Reduction Of Imines Research Articles

Front Cover Picture: Asymmetric Synthesis of Trisubstituted Piperidines via Biocatalytic Transamination and Diastereoselective Enamine or Imine Reduction (Adv. Synth. Catal. 13/2023)

The front cover picture shows the assembly of a trisubstituted piperidine derivative through the controlled formation of C−N and C−H bonds. Different stereoselective synthetic tools – namely transaminase and IRED enzymes, and platinum(0)-catalysed flow hydrogenation – are combined to obtain the target N-heterocycles from achiral, open-chain precursors with excellent enantio- and diastereocontrol. The cover design is by Verena Resch and used with her permission. Details can be found in the Research Article by Joerg Schrittwieser and co-workers (P. Petermeier, C. Kohlfuerst, A. Torvisco, R. C. Fischer, A. Mata, D. Dallinger, C. O. Kappe, J. H. Schrittwieser, W. Kroutil, Adv. Synth. Catal. 2023, 365, XXXX–XXXX; DOI: 10.1002/adsc.202300050)

Reduced Chitosan as a Strategy for Removing Copper Ions from Water.

Toxic heavy metals are priority pollutants in wastewater, commonly present in dangerous concentrations in many places across the globe. Although in trace quantities copper is a heavy metal essential to human life, in excess it causes various diseases, whereby its removal from wastewater is a necessity. Among several reported materials, chitosan is a highly abundant, non-toxic, low-cost, biodegradable polymer, comprising free hydroxyl and amino groups, that has been directly applied as an adsorbent or chemically modified to increase its performance. Taking this into account, reduced chitosan derivatives (RCDs 1-4) were synthesised by chitosan modification with salicylaldehyde, followed by imine reduction, characterised by RMN, FTIR-ATR, TGA and SEM, and used to adsorb Cu(II) from water. A reduced chitosan (RCD3), with a moderate modification percentage (43%) and a high imine reduction percentage (98%), proved to be more efficient than the remainder RCDs and even chitosan, especially at low concentrations under the best adsorption conditions (pH 4, RS/L = 2.5 mg mL-1). RCD3 adsorption data were better described by the Langmuir-Freundlich isotherm and the pseudo-second-order kinetic models. The interaction mechanism was assessed by molecular dynamics simulations, showing that RCDs favour Cu(II) capture from water compared to chitosan, due to a greater Cu(II) interaction with the oxygen of the glucosamine ring and the neighbouring hydroxyl groups.

Asymmetric Synthesis of Trisubstituted Piperidines via Biocatalytic Transamination and Diastereoselective Enamine or Imine Reduction

AbstractSubstituted piperidine rings are a common motif in natural products and pharmaceutical drugs. The asymmetric synthesis of piperidines bearing multiple stereocentres remains a challenge, and current approaches often rely on lengthy reaction sequences and ‘chiral pool’ strategies. Herein, we report multi‐enzymatic and chemo‐enzymatic methods that allow the preparation of piperidines with three chirality centres in only two steps from achiral diketoester precursors. Stereocontrol is achieved by a highly enantioselective transamination leading to optically pure (ee >99%) enamine or imine intermediates, followed by diastereoselective reduction of these unsaturated N‐heterocycles using either platinum(0)‐catalysed flow hydrogenation or enzymatic imine reduction. In the latter case, coupling of the two biocatalytic reactions in a concurrent one‐pot process is possible, thus reducing the synthetic sequence to a single biotransformation. In total, nine trisubstituted piperidines were prepared in high stereoisomeric purities (dr ≥98:2) and isolated yields of up to 73%. Lead‐likeness analysis of five representative products using an open‐source webtool suggests that these compounds possess considerable application potential as building blocks in drug discovery.

A Reductive Aminase Switches to Imine Reductase Mode for a Bulky Amine Substrate.

Imine reductases (IREDs) catalyze the asymmetric reduction of cyclic imines, but also in some cases the coupling of ketones and amines to form secondary amine products in an enzyme-catalyzed reductive amination (RedAm) reaction. Enzymatic RedAm reactions have typically used small hydrophobic amines, but many interesting pharmaceutical targets require that larger amines be used in these coupling reactions. Following the identification of IR77 from Ensifer adhaerens as a promising biocatalyst for the reductive amination of cyclohexanone with pyrrolidine, we have characterized the ability of this enzyme to catalyze couplings with larger bicyclic amines such as isoindoline and octahydrocyclopenta(c)pyrrole. By comparing the activity of IR77 with reductions using sodium cyanoborohydride in water, it was shown that, while the coupling of cyclohexanone and pyrrolidine involved at least some element of reductive amination, the amination with the larger amines likely occurred ex situ, with the imine recruited from solution for enzyme reduction. The structure of IR77 was determined, and using this as a basis, structure-guided mutagenesis, coupled with point mutations selecting improving amino acid sites suggested by other groups, permitted the identification of a mutant A208N with improved activity for amine product formation. Improvements in conversion were attributed to greater enzyme stability as revealed by X-ray crystallography and nano differential scanning fluorimetry. The mutant IR77-A208N was applied to the preparative scale amination of cyclohexanone at 50 mM concentration, with 1.2 equiv of three larger amines, in isolated yields of up to 93%.

The Discovery of Imine Reductases and their Utilisation for the Synthesis of Tetrahydroisoquinolines.

Imine reductases (IREDs) are NADPH-dependent enzymes with significant biocatalytic potential for the synthesis of primary, secondary, and tertiary chiral amines. Their applications include the reduction of cyclic imines and the reductive amination of prochiral ketones. In this study, twenty-nine novel IREDs were revealed through genome mining. Imine reductase activities were screened at pH 7 and 9 and in presence of either NADPH or NADH; some IREDs showed good activities at both pHs and were able to accept both cofactors. IREDs with Asn and Glu at the key 187 residue showed preference for NADH. IREDs were also screened against a series of dihydroisoquinolines to synthesise tetrahydroisoquinolines (THIQs), bioactive alkaloids with a wide range of therapeutic properties. Selected IREDs showed high stereoselectivity, as well high THIQ yields (>90 %) when coupled to a glucose-6-phosphate dehydrogenase for NADPH cofactor recycling.

Chemoselective reduction of imines and azobenzenes catalyzed by silver N-heterocyclic carbene complexes

The first example of NHC (N-heterocyclic carbene) ligand-promoted reduction of imines and azobenzenes with a homogeneous silver catalyst is reported.

MgCl2-Catalyzed Chemoselective Reduction of Aldehydes, Ketones and Imines

MgCl₂-Catalyzed Chemoselective Reduction of Aldehydes, Ketones and Imines

A robust Zintl cluster for the catalytic reduction of pyridines, imines and nitriles.

Despite p-block clusters being known for over a century, their application as catalysts to mediate organic transformations is underexplored. Here, the boron functionalized [P7] cluster [(BBN)P7]2- ([1]2-; BBN = 9-borabicyclo[3.3.1]nonane) is applied in the dearomatized reduction of pyridines, as well as the hydroboration of imines and nitriles. These transformations afford amine products, which are important precursors to pharmaceuticals, agrochemicals, and polymers. Catalyst [1]2- has high stability in these reductions: recycling nine times in quinoline hydroboration led to virtually no loss in catalyst performance. The catalyst can also be recycled between two different organic transformations, again with no loss in catalyst competency. The mechanism for pyridine reduction was probed experimentally using variable time normalization analysis, and computationally using density functional theory. This work demonstrates that Zintl clusters can mediate the reduction of nitrogen containing substrates in a transition metal-free manner.

Reductive Alkenylation of Ketimines via Hydride Transfer from Aldehydes.

The first direct N-heterocyclic carbene (NHC)-catalyzed preparation of allylic amines bearing a quaternary center (α-tertiary amine) from isatin-derived ketimines in the presence of vinyl selenones and aldehydes is reported. This multicomponent reaction is expected to proceed via unprecedented in situ reduction of imines through a hydride transfer from the aldehydes.

Engineered Imine Reductase for Larotrectinib Intermediate Manufacture

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

Zn-Catalyzed Regioselective and Chemoselective Reduction of Aldehydes, Ketones and Imines.

An operationally convenient Zn-catalyzed synthesis of alcohols by the reduction of aldehydes, ketones, and α,β-unsaturated aldehydes/ketones is reported. It is a rare example of using mild and sustainable HBpin as a reductant for catalytic reduction of carbonyl compounds in the absence of acid or base as hydrolysis reagent. The reaction is upscalable and proceeds in high selectivity without the formation of boronate ester by-products, and tolerates sensitive functionalities, such as iodo, bromo, chloro, fluoro, nitro, trifluoromethyl, aminomethyl, alkynyl, and amide. The Zn(OAc)2/HBpin combination has been also proved to be chemoselective for the C=N reduction of imine analogs.

Imine Reductases: Multifunctional Biocatalysts with Varying Active Sites and Catalytic Mechanisms

AbstractThe synthesis of chiral amines is significant in the pharmaceutical industry. Imine reductase (IRED), a promising biocatalyst that was previously known to only catalyze asymmetric imine reduction (IR), was revealed to achieve direct asymmetric reductive amination (RA) of ketones with excess amines, producing secondary and tertiary amines. Moreover, conjugate reduction (CR) and RA activity by a single IRED has been reported for the preparation of valuable amine diastereomers. IREDs catalyzing these different reactions share the same standard quaternary structure, but possess varying active sites, indicating correlations and differences between their catalytic mechanisms. In this review, we trace the catalytic mechanisms reported for IRED‐catalyzed IR, RA, and CR‐RA. Insights obtained from structural and protein engineering in understanding the IRED‐catalyzed asymmetric synthesis are also included. This review will help readers acquire comprehensive insights into the catalytic mechanism of IREDs and ultimately inspire the engineering of IREDs for industrial applications.

Enantioselective Imine Reduction of Dihydro-β-carbolines by Fe-Thiosquaramide Catalyst.

Enantioselective imine reduction of dihydro-β-carbolines (DHBCs) is a reliable and powerful tool to construct bioactive chiral tetrahydro-β-carbolines (THBCs). Here, we report an efficient enantioselective imine reduction employing in situ generated Fe-thiosquaramides (Fe-TSQs) 3a and 3b as asymmetric organometallic catalysts to produce chiral THBCs (2a-h). The catalyst 3a at 15 mol % was found to be suitable for the substrates with alkyl and aryl groups which afford corresponding chiral THBCs with excellent enantioselectivities (up to ee 99%).

Fe-catalyzed reduction of aldimines with HBpin

We develop an efficient and workable method for the reduction of imines via hydroboration with HBpin. The low cost and non-toxic Fe exhibits high catalytic activity to this hydroboration. A large range of aldimines comprising diverse aryl groups, alkyl groups and heterocycles proceed the hydroboration well to yield secondary amines in good to excellent yields. Kinetic mechanistic studies indicate the importance of Fe in transformation of HBpin into an active species. The preparation of several commercially available pharmaceuticals by means of this strategy highlights its potential application in medicinal chemistry.

Water-Soluble Tris(cyclometalated) Iridium(III) Complexes for Aqueous Electron and Energy Transfer Photochemistry.

ConspectusCyclometalated iridium(III) complexes are frequently employed in organic light emitting diodes, and they are popular photocatalysts for solar energy conversion and synthetic organic chemistry. They luminesce from redox-active excited states that can have high triplet energies and long lifetimes, making them well suited for energy transfer and photoredox catalysis. Homoleptic tris(cyclometalated) iridium(III) complexes are typically very hydrophobic and do not dissolve well in polar solvents, somewhat limiting their application scope. We developed a family of water-soluble sulfonate-decorated variants with tailored redox potentials and excited-state energies to address several key challenges in aqueous photochemistry.First, we aimed at combining enzyme with photoredox catalysis to synthesize enantioenriched products in a cyclic reaction network. Since the employed biocatalyst operates best in aqueous solution, a water-soluble photocatalyst was needed. A new tris(cyclometalated) iridium(III) complex provided enough reducing power for the photochemical reduction of imines to racemic mixtures of amines and furthermore was compatible with monoamine oxidase (MAO-N-9), which deracemized this mixture through a kinetic resolution of the racemic amine via oxidation to the corresponding imine. This process led to the accumulation of the unreactive amine enantiomer over time. In subsequent studies, we discovered that the same iridium(III) complex photoionizes under intense irradiation to give hydrated electrons as a result of consecutive two-photon excitation. With visible light as energy input, hydrated electrons become available in a catalytic fashion, thereby allowing the comparatively mild reduction of substrates that would typically only be reactive under harsher conditions. Finally, we became interested in photochemical upconversion in aqueous solution, for which it was desirable to obtain water-soluble iridium(III) compounds with very high triplet excited-state energies. This goal was achieved through improved ligand design and ultimately enabled sensitized triplet–triplet annihilation upconversion unusually far into the ultraviolet spectral range.Studies of photoredox catalysis, energy transfer catalysis, and photochemical upconversion typically rely on the use of organic solvents. Water could potentially be an attractive alternative in many cases, but photocatalyst development lags somewhat behind for aqueous solution compared to organic solvent. The purpose of this Account is to provide an overview of the breadth of new research perspectives that emerged from the development of water-soluble fac-[Ir(ppy)]3 complexes (ppy = 2-phenylpyridine) with sulfonated ligands. We hope to inspire the use of some of these or related coordination compounds in aqueous photochemistry and to stimulate further conceptual developments at the interfaces of coordination chemistry, photophysics, biocatalysis, and sustainable chemistry.

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor.

We have successfully synthesized piperidine and pyrrolidine derivatives by electroreductive cyclization using readily available imine and terminal dihaloalkanes in a flow microreactor. Reduction of the substrate imine on the cathode proceeded efficiently due to the large specific surface area of the microreactor. This method provided target compounds in good yields compared to a conventional batch-type reaction. Furthermore, piperidine and pyrrolidine derivatives could be obtained on preparative scale by continuous electrolysis for approximately 1 hour.

Thermal and photocatalytic cascade one-pot synthesis of secondary amine using multifunctional Pd decorated MOF-derived CeO2

The use of a single catalyst to perform thermal and photochemical N-alkylation of amine is challenging work. Herein, Pd decorated MOF-derived CeO2 was prepared for the cascade one-pot synthesis of secondary amine by thermal and photocatalytic routes. Among the designed catalysts, Pd(0.5%)/CeO2-300 exhibited the best activity for thermal and photocatalytic one-pot secondary amine synthesis involving benzyl alcohol and aniline. The physicochemical characteristics of Pd(0.5%)/CeO2-300 suited for the oxidation of benzyl alcohol followed by condensation with aniline to form an imine. Further, reduction of imine over Pd NPs decorated on CeO2-300 took place to form secondary amine. An excellent conversion of benzyl alcohol and secondary amine selectivity was observed thermally at 100 °C in 26 h. The Pd(0.5%)/CeO2-300 exhibited excellent activity in white LED. Interestingly, more activity was achieved in sunlight. The Pd(0.5%)/CeO2-300 demonstrated excellent stability under thermal and photocatalytic conditions and was recycled 5 times without losing any significant activity. The surface area, acidity, and elemental compositions were characterized by various physicochemical techniques. The light absorption property, bandgap, charge carrier separation, and photocurrent measurements were carried out by photoelectrochemical and optoelectronic analysis. The reaction mechanism and structural activity relationship correlated with control experiments, catalytic activity data, physicochemical, and optoelectronic characterization. One catalyst affording efficient activity in conventional thermal and photocatalytic conditions, especially sunlight, would be exciting to researchers and industrial practitioners.

Rheology—Composition relationship of vitrimers based on polyethyleneimine

AbstractThe effect of chemical composition on the rheology of a reversible covalent bond containing polyethyleneimine (RCBP) was studied. RCBPs, also known as vitrimers, exhibit thermoplastic‐like processability, but unlike thermoplastic polymers, their behavior is not driven by disentanglement, and all the bonds undergo transformation (almost) simultaneously at constant average crosslink density. Therefore, no lower plateau was observed in a viscosity‐shear rate plot. Transimination, the principal mechanism that imparts flowability, consists of two mechanisms—imine exchange and imine metathesis. Metathesis is only activated by heat, while imine exchange is activated also by stress. Imine metathesis provides low viscosity values at higher crosslink density. A lower viscosity (1092 compared to 22,986 at 100 Hz) was accomplished by adding 4 wt% triethylenetetramine (TETA). An Arrhenius‐type behavior is shown via relaxation tests with three distinct regions—up to 125°C (only imine exchange), between 125°C and 160°C (imine exchange and imine metathesis) and above 160°C (imine reduction to amine). Imine metathesis seems to promote flow at intermediate temperatures, and at around 150°C, the material behaves as a viscous fluid, otherwise at higher or lower temperatures the dynamic behavior is that of an elastic solid.

Gold(I)-Mediated Rapid Cyclization of Propargylated Peptides via Imine Formation.

In fundamental research and drug discovery, there is still a need for effective and straightforward chemical approaches for generating cyclic peptides. The divergent synthesis of cyclic peptides remains a challenge, in particular when cyclization is carried out in the presence of unprotected side chains and a nonpeptidic component within the cycle is needed. Herein, we describe a novel and efficient strategy based on Au(I)-mediated cyclization of unprotected peptides through rapid (30–60 min) amine addition on a propargyl group to generate an imine linkage. Mechanistic insights reveal that the reaction proceeds via regioselective Markovnikov’s addition of the amine on the Au(I)-activated propargyl. This strategy was successfully applied to prepare efficiently (56–94%) over 35 diverse cyclic peptides having different sequences and lengths. We have also achieved stereoselective reduction of cyclic imines employing chiral ligands. The practicality of our method was extended for the synthesis of cyclic peptides that bind Lys48-linked di-ubiquitin chains with high affinity, leading to apoptosis of cancer cells.

The ornithine cyclodeaminase/µ-crystallin superfamily of proteins: A novel family of oxidoreductases for the biocatalytic synthesis of chiral amines

• The Ornithine Cyclodeaminase/μ-Crystallin (OCD/CRYM) superfamily, a ubiquitously distributed but relatively unexplored family of proteins catalyzing imine reduction, is reviewed. • The physiological role and biochemical properties of the known members are summarized. • The structure and enzymatic mechanism in the superfamily are critically analyzed. • The current and prospective applications are discussed in detail. Biocatalysis, one of the most ecologically friendly methods for synthesising chiral synthons, has emerged as a desirable process for manufacturing active pharmaceutical ingredients and agrochemicals, most of which contain one or more chiral amine moieties. Compared with the traditional biocatalytic processes for the synthesis of chiral amines involving lipases or transaminases, enzymatic imine reduction is a more promising approach. The single-step enzymatic reduction of prochiral imines to the corresponding amines can yield 100% of the required enantiomer without any by-products. Furthermore, the reduction of imines generated in situ through the condensation of amines and carbonyl compounds can be used to synthesise almost any primary, secondary, or tertiary amine. In the past decade, several imine-reducing enzyme families, such as Streptomyces imine reductases (IReds), native amine dehydrogenases and engineered leucine/phenylalanine dehydrogenases and opine dehydrogenases, have been explored. The ornithine cyclodeaminase/μ-crystallin (OCD/CRYM) superfamily consists of proteins capable of imine reduction, which have been relatively unexplored regarding the synthesis of chiral amines. The proteins in this family are ubiquitously distributed in all three domains of life and catalyse diverse and unique reactions. This review is aimed at summarising current knowledge on this superfamily and exploring its potential in biocatalysis. After a brief discussion of their discovery, the known members of the OCD/CRYM superfamily are broadly classified on the basis of the reactions that they catalyse, and their biochemical characteristics and biological roles are described in detail. This is followed by a discussion of the overall structure, active sites and proposed reaction mechanisms, with common themes drawn among members. Finally, the applications of these enzymes, particularly in the synthesis of various chiral synthons, are summarised.