Amine Donor Research Articles

A system for ω-transaminase mediated (R)-amination usingl-alanine as an amine donor

Introduction of an alanine racemase allowed the use ofl-alanine as an initial amine source for the biocatalytic amination leading to (R)-amines.

Synthesis and dye sensitized solar cell applications of Bodipy derivatives with bis-dimethylfluorenyl amine donor groups

Bulky donor and thiophene π-linker groups have been used with Bodipy molecules and their solar cell efficiencies have been investigated.

A rapid, sensitive colorimetric assay for the high-throughput screening of transaminases in liquid or solid-phase.

A new colorimetric method has been developed to screen transaminases using an inexpensive amine donor. The assay is sensitive, has a low level of background coloration, and can be used to identify and profile transaminase activities against aldehyde and ketone substrates in a high-throughput format. Significantly it is also amendable to solid phase colony screening.

Anthraquinone-based intramolecular charge-transfer compounds: computational molecular design, thermally activated delayed fluorescence, and highly efficient red electroluminescence.

Red fluorescent molecules suffer from large, non-radiative internal conversion rates (k(IC)) governed by the energy gap law. To design efficient red thermally activated delayed fluorescence (TADF) emitters for organic light-emitting diodes (OLEDs), a large fluorescence rate (k(F)) as well as a small energy difference between the lowest singlet and triplet excited states (ΔE(ST)) is necessary. Herein, we demonstrated that increasing the distance between donor (D) and acceptor (A) in intramolecular-charge-transfer molecules is a promising strategy for simultaneously achieving small ΔE(ST) and large k(F). Four D-Ph-A-Ph-D-type molecules with an anthraquinone acceptor, phenyl (Ph) bridge, and various donors were designed, synthesized, and compared with corresponding D-A-D-type molecules. Yellow to red TADF was observed from all of them. The k(F) and ΔE(ST) values determined from the measurements of quantum yield and lifetime of the fluorescence and TADF components are in good agreement with those predicted by corrected time-dependent density functional theory and are approximatively proportional to the square of the cosine of the theoretical twisting angles between each subunit. However, the introduction of a Ph-bridge was found to enhance k(F) without increasing ΔE(ST). Molecular simulation revealed a twisting and stretching motion of the N-C bond in the D-A-type molecules, which is thought to lower ΔE(ST) and k(F) but raise k(IC), that was experimentally confirmed in both solution and doped film. OLEDs containing D-Ph-A-Ph-D-type molecules with diphenylamine and bis(4-biphenyl)amine donors demonstrated maximum external quantum efficiencies of 12.5% and 9.0% with emission peaks at 624 and 637 nm, respectively.

The pentadentate ligands 2PyN2Q and N4Py, and their Cu(II) and Zn(II) complexes: A synthetic, spectroscopic and crystallographic structural study

The synthesis and characterization of the new ligand N,N-bis(2-quinolylmethyl)-N-bis(2-pyridyl)methylamine (2PyN2Q), a derivative of N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine (N4Py) is reported. Purification of both N4Py and 2PyN2Q on Dowex cation exchange columns as their hydrochloride salts allowed the isolation of the byproducts N3Py and 2PyNQ, respectively. The X-ray crystal structure of [H2N4Py](PF6)2 shows that the two more basic picolyl nitrogens are protonated. X-ray structural analyses of the copper(II) complexes [Cu(N4Py)(NO3)](NO3) (1) and [Cu(2PyN2Q)(NO3)](NO3) (2) show that the binding of the nitrate ligand is influenced by the steric bulk of the quinoline rings while electrochemical studies show that the poorer basicity of the quinolinyl donors makes 2 more easily reduced than 1. X-ray structural analyses of the zinc(II) complexes [Zn(N4Py)(OH2)](CF3SO3)2·H2O (3a·H2O), [Zn(N4Py)(CH3OH)](ClO4)2·CH3OH (4·CH3OH) and [Zn(2PyN2Q)(NCCH3)](ClO4)2·CH3CN (6·CH3CN) again show that the quinoline rings have a significant influence on the way in which the monodentate ligand can bind to the zinc center. The X-ray crystal structure of [Zn(2PyNQ)2](ClO4)2 (7) is also reported. In 7 the zinc(II) ion is bonded to two pyridyl donors and one amine donor from each of two ligands and the quinolinyl donors are not bound.

Structural and biochemical characterization of the dual substrate recognition of the (R)-selective amine transaminase from Aspergillus fumigatus.

Chiral amines are important precursors for the pharmaceutical and fine-chemical industries. Because of this, the demand for enantiopure amines is currently increasing. Amine transaminases can produce a large spectrum of chiral amines in the (R)- or (S)-configuration, depending on their substrate scope and stereo-preference, by converting a prochiral ketone into the chiral amine while using alanine as the amine donor producing pyruvate as an α-keto acid product. In order to guide the protein engineering of transaminases to improve substrate specificity and enantioselectivity, we carried out a crystal structure analysis at 1.6 Å resolution of the (R)-amine transaminase from Aspergillus fumigatus with the bound inhibitor gabaculine. This revealed that Arg126 has an important role in the dual substrate recognition of this enzyme because mutating this residue to alanine reduced substantially the ability of the enzyme to use pyruvate as an amino acceptor.

Evaluation of CV2025 ω-transaminase for the bioconversion of lignin breakdown products into value-added chemicals: synthesis of vanillylamine from vanillin

Lignin is an essential component of the cell wall of various plants and represents an abundant and renewable natural resource. Both thermo-chemical and biological pre-treatment can be applied to break down the phenylpropanoid polymer subunits present in lignin. These liberate a range of phenolic compounds which represent potential substrates for bioconversion by ω-transaminases. In this work, the CV2025 ω-transaminase (ω-TAm) from Chromobacterium violaceum DSM30191, heterologously expressed in E. coli, was explored for selective amination of lignin breakdown intermediates into value-added products. Eight potential ω-TAm substrates were initially screened using (S)-α-methylbenzylamine (MBA) as the amino donor. Vanillin was identified as the best potential substrate which is converted into vanillylamine; an intermediate in the preparation of pelargonic acid vanillylamide used as a hyperemia inducing active substance in wound dressings. At low vanillin and MBA concentrations (< 10 mM) and with an excess of the amine donor (1:4 mol/mol) 100% w/w conversion of vanillin into vanillylamine was observed within 25 min. At vanillin concentrations above 10 mM, substrate inhibition was observed decreasing the rate and yield of the bioconversion. High concentrations of the reaction product (vanillylamine) and by-product (acetophenone) also limited the conversion due to increased backward reaction rate and inhibition. Vanillylamine synthesis could be carried out by both whole cell and clarified lysate forms of the CV2025 ω-TAm while fed-batch bioconversions (feeding low concentrations of both vanillin and MBA) could help overcome substrate inhibition and double the final product concentrations obtained. These results demonstrate the potential for bioconversion of lignin breakdown products into value-added chemicals but illustrate the need for enzymes with improved substrate range and implementation of techniques to overcome product inhibition and equilibrium constraints.

The conformational flexibility of the tetradentate ligand (tBu)N4 is essential for the stabilization of ((tBu)N4)Pd(III) complexes.

The conformationally flexible tetradentate pyridinophane ligand (tBu)N4 effectively lowers the oxidation potential of ((tBu)N4)Pd(II) complexes and promotes their facile chemical and electrochemical oxidation, including unpredecented aerobic oxidation reactivity. While the low potential of a number of Pd(II) (and Pt(II)) complexes supported by various fac-chelating polydentate ligands is often attributed to the presence of a coordinating group in the axial position of the metal center, no detailed electrochemical studies have been reported for such systems. Described herein is the detailed electrochemical investigation of the effect of ligand conformation on the redox properties of the corresponding Pd(II) complexes. These Pd complexes adopt different conformations in solution, as supported by studies using variable scan rate, variable-temperature cyclic voltammetry (CV), differential pulse voltammety, and digital CV simulations at variable scan rates. The effect of the axial amine protonation on the spectroscopic and electrochemical properties of the complexes was also investigated. A number of new Pd(III) complexes were characterized by electron paramagnetic resonance, UV-vis spectroscopy, and X-ray diffraction including [((tBu)N4)Pd(III)Cl2]ClO4, a dicationic [((tBu)N4)Pd(III)Me(MeCN)](OTf)2, and an unstable tricationic [((tBu)N4)Pd(III)(EtCN)2](3+) species. Although the electron-rich neutral complexes ((tBu)N4)PdMeCl and ((tBu)N4)PdMe2 are present in solution as a single isomer with the axial amines not interacting with the metal center, their low oxidation potentials are due to the presence of a minor conformer in which the (tBu)N4 ligand adopts a tridentade (κ(3)) conformation. In addition, the redox properties of the ((tBu)N4)Pd complexes show a significant temperature dependence, as the low-temperature behavior is mainly due to the contribution from the major, most stable conformer, while the room-temperature redox properties are due to the formation of the minor, more easily oxidized conformer(s) with the (tBu)N4 ligand acting as a tridentate (κ(3)) or tetradentate (κ(4)) ligand. Overall, the coordination to the metal center of each axial amine donor of the (tBu)N4 ligand leads to a lowering of the Pd(II/III) oxidation potential by ∼0.6 V. These detailed electrochemical studies can thus provide important insights into the design of new ligands that can promote Pd-catalyzed oxidation reactions employing mild oxidants such as O2.

Nickel Complexes Featuring Iminophosphorane–Phenoxide Ligands for Catalytic Ethylene Dimerization

A series of bidentate ligands associating an iminophosphorane and a phenoxide were synthesized and coordinated to nickel(II), leading initially to bimetallic KNi adducts. Replacement of the potassium by another metal allowed the isolation and characterization of bimetallic LiNi and AlNi complexes, while addition of one equivalent of triphenylphosphine gave access to monometallic complexes. The same type of complex was obtained with the coordination of a tridentate ligand incorporating a supplementary amine donor. These paramagnetic complexes were characterized by elemental analysis, and some of them by X-ray diffraction, evidencing a tetrahedral nickel center. They were shown to efficiently catalyze the oligomerization of ethylene in the presence of Et2AlCl (Al/Ni = 22.5) with TOF up to 72 000 mol(C2H4)/mol(Ni)/h, giving selectively butene (more than 97%) with at best 93% of 1-C4.

Boryl-metal bonds facilitate cobalt/nickel-catalyzed olefin hydrogenation.

New approaches toward the generation of late first-row metal catalysts that efficiently facilitate two-electron reductive transformations (e.g., hydrogenation) more typical of noble-metal catalysts is an important goal. Herein we describe the synthesis of a structurally unusual S = 1 bimetallic Co complex, [((Cy)PBP)CoH]2 (1), supported by bis(phosphino)boryl and bis(phosphino)hydridoborane ligands. This complex reacts reversibly with a second equivalent of H2 (1 atm) and serves as an olefin hydrogenation catalyst under mild conditions (room temperature, 1 atm H2). A bimetallic Co species is invoked in the rate-determining step of the catalysis according to kinetic studies. A structurally related Ni(I)Ni(I) dimer, [((Ph)PBP)Ni]2 (3), has also been prepared. Like Co catalyst 1, Ni complex 3 displays reversible reactivity toward H2, affording the bimetallic complex [((Ph)PBHP)NiH]2 (4). This reversible behavior is unprecedented for Ni(I) species and is attributed to the presence of a boryl-Ni bond. Lastly, a series of monomeric ((tBu)PBP)NiX complexes (X = Cl (5), OTf (6), H (7), OC(H)O (8)) have been prepared. The complex ((tBu)PBP)NiH (7) shows enhanced catalytic olefin hydrogenation activity when directly compared with its isoelectronic/isostructural analogues where the boryl unit is substituted by a phenyl or amine donor, a phenomenon that we posit is related to the strong trans influence exerted by the boryl ligand.

Probing the role of secondary versus tertiary amine donor ligands for indium catalysts in lactide polymerization.

The role of the central amine donor in a previously reported dinuclear indium catalyst, [N(Me2)N(H)O)InCl]2(μ-Cl)(μ-OEt) (1), for the polymerization of lactide was investigated through experimental methods. The solid state structural data of a series of dimeric complexes related to 1, including the previously reported bromide derivative [(N(Me2)N(H)O)InBr](μ-Br)(μ-OEt) (2) and the newly synthesized methylated derivative [(N(Me2)N(Me)O)InCl]2(μ-Cl)(μ-OEt) (6), showed that weak hydrogen bonding may be present within some of these complexes in the solid state. The polymerization of rac-lactide with 2, 6, and a related achiral complex [(L(H))InCl]2(μ-Cl)(μ-OEt) (8) synthesized for this study indicates that hydrogen bonding may not influence the reactivity of these compounds. The nature of the central amine donor may play a role in tuning the reactivity of these types of catalysts. Catalysts with central secondary amine donors, such as complexes 1, 2, and 8, are 2 orders of magnitude more reactive than those with central tertiary amine donors, such as complex 6.

Chiral amine synthesis using ω-transaminases: an amine donor that displaces equilibria and enables high-throughput screening.

The widespread application of ω-transaminases as biocatalysts for chiral amine synthesis has been hampered by fundamental challenges, including unfavorable equilibrium positions and product inhibition. Herein, an efficient process that allows reactions to proceed in high conversion in the absence of by-product removal using only one equivalent of a diamine donor (ortho-xylylenediamine) is reported. This operationally simple method is compatible with the most widely used (R)- and (S)-selective ω-TAs and is particularly suitable for the conversion of substrates with unfavorable equilibrium positions (e.g., 1-indanone). Significantly, spontaneous polymerization of the isoindole by-product generates colored derivatives, providing a high-throughput screening platform to identify desired ω-TA activity.

Chiral Amine Synthesis Using ω‐Transaminases: An Amine Donor that Displaces Equilibria and Enables High‐Throughput Screening

AbstractThe widespread application of ω‐transaminases as biocatalysts for chiral amine synthesis has been hampered by fundamental challenges, including unfavorable equilibrium positions and product inhibition. Herein, an efficient process that allows reactions to proceed in high conversion in the absence of by‐product removal using only one equivalent of a diamine donor (ortho‐xylylenediamine) is reported. This operationally simple method is compatible with the most widely used (R)‐ and (S)‐selective ω‐TAs and is particularly suitable for the conversion of substrates with unfavorable equilibrium positions (e.g., 1‐indanone). Significantly, spontaneous polymerization of the isoindole by‐product generates colored derivatives, providing a high‐throughput screening platform to identify desired ω‐TA activity.

Structural Features of Biomimetic Complexes: The Role of Axial Donor Ligands

An ongoing theme in our research group involves the development of biomimetic transition metal complexes that serve to activate small molecules, promote reactions similar to those of metalloenzymes, and provide new synthetic routes to novel ligands. In one instance, we have developed models of iron-containing bleomycin that rely on robust tetradentate aminopyridine macrocyclic (PyMAC) ligands. These simple systems serve as rigid scaffolds that are suitable for coordination of transition metal ions and their success as structural and functional models has led to the design and study of more elaborate ligand architectures. Our group has developed novel PyMACs containing functionalized pendant arms that can provide an additional donor atom as well as modulate the spin state of the metal center. A second area of focus involves the template synthesis of a wide range of imidoylamidines promoted by a urease model complex containing Ni(II) supported by tert-butyl-dipicolylamine (tBuDPA). Structures of the model complex with a bound imidoylamidine reveal that the tertiary amine donor atom of tBuDPA behaves in a similar fashion to pendant arm donor atoms in PyMAC ligands and its degree of coordination dictates the metal's spin state. Novel iron(II) and copper(II) complexes supported by our modified PyMAC ligands as well as examples of our structurally characterized nickel(II) imidoylamide and imidoylamidine complexes will be presented.

The coupling of ω-transaminase and Oppenauer oxidation reactions via intra-membrane multicomponent diffusion – A process model for the synthesis of chiral amines

Abstract In this study we consider the theoretical coupling of an otherwise thermodynamically limited ω-transaminase reaction to an Oppenauer oxidation, in order to shift the equilibria of both reactions, with the aim of achieving a significant (and important) increase in the yield of the desired chiral amine product. Using 2-propylamine as the amine donor of the ω-transaminase reaction, gives acetone as a by-product, which in turn allows the coupling of the ω-transaminase reaction with the Oppenauer oxidation. The Oppenauer reaction converts secondary alcohols into ketones, and these can subsequently be fed to the ω-transaminase reaction. In this way, one of the products of the ω-transaminase reaction becomes the reactant of the Oppenauer reaction, and vice versa , creating a cycle which shifts the equilibria of both reactions. Such coupled reactions are frequently found in nature. The purpose of this paper is to report the development of a mathematical model as a tool for the simulation and potential design of such a process for the production of a range of chiral amines. The mathematical model developed considers that each reaction is performed in a single ideally mixed isothermal reactor operating sequentially in fed batch–batch mode. Both reactors are interconnected through a semi-permeable membrane, where multicomponent intra-membrane transport takes place by diffusion and viscous flow. The kinetic modeling of both reactions has been carried out and model simulations show that in this way a significant increase in the yield of the chiral amine product may be obtained. Finally, the role of the different parameters involved in the process model has been analyzed.

Palladium complexes of a new phosphine-amido-siloxide pincer ligand with variable degrees of protonation

This manuscript describes the preparation of a new PN(H)SiO(H) pincer-type ligand that is based on the diarylamine backbone and links together phosphine, amine, and silanol donor sites. Treatment of PN(H)SiO(H) with Pd(acac)2, (COD)PdCl2, or Pd(OAc)2 resulted in the formation of (κ2-PNSiO(H))Pd(acac) (3), (κ2-PN(H)SiO(H))PdCl2 (4), and (κ3-PNSiO(H))PdOAc (5), in which the supporting ligand displays different degrees of coordination and protonation. In complex 5, the PNSiO(H) ligand functions as a tridentate phosphine-amido-silanol pincer ligand, with additional strong hydrogen bonding between the silanol OH and one of the oxygens of the Pd-bound acetate. Complex 5 cleanly exchanged acetate for a triflate upon treatment with Me3SiOTf, yielding (κ3-PNSiO(H))PdOTf (6). Analogous treatment with Me3SiCl did not lead cleanly to the expected (κ3-PNSiO(H))PdCl (7), but instead ultimately to (κ2-PN(H)SiO(SiMe3))PdCl2 (8). The dianionic PNSiO ligand was accessed by reactions of 5 with base in the presence of pyridine or PMe3 to give (κ3-PNSiO)Pd(py) (9) and (κ3-PNSiO)Pd(PMe3) (10), respectively. Solid-state structures of 5 and 9 were established by single-crystal X-ray diffractometry and revealed square-planar geometry about Pd with tridentate coordination of the pincer ligand.

Chemoenzymatic synthesis of β-carboline derivatives using McbA, a new ATP-dependent amide synthetase

McbA was characterized in vitro as a novel amide synthetase in the marinacarbolines A–D biosynthetic pathway, catalyzing amide bond formation between 1-acetyl-3-carboxy-β-carboline (1a) and substituted-β-phenethylamines (1b, 2b, 3b) and tryptamine (4b) in an ATP-dependent manner. Enzyme kinetic analyses highlight β-phenethylamine as the most suitable amine donor. McbA showed broad substrate compatibility with substituted amines; 10 new β-carboline analogues were chemoenzymatically generated.

Bispidine dioxotetraaza macrocycles: a new class of bispidines for (64)Cu PET imaging.

The three new dioxo-tetraazamacrocyclic ligands with a fused, very rigid bispidine (3,7-diazabicyclo[3.3.1]nonane) group connecting the two tertiary amine donors, and ethyl, propyl, or benzene groups connecting the two amide donors are highly preorganized and lead to very stable, uncharged Cu(II) complexes. Solution spectroscopy and solid state structures indicate that these are square pyramidal with a solvent molecule occupying the apical position. Cyclic voltammetry defines a reversible Cu(III/II) couple and a strongly negative irreversible Cu(II/I) couple (ca. -2 V vs Fc/Fc(+)), indicating that the Cu(II) complexes are very stable in solution. This is supported by superoxide dismutase (SOD) and human serum challenge experiments as well as the biodistribution, which all show that the benzene-based ligand has the highest in vitro and in vivo stability and that this was expected on the basis of the macrocycle ring size and shape and the highest degree of preorganization. This ligand is easy to functionalize for a possible coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging).

Synthesis of (R)- or (S)-valinol using ω-transaminases in aqueous and organic media

Valinol is part of numerous pharmaceuticals and has various other important applications. Optically pure valinol (ee >99%) was prepared employing different ω-transaminases from the corresponding prochiral hydroxy ketone. By the choice of the enzyme the (R)- as well as the (S)-enantiomer were accessible. Reductive amination was performed in organic solvent (MTBE) using 2-propyl amine as amine donor whereas alanine was applied in or in aqueous medium. Transformations in phosphate buffer were successfully performed even at 200mM substrate concentration (20.4g/L) leading to 99% (R) and 94% (S) conversion with perfect optical purity (>99% ee).

Insight into the Structure and Mechanism of Nickel-Containing Superoxide Dismutase Derived from Peptide-Based Mimics

Nickel superoxide dismutase (NiSOD) is a nickel-containing metalloenzyme that catalyzes the disproportionation of superoxide through a ping-pong mechanism that relies on accessing reduced Ni(II) and oxidized Ni(III) oxidation states. NiSOD is the most recently discovered SOD. Unlike the other known SODs (MnSOD, FeSOD, and (CuZn)SOD), which utilize "typical" biological nitrogen and oxygen donors, NiSOD utilizes a rather unexpected ligand set. In the reduced Ni(II) oxidation state, NiSOD utilizes nitrogen ligands derived from the N-terminal amine and an amidate along with two cysteinates sulfur donors. These are unusual biological ligands, especially for an SOD: amine and amidate donors are underrepresented as biological ligands, whereas cysteinates are highly susceptible to oxidative damage. An axial histidine imidazole binds to nickel upon oxidation to Ni(III). This bond is long (2.3-2.6 Å) owing to a tight hydrogen-bonding network. All of the ligating residues to Ni(II) and Ni(III) are found within the first 6 residues from the NiSOD N-terminus. Thus, small nickel-containing metallopeptides derived from the first 6-12 residues of the NiSOD sequence can reproduce many of the properties of NiSOD itself. Using these nickel-containing metallopeptide-based NiSOD mimics, we have shown that the minimal sequence needed for nickel binding and reproduction of the structural, spectroscopic, and functional properties of NiSOD is H2N-HCXXPC. Insight into how NiSOD avoids oxidative damage has also been gained. Using small NiN2S2 complexes and metallopeptide-based mimics, it was shown that the unusual nitrogen donor atoms protect the cysteinates from oxidative damage (both one-electron oxidation and oxygen atom insertion reactions) by fine-tuning the electronic structure of the nickel center. Changing the nitrogen donor set to a bis-amidate or bis-amine nitrogen donor led to catalytically nonviable species owing to nickel-cysteinate bond oxidative damage. Only the amine/amidate nitrogen donor atoms within the NiSOD ligand set produce a catalytically viable species. These metallopeptide-based mimics have also hinted at the detailed mechanism of SOD catalysis by NiSOD. One such aspect is that the axial imidazole likely remains ligated to the Ni center under rapid catalytic conditions (i.e., high superoxide loads). This reduces the degree of structural rearrangement about the nickel center, leading to higher catalytic rates. Metallopeptide-based mimics have also shown that, although an axial ligand to Ni(III) is required for catalysis, the rates are highest when this is a weak interaction, suggesting a reason for the long axial His-Ni(III) bond found in NiSOD. These mimics have also suggested a surprising mechanistic insight: O2(-) reduction via a "H(•)" tunneling event from a R-S(H(+))-Ni(II) moiety to O2(-) is possible. The importance of this mechanism in NiSOD has not been verified.