Enantioselective Synthesis Of Chiral Amines Research Articles

Recent Advances in the Enantioselective Synthesis of Chiral Amines via Transition Metal-Catalyzed Asymmetric Hydrogenation.

Chiral amines are key structural motifs present in a wide variety of natural products, drugs, and other biologically active compounds. During the past decade, significant advances have been made with respect to the enantioselective synthesis of chiral amines, many of them based on catalytic asymmetric hydrogenation (AH). The present review covers the use of AH in the synthesis of chiral amines bearing a stereogenic center either in the α, β, or γ position with respect to the nitrogen atom, reported from 2010 to 2020. Therefore, we provide an overview of the recent advances in the AH of imines, enamides, enamines, allyl amines, and N-heteroaromatic compounds.

Application of Rh(I)/Bicyclo[2.2.1]heptadiene Catalysts to the Enantioselective Synthesis of Chiral Amines.

The development of efficient synthetic methods for accessing enantioenriched α-chiral amines is of great importance in the disciplines of medicinal and synthetic organic chemistry. Enantioselective Rh-catalyzed 1,2-addition reactions to activated imine derivatives are regarded as useful protocols for forming α-chiral amines. This personal account outlines our efforts to develop chiral bicyclo[2.2.1]heptadiene ligands for Rh-catalyzed asymmetric additions of various organoboron reagents to a wide range of imine derivatives. Transformations of the thus-obtained adducts into known natural products or molecules of pharmaceutical importance serve to confirm their synthetic usefulness.

Transition metal-catalyzed asymmetric carbene insertion for synthesis of chiral amines

Chiral amines are an important class of organic compounds. They are ubiquitous in organic chemistry and often serve as fundamental building blocks, versatile synthons, efficient chiral catalysts, ligands or auxiliaries in asymmetric synthesis and medicinal chemistry. During the past few decades, there has been remarkable progress in the development of efficient asymmetric methods. Accordingly, asymmetric synthesis, particularly catalytic enantioselective synthesis of chiral amines has received considerable attention from both academia and industry. Among them, transition metal-catalyzed asymmetric carbene insertion has emerged as one of the most useful and powerful methods for synthesis of various chiral amines through the efficient construction of the C−N bonds. In this review, we present the progress and advances that have been made using copper, rhodium, palladium, and iron catalysts to perform enantioselective N−H insertion reactions with diazo compounds. An overview of early examples of Cu(I) and Ag(I)-bisoxazoline-catalyzed asymmetric N−H insertion and the subsequent developments by using copper(I) complexes with chiral spiro bisoxazolines, bipyridines and binol derivatives, as well as with rhodium(II)-, palladium(II)-, iron(II)-carbene chemistry is provided. In these work, catalytic asymmetric metal-carbene insertion into the N−H bond of aromatic amines, amides (BocNH2, CbzNH2), substituted carbazoles and indoles, and benzophenone imines were achieved under mild reaction conditions, allowing access to a wide variety of structurally important chiral amines in enantiomerically enriched form. In particular, with the use of α-aryl or α-alkyl α-diazoesters as carbene precusors, both aryl and alkyl substituted α-amino esters could be prepared in good yields with high enantioselectivities. A recent major breakthrough in enantioselective transition-metal-catalyzed N−H insertion reactions with aliphatic amines is also discussed. By using a combination of an achiral copper complex and chiral amino-thiourea catalyst, highly enantioselective carbene insertion into N−H bonds of aliphatic amines was achieved to produce various chiral α-alkyl α-amino acid derivatives bearing secondary and tertiary amino substituents in good yields. Overall, this review summarizes the most prominent work on transition-metal-catalyzed asymmetric carbene N−H insertion and their applications in chiral amines and natural or unnatural chiral α-amino acid derivatives synthesis.

Asymmetric Oxidative Mannich Reactions

AbstractThe asymmetric Mannich reaction is one of the most straightforward methodologies for the enantioselective synthesis of chiral amines. In general, asymmetric Mannich reactions involve the use of imines as electrophiles. However, in recent years, several asymmetric oxidative Mannich reactions have been reported using amines as electrophiles. This review provides an overview of these recent publications, including the different oxidants used and the scope and limitations of the different catalytic systems.magnified image

Enantioselective Synthesis of Chiral Amines via Biocatalytic Carbene N-H Insertion.

Optically active amines represent highly valuable building blocks for the synthesis of advanced pharmaceutical intermediates, drug molecules, and biologically active natural products. Hemoproteins have recently emerged as promising biocatalysts for the formation of C-N bonds via carbene transfer, but asymmetric N-H carbene insertion reactions using these or other enzymes have so far been elusive. Here, we report the successful development of a biocatalytic strategy for the asymmetric N-H carbene insertion of aromatic amines with 2-diazopropanoate esters using engineered variants of myoglobin. High activity and stereoinduction in this reaction could be achieved by tuning the chiral environment around the heme cofactor in the metalloprotein in combination with catalyst-matching and tailoring of the diazo reagent. Using this approach, an efficient biocatalytic protocol for the synthesis of a broad range of substituted aryl amines with up to 82% ee was obtained. In addition, a stereocomplementary catalyst useful for accessing the mirror-image form of the N-H insertion products was identified. This work paves the way to asymmetric amine synthesis via biocatalytic carbene transfer, and the present strategy based on the synergistic combination of protein and diazo reagent engineering is expected to prove useful in the context of these as well as other challenging asymmetric carbene transfer reactions.

Catalyst free enantioselective amination via SN2 nucleophilic substitution reaction: a computational study

ABSTRACT Herein, we have developed a new route towards the enantioselective synthesis of chiral amines without any chiralcatalyst through SN2 nucleophilic substitution reaction of 5-dichloromethyl-4-difluoromethylene-2,3-dimethyl-3,4-dihydro-quinazoline [A] with methylamine using Density Functional Theory (DFT) framework. DFT results reveal that the formation of both the enantiomers are exothermic in nature. The activation energy for R- and S-enantiomer comes out to be 52.02 and 37.15 kcal/mol respectively. Also, the bond distance of hydrogen bonding (N1–H-----F–C=C–) in S-enantiomer comes out to be 2.10 Ǻ which is not feasible in R-enantiomer. Thus, the free energy profiles and structural parameters along the reaction coordinates provide enough evidence to conclude that amination will result in the enantioselective formation of S-enantiomer and this stereoselectivity is accredited to intramolecular H bonding (N–H-----F–C = C–) involved in the transition state corresponding to the formation of S-enantiomer. To the very best of our information, this is the first report proposing enantioselectivity in SN2 reaction without any chiral catalyst/chiral auxiliary through intramolecular hydrogen bonding.

Enantioselective Synthesis of d‐ and l‐α‐Amino Acids by Enzymatic Transamination Using Glutamine as Smart Amine Donor

AbstractEnzymatic transamination is a useful method for the green and highly enantioselective synthesis of chiral amines and non‐canonical amino acids which are of major importance as intermediates in medicinal chemistry. However, transamination reactions are usually reversible and synthetic applications of transaminases often require the implementation of an equilibrium shift strategy. Herein, we report a highly effective approach using glutamine as smart amine donor. This amino acid is converted upon transamination into 2‐oxoglutaramate which undergoes a fast cyclisation displacing the transamination equilibrium. We have developed a new activity assay in order to identify transaminases from biodiversity able to convert various α‐keto acids into valuable amino acids of l‐ or d‐series in the presence of glutamine as amine donor. Discovered transaminases were then used to prepare in high yield and with high enantioselectivity three amino acids of pharmaceutical importance, homophenylalanine, homoalanine and tert‐leucine by simply using a nearly stoichiometric amount of glutamine as amine donor.magnified image

Recent Advances in ω-Transaminase-Mediated Biocatalysis for the Enantioselective Synthesis of Chiral Amines

Chiral amines are important components of 40–45% of small molecule pharmaceuticals and many other industrially important fine chemicals and agrochemicals. Recent advances in synthetic applications of ω-transaminases for the production of chiral amines are reviewed herein. Although a new pool of potential ω-transaminases is being continuously screened and characterized from various microbial strains, their industrial application is limited by factors such as disfavored reaction equilibrium, poor substrate scope, and product inhibition. We present a closer look at recent developments in overcoming these challenges by various reaction engineering approaches. Furthermore, protein engineering techniques, which play a crucial role in improving the substrate scope of these biocatalysts and their operational stability, are also presented. Last, the incorporation of ω-transaminases in multi-enzymatic cascades, which significantly improves their synthetic applicability in the synthesis of complex chemical compounds, is detailed. This analysis of recent advances shows that ω-transaminases will continue to provide an efficient alternative to conventional catalysis for the synthesis of enantiomerically pure amines.

Mapping the substrate scope of monoamine oxidase (MAO-N) as a synthetic tool for the enantioselective synthesis of chiral amines

A library of 132 racemic chiral amines (α-substituted methylbenzylamines, benzhydrylamines, 1,2,3,4-tetrahydronaphthylamines (THNs), indanylamines, allylic and homoallylic amines, propargyl amines) was screened against the most versatile monoamine oxidase (MAO-N) variants D5, D9 and D11. MAO-N D9 exhibited the highest activity for most substrates and was applied to the deracemisation of a comprehensive set of selected primary amines. In all cases, excellent enantioselectivity was achieved (e.e. >99%) with moderate to good yields (55–80%). Conditions for the deracemisation of primary amines using a MAO-N/borane system were further optimised using THN as a template addressing substrate load, nature of the enzyme preparation, buffer systems, borane sources, and organic co-solvents.

Enzymatic resolution of an amine under solvent-free conditions with diethyl malonate as reagent for acylation

The extension of the enzymatic resolution of amines catalyzed by an immobilized lipase in combination with diethyl malonate as acyl donor towards a solvent-free process is described. In such a resolution process the resulting chiral amide was formed with both high conversion and enantioselectivity, and this solvent-free synthetic method turned out to be robust and efficient also at an elevated 50 mmol-scale reaction, leading to the desired amide with 50% conversion, in 43.5% yield and with excellent enantiomeric excess of 99% ee. This method proceeding at a short reaction time (4.5 h) opens up a perspective for future development towards a large-scale feasible process technology for the enantioselective synthesis of chiral amines. <div class= textboxdefaultfig >

Reversal Diastereoselectivity Between the Organomagnesium and Organolithium Reagents on Chiral N-Tert-Butylsulfinylaldimines for the Preparation of Chiral Amines

The asymmetric synthesis of both the enantiomer of chiral amines from the single chiral source of N-tert-butylsulfinylaldimines (3) by simply changing the organometallic reagents through diastereoselective addition. An efficient enantioselective synthesis of chiral amines including (S)-3-methyl-1-(2-piperidin-1-yl-phenyl)butyl amine (6a), a key intermediate to prepare antidiabetic drug repaglinide (1), is reported.

ChemInform Abstract: Asymmetric Imine Isomerization in the Enantioselective Synthesis of Chiral Amines from Prochiral Ketones.

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