydride, as the second step of the standard reductive amination protocol, was omitted. Glucose was used as a model analyte and 7-amino-1,3-naphthalenedisulfonic acid as the labeling agent. Our experiments showed that the direct reaction of the saccharide with the labeling agent in 2.5-M acetic acid yields a labeled product that is sufficiently stable to be separated from the labeling agent in 20-mM phosphate buffer, pH 3.5, and detected using UV detection. The glucose and label zones were introduced separately into the capillary and mixed using a negative voltage. Mixing voltage, its duration, the concentration of acetic acid in the reaction zone, and the waiting time between mixing and separation were optimized. To show the applicability of the procedure to a broader range of analytes, a mixture of different types of saccharides, that is, xylose (pentose), fucose (hexose), glucose (hexose), N-acetylglucosamine (N-acetylaminosaccharide), and lactose (disaccharide), was subjected to derivatization and analysis under the optimal conditions. The linearity and repeatability of the process were evaluated as critical parameters for its analytical applications. Six-point calibration dependences in the 1-50 mM range showed excellent determination coefficients of 0.9992 or higher for all five saccharides tested. The repeatability of the labeled saccharide peak areas was between 2.2% and 4.3%.

Direct Alkylative Amination Using 1-Allylsilatrane.

Homoallylic amines prepared via addition of allylsilanes often require preformed imine substrates, metal catalysts, fluoride activators, or use of protected amines. In this metal-free, air- and water-tolerant procedure, aromatic aldehyde and aniline substrates undergo direct alkylative amination using easily accessible 1-allylsilatrane.

N-Fluoroalkylated Morpholinos - a New Class of Nucleoside Analogues.

The first concise and efficient synthesis of some fluorine-containing morpholino nucleosides has been developed. One synthetic strategy was based on the oxidative ring cleavage of the vicinal diol unit of uridine, cytidine adenosine and guanosine derivatives, followed by cyclisation of the dialdehyde intermediates by double reductive amination with fluorinated primary amines to obtain various N-fluoroalkylated morpholinos. Another approach involved cyclisation of the diformyl intermediates with ammonia source, followed by dithiocarbamate formation and desulfurization-fluorination with diethylaminosulfur trifluoride yielding the corresponding morpholine-based nucleoside analogues with a N-CF3 element in their structure.

Promoting Amination of Furfural to Furfurylamine by Metal-Support Interactions on Pd/MoO3-x Catalysts.

The reductive amination of carbonyl compounds is one of the most straightforward protocols to construct C-N bonds, but highly desires active and selective catalysts. Herein, Pd/MoO3-x catalysts are proposed for furfural amination, in which the interactions between Pd nanoparticles and MoO3-x supports can be easily ameliorated by varying the preparation temperature toward efficient catalytic turnover. Thanks to the synergistic cooperation of MoV -rich MoO3-x and highly dispersed Pd, the optimal catalysts afford the high yield of furfurylamine (84 %) at 80 °C. Thereinto, MoV species not only acts as the acidic promoter to facilitate the activation of carbonyl groups, but also interacts with Pd nanoparticles to promote the subsequent hydrogenolysis of Schiff base N-furfurylidenefurfurylamine and its germinal diamine. The good efficiency of Pd/MoO3-x within a broad substrate scope further highlights the key contribution of metal-support interactions to the refinery of biomass feedstocks.

Opine dehydrogenases, an underexplored enzyme family for the enzymatic synthesis of chiral amines.

Opines and opine-type chemicals are valuable natural products with diverse biochemical roles, and potential synthetic building blocks of bioactive compounds. Their synthesis involves reductive amination of ketoacids with amino acids. This transformation has high synthetic potential in producing enantiopure secondary amines. Nature has evolved opine dehydrogenases for this chemistry. To date, only one enzyme has been used as biocatalyst, however, analysis of the available sequence space suggests more enzymes to be exploited in synthetic organic chemistry. This review summarizes the current knowledge of this underexplored enzyme class, highlights key molecular, structural, and catalytic features with the aim to provide a comprehensive general description of opine dehydrogenases, thereby supporting future enzyme discovery and protein engineering studies.

Assisted Reductive Amination for Quantitation of Tryptophan, 5-Hydroxytryptophan, and Serotonin by Ultraperformance Liquid Chromatography Coupled with Tandem Mass Spectrometry.

Herein, we used isotopic formaldehyde and sodium cyanoborohydride via reductive amination to label two methyl groups on primary amine to arrange the standards (h2-formaldehyde-modified) and internal standards (ISs, d2-formaldehyde-modified) of tryptophan and its metabolites, such as serotonin (5-hydroxytryptamine) and 5-hydroxytryptophan. These derivatized reactions with a high yield are very satisfactory for manufacturing standards and ISs. This strategy will generate one or two methyl groups on amine to create different mass unit shifts with 14 vs. 16 or 28 vs. 32 in individual compounds for biomolecules with amine groups. In other words, multiples of two mass units shift are created using this derivatized method with isotopic formaldehyde. Serotonin, 5-hydroxytryptophan, and tryptophan were used as examples to demonstrate isotopic formaldehyde-generating standards and ISs. h2-formaldehyde-modified serotonin, 5-hydroxytryptophan, and tryptophan are standards to construct calibration curves, and d2-formaldehyde-modified analogs such as ISs spike into samples to normalize the signal of each detection. We utilized multiple reaction monitoring modes and triple quadrupole mass spectrometry to demonstrate the derivatized method suitable for these three nervous biomolecules. The derivatized method demonstrated a linearity range of the coefficient of determinations between 0.9938 to 0.9969. The limits of detection and quantification ranged from 1.39 to 15.36 ng/mL.

Expanding Glycomic Investigations through Thiol-Derivatized Glycans.

N-(2-thioethyl)-2-aminobenzamide (TEAB), a novel glycan auxiliary, was synthesized and its utility was evaluated. The auxiliary was conjugated to glycans by reductive amination with the water-stable reagent 2-picoline borane complex. Glycan products, which ranged from 1 to 7 linked hexoses, were all isolated in yields ranging from 60% to 90% after purification by reverse-phase chromatography. The novel conjugate introduces a convenient, shelf-stable thiol directly onto the desired free glycans with purification advantages and direct modification with efficient reactions through alkenes, halides, epoxides, disulfides, and carboxylates in yields of 49% to 93%. Subsequently, a thiol-selective modification of the BSA protein was used to generate a neoglycoprotein with a bifunctional PEG-maleimide linker. To further illustrate the utility of a thiol motif, 2-thiopyridine activation of a thiol-containing support facilitated the covalent chromatographic purification of labeled glycans in yields up to 63%. Finally, initial proof of concept of implementation in a light printed microarray was explored and validated through FITC-labeled concanavalin A binding. In conclusion, the thiol-functionalized glycans produced greatly expand the diversity of bioconjugation tools that can be developed with glycans and enable a variety of biological investigations.