Asymmetric Reduction Of Imines Research Articles

Synthesis of Substituted Acyclic and Cyclic N-Alkylhydrazines by Enzymatic Reductive Hydrazinations.

Imine reductases (IREDs) provide promising opportunities for the synthesis of various chiral amines. Initially, asymmetric imine reduction was reported, followed by reductive aminations of aldehydes and ketones via imines. Herein we present the reductive amination of structurally diverse carbonyls and dicarbonyls with hydrazines (reductive hydrazination), catalyzed by the IRED from Myxococcus stipitatus. In analogy to IRED-catalyzed reductive aminations, various carbonyls and dicarbonyls could react with simple hydrazines to produce substituted acyclic and cyclic N-alkylhydrazines. By incorporating and scaling up hydrogenase cofactor regeneration system, we demonstrated the scalability and atom-efficiency of an H2-driven double reductive hydrazination, highlightling the potential of IREDs in biocatalysis.

Manganese Pentacarbonyl Bromide as Regeneration Catalyst Enabled Biomimetic Asymmetric Reduction.

Using readily available manganese pentacarbonyl bromide as a regeneration catalyst, biomimetic asymmetric reduction of imines including quinoxalinones, benzoxazinones, and benzoxazine has been successfully developed in the presence of transfer catalyst chiral phosphoric acids, providing the chiral amines with high yields and enantioselectivities.

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.

Recent advances in the asymmetric reduction of imines by recycled catalyst systems

Recent advances relating to the asymmetric reduction of imines to afford optically active amines via recyclable catalyst systems are reviewed.

Biomimetic reduction of imines and heteroaromatics with chiral and regenerable [2.2]Paracyclophane-Based NAD(P)H model CYNAM

In our previous work, we reported the synthesis of chiral and regenerable [2.2]paracyclophane-derived NAD(P)H models CYNAMs and their application in biomimetic asymmetric reduction of tetrasubstituted olefins. Herein, the biomimetic asymmetric reduction of imines and heteroaromatics has been successfully achieved using the chiral and regenerable CYNAMs and simple achiral phosphoric acid as the transfer catalyst, providing the chiral amines with up to 99% yield and 99% ee.

Engineering of Thermostable β‐Hydroxyacid Dehydrogenase for the Asymmetric Reduction of Imines

The β‐hydroxyacid dehydrogenase from Thermocrinus albus (Ta‐βHAD), which catalyzes the NADP+‐dependent oxidation of β‐hydroxyacids, was engineered to accept imines as substrates. The catalytic activity of the proton‐donor variant K189D was further increased by the introduction of two nonpolar flanking residues (N192 L, N193 L). Engineering the putative alternative proton donor (D258S) and the gate‐keeping residue (F250 A) led to a switched substrate specificity as compared to the single and triple variants. The two most active Ta‐βHAD variants were applied to biocatalytic asymmetric reductions of imines at elevated temperatures and enabled enhanced product formation at a reaction temperature of 50 °C.

Systematic Evaluation of Imine-Reducing Enzymes: Common Principles in Imine Reductases, β-Hydroxy Acid Dehydrogenases, and Short-Chain Dehydrogenases/ Reductases.

The enzymatic, asymmetric reduction of imines is catalyzed by imine reductases (IREDs), members of the short‐chain dehydrogenase/reductase (SDR) family, and β‐hydroxy acid dehydrogenase (βHAD) variants. Systematic evaluation of the structures and substrate‐binding sites of the three enzyme families has revealed four common principles for imine reduction: structurally conserved cofactor‐binding domains; tyrosine, aspartate, or glutamate as proton donor; at least four characteristic flanking residues that adapt the donor's pK a and polarize the substrate; and a negative electrostatic potential in the substrate‐binding site to stabilize the transition state. As additional catalytically relevant positions, we propose alternative proton donors in IREDs and βHADs as well as proton relays in IREDs, βHADs, and SDRs. The functional role of flanking residues was experimentally confirmed by alanine scanning of the imine‐reducing SDR from Zephyranthes treatiae. Mutating the “gatekeeping” phenylalanine at standard position 200 resulted in a tenfold increase in imine‐reducing activity.

A diversity of recently reported methodology for asymmetric imine reduction

This review describes recent developments in enantioselective imine reduction, including related substrates in which a CN bond is the target for reduction, and in situ methods.

An efficient proline-based homogeneous organocatalyst with recyclability

A homogeneous organocatalyst for asymmetric reduction of imines can be reused for several cycles through a self-assembly method using MNPs.

Asymmetric Reduction of Imines on a Polystyrene-Supported Organocatalyst

Asymmetric Reduction of Imines on a Polystyrene-Supported Organocatalyst

Asymmetric Ketone Reduction by Imine Reductases

The rapidly growing area of asymmetric imine reduction by imine reductases (IREDs) has provided alternative routes to chiral amines. Here we report the expansion of the reaction scope of IREDs by showing the stereoselective reduction of 2,2,2-trifluoroacetophenone. Assisted by an in silico analysis of energy barriers, we evaluated asymmetric hydrogenations of carbonyls and imines while considering the influence of substrate reactivity on the chemoselectivity of this novel class of reductases. We report the asymmetric reduction of C=N as well as C=O bonds catalysed by members of the IRED enzyme family.

A Ferrocene‐Based Phosphane/Borane Frustrated Lewis Pair for Asymmetric Imine Reduction

The α‐phosphanylferrocenecarbaldehyde (pS)‐1 was converted into the β‐styryl derivative (pS)‐4 by Wittig–Horner olefination. Subsequent hydroboration with Piers' borane [HB(C6F5)2] followed by H2 splitting and crystallization gave the phosphonium/hydridoborate product (pS,R)‐5, which was used as a frustrated Lewis pair catalyst for the asymmetric hydrogenation of a series of imines (up to 69 % ee).

Sulfinamide Phosphinates as Chiral Catalysts for the Enantioselective Organocatalytic Reduction of Imines.

A new type of chiral sulfinamide phosphinate catalysts with up to three stereogenic centers, readily accessible from commercially available starting materials, is reported. The naphthyl derivative SulPhos proved to be highly efficient in the organocatalytic asymmetric imine reduction, leading to a wide range of arylmethylamines in high yields with up to 99% ee under 10% catalyst loading. The synthetic utility of this method was demonstrated by the expeditious enantioselective synthesis of the calcimimetic NPS-R568.

Cultivation and purification of two stereoselective imine reductases from Streptosporangium roseum and Paenibacillus elgii

The reductive amination is one of the most important reactions in the synthesis of chiral amines. Imine reductases (IREDs) are novel enzymes that catalyze the asymmetric reduction of imines and reductive aminations using NADPH as hydride donor. In this study, we have developed a simple method to produce two enantiocomplementary IREDs from Streptosporangium roseum DSM 43021 (R-IRED-Sr) and Paenibacillus elgii (S-IRED-Pe). The proteins were expressed efficiently in Escherichia coli (E. coli) JW5510 at the 4-L-cultivation scale and were purified to 95% homogeneity in two steps by immobilized metal ion affinity and anion-exchange chromatography. The total protein yield was about 9 g per liter of E. coli culture and resulted in 150–220 mg purified IRED per liter of E. coli culture. The bioactivity of both IREDs was measured by the depletion of the NADPH cofactor in the reduction of model substrates 2-methylpyrroline (R-IRED-Sr) and 3,4-dihydroisoquinoline (S-IRED-Pe). High level reducing activity was found demonstrating the production of correctly folded and active IRED proteins. Specific activities of about 2.58 U/mg and 0.24 U/mg for the R- and S-selective IREDs were obtained, being in agreement with activities reported in the literature.

Progress on the Lewis-Basic Organocatalytic Asymmetric Reduction of Imines

Recently, the asymmetric reduction of imines catalyzed by Lewis-basic organocatalyst has been received much attention as the cheap hydrogen source and the simple post treatment. Based on the different functional groups of organocatalysts, this paper introduced formamide, pyridine amide, sulfonamide, supported and other Lewis basic organocatalysts. The structural characteristics, catalytic activity and mechanism of the Lewis-basic organocatalysts were summarized.

ChemInform Abstract: Asymmetric Reduction of Imines with Trichlorosilane Catalyzed by Valine‐Derived Formamide Immobilized onto Magnetic Nano‐Fe3O4.

AbstractFormyl‐valine containing iron oxide/silica nanoparticles catalyze the asymmetric reduction of imines.

Asymmetric Reduction of Imines Catalyzed by a Supported Organocatalyst

Asymmetric Reduction of Imines Catalyzed by a Supported Organocatalyst

ChemInform Abstract: Biocatalytic Imine Reduction and Reductive Amination of Ketones

AbstractReview: [110 refs.

Biocatalytic Imine Reduction and Reductive Amination of Ketones

AbstractChiral amines represent a prominent functional group in pharmaceuticals and agrochemicals and are hence attractive targets for asymmetric synthesis. Since the pharmaceutical industry has identified biocatalysis as a valuable tool for synthesising chiral molecules with high enantiomeric excess and under mild reaction conditions, enzymatic methods for chiral amine synthesis are increasing in importance. Among the strategies available in this context, the asymmetric reduction of imines by NAD(P)H‐dependent enzymes and the related reductive amination of ketones have long remained underrepresented. However, recent years have witnessed an impressive progress in the application of natural or engineered imine‐reducing enzymes, such as imine reductases, opine dehydrogenases, amine dehydrogenases, and artificial metalloenzymes. This review provides a comprehensive overview of biocatalytic imine reduction and reductive amination of ketones, highlighting the natural roles, substrate scopes, structural features, and potential application fields of the involved enzymes.magnified image

ChemInform Abstract: Synthesis of Novel Carbohydrate‐Based Valine‐Derived Formamide Organocatalysts by CuAAC Click Chemistry and Their Application in Asymmetric Reduction of Imines with Trichlorosilane.

AbstractThe applied catalyst can be recycled and reused at least five times.