Asymmetric Amination Research Articles

Asymmetric amination of α,α-dialkyl substituted aldehydes catalyzed by a simple chiral primary amino acid and its application to the preparation of a S1P1 agonist.

The chiral catalytic amination of an α,α-dialkyl substituted aldehyde usually proceeds with low enantioselectivity. We selected naphthyl-l-alanine as the catalyst and observed improved enantioselectivity for the amination. Using this method, racemic α-methyl-α-benzyloxypropanal was aminated to give chiral serine derivatives in 74% ee, which was further increased to >99% ee after recrystallization. Moreover, we also successfully synthesized a chiral phosphonium salt 9 for the preparation of one α-substituted alaninol compound 14 as an S1P1 agonist in high overall yield.

Design of Efficient Chiral Bifunctional Phase-Transfer Catalysts Possessing an Amino Functionality for Asymmetric Aminations

An efficient, chiral bifunctional phase-transfer catalyst with an intramolecular amino functionality has been designed and successfully applied to highly enantioselective amination of 3-aryloxindoles and 3-arylbenzofuran-2(3H)-ones with bis(adamantyl) azodicarboxylate. Optically active amination products were generally obtained in high yield with high enantioselectivity. The origin of stereoselectivity was explained by means of the DFT calculations.

A radical approach to asymmetric amines

Organic Chemistry Converting aliphatic C–H bonds into C–N bonds is a broadly useful reaction in pharmaceutical research. A persistent challenge is to obtain just one of the two possible mirror-image products, or enantiomers, in this context. Li et al. report an odd-electron cobalt porphyrin complex that catalyzes highly enantioselective intramolecular C–H amination in a variety of substrates with pendant sulfamoyl azides. The reaction selectively targets carbon centers that are five atoms away from the activated nitrogen, producing six-membered rings that can be opened by hydrolytic sulfonyl removal. Isotopic labeling and trapping studies implicate a radical mechanism. Angew. Chem. Int. Ed. 10.1002/anie.201808923 (2018).

Organocatalytic Enantioselective α‐Amination of Thiazol‐4‐one‐5‐carboxylates with Azodicarboxylates

AbstractAn effective method for the asymmetric synthesis of 5‐hydrazinothiazol‐4‐one‐5‐carboxylates was developed. The tetrasubstituted chiral carbon center was generated by asymmetric amination of thiazol‐4‐one‐5‐carboxylate with azodicarboxylate catalyzed by a bifunctional squaramide‐based (1R,2R)‐cyclohexane‐1,2‐diamine backbone in good to excellent yields (40–96%) with high levels of enantioselectivity (92–98% ee). A representative transformation of the amination product to a biologically important 1,3,4‐oxadiazol‐2(3H)‐one is achieved without any appreciable loss in enantioselectivity. Additionally, upon treatment with NaBH3CN, the amination product could also be converted into a biologically important thiazolidin‐4‐one derivative in good yield without any loss of stereochemical integrity.

Regioselective Biocatalytic Transformations Employing Transaminases and Tyrosine Phenol Lyases

Regioselective reactions allow the differentiation between two or more chemically identical reactive centers within the same molecule. They are highly desirable transformations in organic synthesis, as they avoid additional chemical operations and sophisticated protection/deprotection strategies. In this context, enzymes, which present exquisite selectivity and reactivity, have been widely employed as catalysts in numerous regioselective transformations. This review focuses on two recently developed biocatalytic processes that present outstanding regioselectity: the transaminase-catalyzed asymmetric amination of di- and triketo compounds, and the stereoselective C–C coupling between phenol derivatives, ammonia and pyruvate for the synthesis of tyrosine analogues, catalyzed by tyrosine phenol lyases. Additionally, elegant and straightforward cascades that have combined the aforementioned biotransformations with other enzymatic and/or chemocatalytic processes are compiled in this contribution. Overall, this review aims to provide a general view of the synthetic possibilities that two relatively recently described regio- and stereoselective biotransformations can provide.

Tackling Challenges in Industrially Relevant Homogeneous Catalysis: The Catalysis Research Laboratory (CaRLa), an Industrial-Academic Partnership.

Industrial-academic collaborations are broadly used for the development of new industrial processes. To achieve a strong and deep collaboration in the field of homogeneous catalysis, BASF and the Heidelberg University have been running the Catalysis Research Laboratory together in Heidelberg since 2006. This Perspective highlights the concept of this laboratory and our experiences over the past few years in this joint laboratory. How this collaboration works is explained in more detail using three selected projects: sodium acrylate based on CO2, the selective decomposition of cyclohexyl hydroperoxide to cyclohexanone, and the asymmetric amination of ketones with NH3/H2.

Catalytic Asymmetric Amination of meso-Epoxide Using Soy Polysaccharide (Soyafibe S-DN)

Abstract The asymmetric amination of epoxides is an effective method to synthesize chiral β-aminoalcohols and their components as pharmaceuticals. We have developed a new catalyst system for the asymmetric amination of 1,2-epoxycyclohexane with cyclopropylamine. We have also found that water-soluble soy polysaccharide (Soyafibe S-DN) functions as a catalyst. This catalytic reaction proceeded under mild conditions in hydrous toluene at 37–40 °C. (1R,2R)-2-(cyclopropylamino)cyclohexan-1-ol was obtained at 64% enantiomeric excess (ee) by the asymmetric amination of 1,2-epoxycyclohexane with cyclopropylamine using this catalyst system; it was also made at >99% ee by purification as the fumarate salt. The catalytic activity of this soluble soy polysaccharide remained unchanged, even when treated with a protease, but its activity disappeared when treated with a sugar chain degrading enzyme. These results indicate that the polysaccharide rather than the protein acts as the catalyst for this reaction. Thus, we have discovered for the first time that polysaccharides can act as asymmetric catalysts for the amination of 1,2-epoxycyclohexane.

One step synthesis of unnatural β-arylalanines using mutant phenylalanine aminomutase from Taxus chinensis with high β-regioselectivity.

Phenylalanine aminomutase (TcPAM) from Taxus chinensis catalyzes the regioselective hydroamination of trans-cinnamic acid (t-CA) to yield β-phe. However, the final product mixture consists of both α- and β-phe owing to low regioselectivity, which is still a challenge to synthesize highly pure β-phe. Therefore, a modified TcPAM with high β-selectivity is expected. Based on the catalytic mechanism and structure, two amino acid residues (Asn458 and Leu108) in active sites were identified as the key residues for controlling the regioselective hydroamination of t-CA and as promising candidates for mutagenesis to enhance β-selectivity and decrease α-selectivity. The Asn458 and Leu108 residues were mutated to yield variant TcPAM-Asn458Phe/Leu108Glu, and the β-selectivity was approximately 5.2-fold higher than that of wild-type TcPAM, while α-selectivity decreased to 68%, and the percentage of β-phe in the product mixture increased from 42% to 83%. In addition, the mutant was applied to synthesize β-arylalanines using substituent t-CA as a substrate. The regioselectivity was also affected by the substituent groups at the phenyl ring of t-CA with respect to their electronic properties and position, and the 4-methoxy and methyl substituent t-CA were transferred into β-arylalanines. The conversion rate also exceeded 90%. In summary, the engineered TcPAM proved to be useful for one-step asymmetric amination of t-CA and its derivatives to synthesize highly pure β-arylalanines.

Construction of Isoxazolidin‐5‐ones with a Tetrasubstituted Carbon Center: Enantioselective Conjugate Addition Mediated by Phase‐Transfer Catalysis

AbstractAn efficient enantioselective Michael reaction of readily available α‐substituted N‐Boc isoxazolidin‐5‐ones is described under phase transfer conditions with up to 95:5 er. The organocatalytic process is promoted by a low catalytic loading of a commercially available N‐spiro quaternary ammonium salt. This sequence opens an entry to chiral heterocyclic platforms displaying a β‐amino carbonyl motif with an α‐all‐carbon quaternary stereogenic center. The methodology was also successfully extended to the asymmetric amination reaction using an azodicarboxylate electrophile.magnified image

Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases.

Several chemoenzymatic routes have been explored for the preparation of cinacalcet, a calcimimetic agent. Transaminases (TAs) and ketoreductases (KREDs) turned out to be useful biocatalysts for the preparation of key optically active precursors. Thus, the asymmetric amination of 1‐acetonaphthone yielded an enantiopure (R)‐amine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (S)‐alcohol, which was easily converted into the previous (R)‐amine. In addition, the reduction was efficiently performed with the KRED and its cofactor co‐immobilized on the same porous surface. This self‐sufficient heterogeneous biocatalyst presented an accumulated total turnover number (TTN) for the cofactor of 675 after 5 consecutive operational cycles. Finally, in a preparative scale synthesis the TA‐based approach was performed in aqueous medium and led to enantiopure cinacalcet in two steps and 50% overall yield.

Hydrogen-Borrowing Alcohol Bioamination with Coimmobilized Dehydrogenases.

The amination of alcohols is an important transformation in chemistry. The redox‐neutral (i.e., hydrogen‐borrowing) asymmetric amination of alcohols is enabled by the combination of an alcohol dehydrogenase (ADH) with an amine dehydrogenase (AmDH). In this work, we enhanced the efficiency of hydrogen‐borrowing biocatalytic amination by co‐immobilizing both dehydrogenases on controlled porosity glass FeIII ion‐affinity beads. The recyclability of the dual‐enzyme system was demonstrated (5 cycles) with total turnover numbers of >4000 and >1000 for ADH and AmDH, respectively. A set of (S)‐configured alcohol substrates was aminated with up to 95 % conversion and >99 % ee (R). Preparative‐scale amination of (S)‐phenylpropan‐2‐ol resulted in 90 % conversion and 80 % yield of the product in 24 h.

Origin of stereoselectivity in the amination of alcohols using cooperative asymmetric dual catalysis involving chiral counter-ions.

Asymmetric catalysis using two chiral catalysts in combination using one-pot reaction conditions is in its initial stages of development and understanding. We employ density functional theory (SMD(toluene)/M06/6-31G**,SDD(Ir)) computations to shed light on the action of chiral phosphoric acid and a chiral Cp*Ir(diamine) in stereoinduction in an asymmetric amination reaction of an alcohol. First, the protonation of the Ir-diamine complex by the phosphoric acid forms an ion-pair of the active catalytic dyad. Both chiral catalysts are involved throughout the catalytic cycle, thus constituting an important example of true cooperative catalysis. A borrowing hydrogen mechanism operates, wherein the phosphate abstracts the hydroxyl proton of the alcohol while the electrophilic Ir(iii) simultaneously extracts the α-hydrogen to form a [Ir]-H species. The ketone thus derived from the alcohol through dehydrogenation condenses with aniline to form an imine. In the diastereocontrolling transition state, the hydride adds to the activated iminium, held in position in the chiral pocket of the catalytic dyad through a network of noncovalent interactions (C-H···π, N-H···O and C-H···O). The enantioselectivity in this DYKAT process is identified as taking place at an earlier stage of the catalytic cycle prior to the diastereo-determining transition state.

Deletion of a dynamic surface loop improves thermostability of (R)-selective amine transaminase from Aspergillus terreus

Chiral amines are important building blocks for the synthesis of pharmaceutical products and fine chemicals. Highly stereoselective synthesis of chiral amines compounds through asymmetric amination has attracted more and more attention. ω-transaminases (ω-TAs) are a promising class of natural biocatalysts which provide an efficient and environment-friendly access to production of chiral amines with stringent enantioselectivity and excellent catalytic efficiency. Compared with (S)-ω-TA, the research focused on (R)-ω-TA was relatively less. However, increasing demand for chiral (R)-amines as pharmaceutical intermediates has rendered industrial applications of (R)-ω-TA more attractive. Improving the thermostability of (R)-ω-TA with potential biotechnological application will facilitate the preparation of chiral amines. In this study, the dynamic surface loop with higher B-factor from Aspergillus terreus (R)-ω-TA was predicted by two computer softwares (PyMOL and YASARA). Then mutant enzymes were obtained by deleting amino acid residues of a dynamic surface loop using site-directed mutagenesis. The results showed that the best two mutants R131del and P132-E133del improved thermostability by 2.6 ℃ and 0.9 ℃ in T₅₀¹⁰ (41.1 ℃ and 39.4 ℃, respectively), and 2.2-fold and 1.5-fold in half-life (t1/2) at 40 ℃ (15.0 min and 10.0 min, respectively), compared to that of wild type. Furtherly, the thermostability mechanism of the mutant enzymes was investigated by molecular dynamics (MD) simulation and intermolecular interaction analysis. R131del in the loop region has lower root mean square fluctuation (RMSF) than the wild type at 400 K for 10 ns, and mutant enzyme P132-E133del increases four hydrogen bonds in the loop region. In this study, we obtain two stability-increased mutants of (R)-ω-TA from A. terreus by deleting its dynamic surface loop and also provide methodological guidance for the use of rational design to enhance the thermal stability of other enzymes.

Asymmetric Amination of α‐Chiral Aliphatic Aldehydes via Dynamic Kinetic Resolution to Access Stereocomplementary Brivaracetam and Pregabalin Precursors

AbstractOver the last decades biocatalysis has emerged as an indispensable and versatile tool for the asymmetric synthesis of active pharmaceutical ingredients (APIs). In this context, especially transaminases (TAs) have been successfully used for the preparation of numerous α‐chiral, optically pure amines, serving as important building blocks for APIs. Here we elaborate on the development of transaminases recognizing the α‐chiral centre adjacent to an aldehyde moiety with aliphatic residues, opening up concepts for novel synthetic routes to the antiepileptic drugs Brivaracetam and Pregabalin. The transformation proceeded via dynamic kinetic resolution (DKR) based on the bio‐induced racemisation of the aldehyde enantiomers, enabling the amination of the racemic substrates with quantitative conversions. Medium, substrate as well as enzyme engineering gave access to both (R)‐ and (S)‐enantiomers of the amine precursors of the stereocomplementary drugs in high optical purity, representing a short route to mentioned APIs.magnified image

Nucleobases as Nucleophiles in Asymmetric Allylic Amination Reactions

Nucleobases as Nucleophiles in Asymmetric Allylic Amination Reactions

Synthesis, characterization and photo physical-theoretical analysis of D-π-A compounds. 2. Chain length effect through even-odd effect on the photophysical properties

In the continuous search for new compounds for solar devices, the family of dipolar D-π-A molecules, which have a donor (D) and an acceptor (A) charge joined by a conjugate bridge, have been the focus of attention in the recent years due their different properties. As we have shown before, there is a connection between the geometry of molecules based on tertiary asymmetric amines and their quantum yield. In the current work, four new compounds based on the same backbone molecule ((E)-2-cyano-3-(5-((E)-2-(9,9-diethyl-7-(phenylamino)-9H-fluoren-2-yl)vinyl)thiophen-2-yl)acrylic acid), but with different substituent, were synthesized. It is shown that the chain-size of the substituent group modifies the quantum yield. The news substituents introduced are a propyl (M8-3), butyl (M8-4), pentyl (M8-5) or hexyl (M8-6) group. In general, it was possible to see that the new substituents were able to increase their performances. Furthermore, an odd-even substituent effect, between propyl/pentyl and butyl/hexyl, was found and the theoretical geometrical data was able to follow the trend. However, theoretically, this substituent effect was inverted in the case of M8-3 and M8-4, which may be due to the disappearance in the emission patterns of an excited state close to 450 nm (at λ2), as it was shown in the experimental data. The most suitable behaviour belongs to [(E)-2-cyano-3-(5-((E)-2-(9,9-diethyl-7-(phenyl(propyl)amino)-9H-fluoren-2-yl)vinyl)thiophen-2-yl)acrylic acid] (M8-3). M8-3 has the highest quantum yields on average in all studied solvents; even higher than the last reported compounds with methyl (M8-1) and ethyl (M8-2) groups. Theoretically, the most likely explanation is that the dihedral angle formed between the carbonyl acceptor and nitrogen electron donor (Aryl-CO), should be as small as the molecule M8-3. This isolated compound has an average quantum yield including all solvents of 58.1% (average value), showing that a long group is not necessary to improve the performance.

In vivo plug-and-play: a modular multi-enzyme single-cell catalyst for the asymmetric amination of ketoacids and ketones

BackgroundTransaminases have become a key tool in biocatalysis to introduce the amine functionality into a range of molecules like prochiral α-ketoacids and ketones. However, due to the necessity of shifting the equilibrium towards the product side (depending on the amine donor) an efficient amination system may require three enzymes. So far, this well-established transformation has mainly been performed in vitro by assembling all biocatalysts individually, which comes along with elaborate and costly preparation steps. We present the design and characterization of a flexible approach enabling a quick set-up of single-cell biocatalysts producing the desired enzymes. By choosing an appropriate co-expression strategy, a modular system was obtained, allowing for flexible plug-and-play combination of enzymes chosen from the toolbox of available transaminases and/or recycling enzymes tailored for the desired application.ResultsBy using a two-plasmid strategy for the recycling enzyme and the transaminase together with chromosomal integration of an amino acid dehydrogenase, two enzyme modules could individually be selected and combined with specifically tailored E. coli strains. Various plug-and-play combinations of the enzymes led to the construction of a series of single-cell catalysts suitable for the amination of various types of substrates. On the one hand the fermentative amination of α-ketoacids coupled both with metabolic and non-metabolic cofactor regeneration was studied, giving access to the corresponding α-amino acids in up to 96% conversion. On the other hand, biocatalysts were employed in a non-metabolic, “in vitro-type” asymmetric reductive amination of the prochiral ketone 4-phenyl-2-butanone, yielding the amine in good conversion (77%) and excellent stereoselectivity (ee = 98%).ConclusionsThe described modularized concept enables the construction of tailored single-cell catalysts which provide all required enzymes for asymmetric reductive amination in a flexible fashion, representing a more efficient approach for the production of chiral amines and amino acids.

Vicinal Diamines as Smart Cosubstrates in the Transaminase‐Catalyzed Asymmetric Amination of Ketones

Transaminases (TAs) have recently been established as catalysts for the asymmetric, reductive amination of prochiral ketones. Depending on the ketone substrate and the amine donor (the cosubstrate), equilibrium constants may limit high conversions; thus, methods to overcome this limitation are required. Removal of the co‐product from the reaction equilibrium through spontaneous, intramolecular reactions has provided a successful solution to this problem; therefore, these amine donors have been named “smart cosubstrates”. Here, we present a comparison of various bifunctional amine donors including vicinal diamines as potential structural cosubstrate motifs. Upon TA‐catalyzed deamination of 1,2‐diamines, spontaneous dimerization of the resulting α‐aminoketones and oxidation gave heteroaromatic pyrazines.

Synthesis, characterization and photophysical-theoretical analysis of compounds A-π-D. 1. Effect of alkyl-phenyl substituted amines in photophysical properties

The study of new dipolar A-π-D molecules, which have an acceptor (A) and donor (D) charge joined by a conjugate bridge, have been an attention focus in the recent years due their different properties. In the current work, a molecular system has been modified in order to compare the effect on properties, such as quantum yield. Thus, two series were generated (alkyl- and alkoxy-substituted) to determine if molecules with tertiary asymmetric amines change their optical properties and whether quantum yield is affected. The different products have been characterized by several techniques such as UV–Vis spectrophotometry, elemental analysis, NMR, FT-IR, mass spectroscopy and fluorescence spectroscopy. Furthermore, their behavior in eight organic solvents, dichloromethane, tetrahydrofuran, ethyl acetate, 1,4-dioxane, acetone, acetonitrile, dimethylformamide and dimethylsulfoxide were experimentally and theoretically studied. The quantum yields were higher for the alkyl-substituted series. Theoretically, the dihedral angles formed between the tertiary amine and carbonyl group moieties have a correlation with quantum yield values, helping to explain why they are higher in non-polar solvents. Consequently, the maximum quantum yield was obtained with (E)-2-cyano-3-(5-((E)-2-(9,9-diethyl-7-(methyl(phenyl)amino)-9H-fluoren-2-yl) vinyl)thiophen-2-yl)acrylic acid (M8-1) in 1,4-dioxane, reaching 98.8%.

Acid-Assisted Ruthenium-Catalyzed Asymmetric Amination of Diols

Acid-Assisted Ruthenium-Catalyzed Asymmetric Amination of Diols