•DFT calculations at 6-311G++ (d, p)/LANL2DZ level were carried on phenazino-18-crown-6-ether with metal ions.•P18C6-1a ligand with metal cations were found to be more stable than those with P18C6-1b.•In alkali and alkaline earth metals ions Be2+ displays highest binding energy with P18C6-1a.•P18C6-Cr6+ metal complexes acquire envelop like geometry with maximum stability.•Ag displays higher binding energies value both in neutral as well as monocation state than Hg.The interactions of phenazino-crown ether ligands with alkali, alkaline earth and selected toxic species were investigated using density functional theory modelling by employing B3PW91/6-311G ++ (d, p) level of theory. The complex stability was analysed in terms of binding energies, perturbation energies, position of highest molecular orbital and energy gap values. In general, the complexes formed by P18C6-1a ligand with metal cations were found to be more stable than those with P18C6-1b. Among alkali and alkaline earth metals complexes having highest stability was observed for the complex formed by P18C6-1a with Be2+. Computational calculations of P18C6 ligand with toxic metal ions reveals that the P18C6-Cr6+ metal complexes acquire envelop like geometry, leading to higher binding energy values. Comparing the binding energies of neutral and monocations of Ag and Hg, the former had higher value both in neutral as well as monocation state. Thus, the stability of metal complexes is determined not only by the ligand but also by the type of metal ion. In solvent systems the stability constants of metal complexes were found increasing with decreasing permittivity of the solvent. This reflects the inherited polar character of the protic solvents stabilises the cation, resulting in decrease of effective interaction of ligand with the metal ion.Download high-res image (317KB)Download full-size image

α,α-Dicyanoolefins have emerged as versatile reactants, finding use as vinylogous nucleophiles, Michael acceptors and dienophiles in a variety of organic reactions. In the last few years, the reactivity of α,α-dicyanoolefins has been explored in various asymmetric transformations catalyzed by organocatalysts. In this review, we are presenting the recent advances in asymmetric organocatalytic transformations involving α,α-dicyanoolefins.

A highly enantioselective Michael addition reaction of indolylnitroalkenes with 1,3-dicarbonyl compounds has been developed to obtain enantiomerically enriched 3-(2-nitro-1-(1-tosyl-1H-indol-3-yl)ethyl)pentane-2,4-dione derivatives in up to 98% ee using BnCPN as an organocatalyst. The transition state structure has been predicted using DFT calculation.

A highly enantioselective Morita–Baylis–Hillman reaction of maleimides with isatin derived ketimines has been developed to obtain enantiomerically enriched 3-substituted-3-aminooxindoles using β-isocupreidine as an organocatalyst. Maleimide acting as a nucleophile provides products with up to 99% ee.

3-Substituted-3-aminooxindoles have attracted the attention of organic and medicinal chemists because these motifs constitute the core structure of a number of natural products and drug candidates. The catalytic potential of chiral organocatalysts and metal catalysts has been successfully exploited for the synthesis of enantioenriched 3-amino-2-oxindoles via the addition of various nucleophiles to isatin imines. This review focuses on the catalytic asymmetric synthesis of chiral 3-amino-3-substituted-2-oxindoles.

An organocatalytic asymmetric aza-Henry reaction of ketimines derived from isatins with nitroalkanes has been achieved using Cinchona alkaloid organocatalysts. This method works efficiently with several ketimines to produce a good (up to 82%) yield of the corresponding 3-substituted 3-amino-2-oxindoles with a good (up to 89%) enantiomeric excess.

A highly enantioselective Friedel–Crafts reaction of activated phenols with isatin derivatives has been developed employing Cinchona-derived thiourea as an organocatalyst. A variety of biologically important 3-aryl-3-hydroxy-2-oxindoles have been synthesized using phenols in good to excellent yield with good enantioselectivity (up to 92% ee).

An organocatalytic enantioselective Friedel–Crafts reaction of 1-naphthols with isatins has been developed employing bifunctional thiourea–tertiary amine organocatalysts. A variety of isatin derivatives react well with 1-naphthols in the presence of Cinchona derived thiourea 1a to provide biologically important chiral 3-aryl-3-hydroxy-2-oxindoles (3a–zg) in good yield (70–84%) and moderate to good enantioselectivity (37–83%).

An unprecedented asymmetric aza-Friedel–Crafts reaction of sesamol with N-sulfonylimines has been reported. A variety of N-sulfonylimines reacts with sesamol derivatives in the presence of 6′-OH Cinchona alkaloids to provide a new series of chiral aminophenol adducts in good yield and good to high level of enantioselectivity.

3-Amino-2-oxindoles bearing tetra-substituted stereocenter are very important constituents of many bioactive and pharmaceutical agents. In the last few years, asymmetric organocatalysis emerged as an excellent approach for the synthesis of optically active 3-substituted-3-amino-2-oxindoles. This review describes the various organocatalytic enantioselective strategies for the synthesis of 3-substituted 3-amino-2-oxindole frameworks.Figure optionsDownload full-size imageDownload as PowerPoint slide

Recent progress in asymmetric catalysis has contributed to the development of a diverse range of chiral organocatalysts that differ in their origin, structure and mode of activation. The bifunctional organocatalysts bearing aromatic hydroxyl (or phenolic) groups have emerged as a privileged class of organocatalyst. In these bifunctional organocatalysts, the aromatic hydroxyl group functions as a weak Brønsted acid or hydrogen bonding site and a nucleophilic or basic moiety such as amine and phosphine serve as a base or hydrogen bond acceptor. The bifunctional organocatalysts having these moieties have not been reviewed. In this review we are presenting the asymmetric transformations catalyzed by the bifunctional organocatalyst bearing an aromatic hydroxyl group.

The recent emergence of biological activities of chiral 3-substituted-3-hydroxy-2-oxindoles has inspired synthetic chemists to develop new methodologies for their synthesis. Both chiral organocatalysts and organometallic catalysts have provided an important platform for their synthesis and in recent years, great achievements have been made in their catalytic asymmetric synthesis. This review summarizes the catalytic strategies for enantioselective synthesis of targeted frameworks.

The asymmetric organocatalytic conjugate addition reaction of various nucleophiles to the unsaturated acceptor provides an important route for the synthesis of valuable chiral entities. Recently, aromatic and hetero-aromatic compounds have been successfully used as nucleophiles in the enantioselective conjugate addition reaction. This review provides an overview on the recent developments made in organocatalytic enantioselective conjugate addition of arenes and hetero-arenes to unsaturated acceptors.

Simple pyrrolidine-based chiral amines were synthesized and used for the Michael addition of different ketones to a variety of nitro-olefins in brine. The effect of different surfactants and acids on the yields and stereochemical outcome of the Michael adducts was studied in detail. Chiral amine 1g was found to catalyze the formation of Michael adducts with high enantioselectivity (up to >99%), diastereoselectivity [up to 98:2 (syn:anti)] and yield (up to 94%).(S)-2-(N-Phenylaminometh-1-yl)pyrrolidineC11H16N2[α]D20=+18.6 (c 0.72, CHCl3)Source of chirality: l-prolineAbsolute configuration: (S)((S)-2-(N-3-Nitrophenylaminometh-1-yl)pyrrolidineC11H15N3O2[α]D20=+16.7 (c 0.61, CHCl3)Source of chirality: l-prolineAbsolute configuration: (S)(S)-2-(N-Naphth-1-ylaminometh-1-yl)pyrrolidineC15H18N2[α]D20=+17.9 (c 0.65, CHCl3)Source of chirality: l-prolineAbsolute configuration: (S)(S)-2-(N-Cyclohexylaminometh-1-yl)pyrrolidineC11H22N2[α]D20=+14.45 (c 0.78, CHCl3)Source of chirality: l-prolineAbsolute configuration: (S)C10H20N2(S)-1-(Pyrrolidin-2-ylmethyl)piperidine[α]D20=+18.3 (c 0.84, CHCl3)Source of chirality: l-prolineAbsolute configuration: (S)(S)-1-Methyl-4-(pyrrolidin-2-ylmethyl)piperazineC10H21N3[α]D20=+17.5 (c 0.83, CHCl3)Source of chirality: l-prolineAbsolute configuration: (S)(S)-1-Methyl-4-(pyrrolidin-2-ylmethyl)piperazineC15H23N3[α]D20=+17.0 (c 0.77, CHCl3)Source of chirality: l-prolineAbsolute configuration: (S)

A new series of water compatible primary-tertiary diamine catalysts derived from natural primary amino acids bearing a hydrophobic side chain have been synthesized. These new primary-tertiary diamine-Brønsted acid conjugates bifunctional organocatalysts efficiently catalyzes the asymmetric direct syn selective cross-aldol reaction of different protected hydroxyacetone with various aldehydes in high yield (94%) and high enantioselectivity (up to 97% ee of syn) and dr of 91:9 (syn/anti) under mild reaction conditions.

The synthesis of enantiopure epoxides, as well as their corresponding vicinal diols is an actively pursued area of research. This is due to the fact that these compounds are essential chiral intermediates for the synthesis of bioactive products in the pharmaceutical and agrochemical industries. Therefore, the developments of efficient and cost effective processes for the preparation of these chiral molecules in enantiopure form are of importance. Epoxide hydrolase has emerged as an important enzyme for the asymmetric synthesis of enantiopure epoxides and diols via biocatalytic hydrolytic kinetic resolution (HKR) and enantioconvergent hydrolysis of racemic epoxides. The hydrolytic kinetic resolution of racemic epoxides provides a single enantiomer of the remaining epoxide and a single enantiomer of the formed diol whereas biocatalysts with complementary enantioselectivities and opposite regioselectivities provide the enantiopure diol as the only product, through enantioconvergent hydrolysis.Epoxide hydrolase has emerged as an important enzyme for the asymmetric synthesis of enantiopure epoxides and diols via biocatalytic hydrolytic kinetic resolution (HKR) and enantioconvergent hydrolysis of racemic epoxides. Hydrolytic kinetic resolution of racemic epoxides provides a single enantiomer of the remaining epoxide and a single enantiomer of the formed diol, whereas biocatalysts with complementary enantioselectivities and opposite regioselectivities provide enantiopure diols as the only product, through enantioconvergent hydrolysis.

The direct aldol reaction of 4-nitrobenzaldehyde and cyclohexanone, catalyzed by a protonated prolinamide catalyst in water, proceeds with the formation of aldol product that has high diastereoselectivity and enantioselectivity in an optimal pH range of 4–5.

Protonated chiral (S)-prolinamide derivatives have been developed as water compatible highly efficient organocatalysts for a direct enantioselective aldol reaction. A simple protonated (S)-prolinamide organocatalyst prepared from l-proline and 3-nitroaniline catalyzes the aldol reaction of unmodified ketones and a variety of aromatic aldehydes yielding aldol product in high yield with enantioselectivities of up to 98% and diastereoselectivity of up to >99:1.(S)-2-(4′-Fluorophenylcarbamoyl)pyrrolidinium bromideC11H14N2OFBr[α]D20=-38.8 (c 1.0, MeOH)Source of chirality: l-prolineAbsolute configuration: (S)(S)-2-(4′-Chlorophenylcarbamoyl)pyrrolidinium bromideC11H14N2OClBr[α]D20=-36.4 (c 1.0, MeOH)Source of chirality: l-prolineAbsolute configuration: (S)(S)-2-(4′-Bromophenylcarbamoyl)pyrrolidinium bromideC11H14N2OBr2[α]D20=-37.4 (c 1.0, MeOH)Source of chirality: l-prolineAbsolute configuration: (S)(S)-2-(4′-Nitrophenylcarbamoyl)pyrrolidinium bromideC11H14N3O3Br[α]D20=-36.3 (c 0.71, MeOH)Source of chirality: l-prolineAbsolute configuration: (S)(S)-2-(3′-Nitrophenylcarbamoyl)pyrrolidinium bromideC11H14N3O3Br[α]D20=-38.1 (c 0.94, MeOH)Source of chirality: l-prolineAbsolute configuration: (S)(S)-2-(2′-Nitrophenylcarbamoyl)pyrrolidinium bromideC11H14N3O3Br[α]D20=-29.7 (c 0.21, MeOH)Source of chirality: l-prolineAbsolute configuration: (S)(S)-2-(1′-Naphthmethylcarbamoyl)pyrrolidinium bromideC16H19N2OBr[α]D20=-22.6 (c 0.41, MeOH)Source of chirality: l-prolineAbsolute configuration: (S)(S)-2-(1′-Naphthmethylcarbamoyl)pyrrolidinium bromideC16H19N2OBr[α]D20=-22.4 (c 0.49, MeOH)Source of chirality: l-prolineAbsolute configuration: (S)

Protonated pyrrolidine based small organic molecules have been designed and evaluated for the asymmetric direct aldol reaction in water. The designed organocatalysts are multifunctional in nature and exploit the combined effect of hydrogen bonding and hydrophobic interactions for enantioselective catalysis in water. As a result a unique direct asymmetric aldol reaction in water catalyzed by a small organic molecule having an amide linkage has been developed. The developed catalyst affords chiral β-hydroxyketones in good yields (93%) and enantioselectivities (upto 62%) in water.(S)-2-(Phenylcarbamoyl)pyrrolidinium bromideC11H15N2OBr[α]D20=-18.0 (c 0.38, MeOH)Source of chirality: commercially available l-proline(S)-2-(Benzylcarbamoyl)pyrrolidinium bromideC12H17N2OBr[α]D20=-29.0 (c 0.61, MeOH)Source of chirality: commercially available l-proline(S)-2-(Naphth-1′-ylcarbamoyl)pyrrolidinium bromideC15H17N2OBr[α]D20=-16.0 (c 0.54, MeOH)Source of chirality: commercially available l-proline(2S,1′R/S)-2-(1′-Phenylethylcarbamoyl)pyrrolidinium bromideC13H19N2OBr[α]D20=-28.5 (c 0.56, MeOH)Source of chirality: commercially available l-proline(2S,1′R)-2-(1′-Phenylethylcarbamoyl)pyrrolidinium bromideC13H19N2OBr[α]D20=+39.0 (c 0.34, MeOH)Source of chirality: commercially available l-proline(2S,1′S)-2-(1′-Phenylethylcarbamoyl)pyrrolidinium bromideC13H19N2OBr[α]D20=-114.8 (c 0.25, MeOH)Source of chirality: commercially available l-proline(S)-2-(Piperidine-1′-carbonyl)pyrrolidinium bromideC10H19N2OBr[α]D20=-53.0 (c 0.54, MeOH)Source of chirality: commercially available l-proline(2S,1′R/S)-2-(1′-Naphth-1″-yl-ethylcarbamoyl)-pyrrolidinium bromideC17H21N2OBr[α]D20=-17.5 (c 0.89, MeOH)Source of chirality: commercially available l-proline(2S,1′R)-2-(1′-Phenylpropylcarbamoyl)pyrrolidinium bromideC14H21N2OBr[α]D20=+42.0 (c 0.39, MeOH)Source of chirality: commercially available l-proline(S)-2-(Pyridinium-2′-ylcarbamoyl)pyrrolidinium dibromideC10H15N3OBr2[α]D20=+1.5 (c 0.80, MeOH)Source of chirality: commercially available l-proline(S)-2-(Pyridinium-3′-ylcarbamoyl)pyrrolidinium dibromideC10H15N3OBr2[α]D20=+4.0 (c 0.70, MeOH)Source of chirality: commercially available l-proline(S)-2-(Pyridinium-4′-ylcarbamoyl)pyrrolidinium dibromideC10H15N3OBr2[α]D20=+2.5 (c 0.65, MeOH)Source of chirality: commercially available l-proline(S)-2-(Pyrrolidine-1′-carbonyl)pyrrolidinium bromideC9H17N2OBr[α]D20=-55.5 (c 0.80, MeOH)Source of chirality: commercially available l-proline(S)-2-(Butylcarbamoyl)pyrrolidinium bromideC9H19N2OBr[α]D20=-14.5 (c 0.29, MeOH)Source of chirality: commercially available l-proline(S)-2-(1′-Methylheptylcarbamoyl)pyrrolidinium bromideC13H27N2OBr[α]D20=-15.5 (c 0.62, MeOH)Source of chirality: commercially available l-proline(S)-2-(Hexylcarbamoyl)pyrrolidinium bromideC11H23N2OBr[α]D20=-21.0 (c 0.27, MeOH)Source of chirality: commercially available l-proline(S)-2-(Heptylcarbamoyl)pyrrolidinium bromideC12H25N2OBr[α]D20=-29.0 (c 1.43, MeOH)Source of chirality: commercially available l-proline(S)-2-(Octylcarbamoyl)pyrrolidinium bromideC13H27N2OBr[α]D20=-19.0 (c 0.52, MeOH)Source of chirality: commercially available l-proline(S)-2-(N,N-Dipropylcarbamoyl)pyrrolidinium bromideC10H23N2OBr[α]D20=-40.0 (c 0.33, MeOH)Source of chirality: commercially available l-proline(S)-2-(N,N-Dimethylcarbamoyl)pyrrolidinium bromideC7H15N2OBr[α]D20=-41.0 (c 0.44, MeOH)Source of chirality: commercially available l-proline(S)-2-(N,N-Diethylcarbamoyl)pyrrolidinium bromideC9H19N2OBr[α]D20=-41.6 (c 0.31, MeOH)Source of chirality: commercially available l-proline(S)-2-(N,N-Dioctylcarbamoyl)pyrrolidinium bromideC21H43N2OBr[α]D20=-26.0 (c 0.49, MeOH)Source of chirality: commercially available l-proline(S)-2-(N,N-Dibutylcarbamoyl)pyrrolidinium bromideC13H27N2OBr[α]D20=-38.0 (c 0.33, MeOH)Source of chirality: commercially available l-proline(S)-2-(N,N-Dihexylcarbamoyl)pyrrolidinium bromideC17H35N2OBr[α]D20=-17.5 (c 0.68, MeOH)Source of chirality: commercially available l-proline(2S,1′R)-2-(1′-Phenylethylcarbamoyl)pyrrolidinium trifluoroacetateC15H18N2F3O3Br[α]D20=+29.5 (c 0.15, MeOH)Source of chirality: commercially available l-proline(S)-2-(N,N-Diisopropylcarbamoyl)pyrrolidinium bromideC11H23N2OBr[α]D20=-18.0 (c 1.19, MeOH)Source of chirality: commercially available l-proline(2S,1′R)-2-(1′-Phenylethylcarbamoyl)pyrrolidinium chlorideC13H19N2OCl[α]D20=-37.0 (c 0.32, MeOH)Source of chirality: commercially available l-proline(R)-4-Hydroxy-4-(4′-nitrophenyl)butan-2-oneC10H11NO4[α]D20=+30.0 (c 1.24, CH2Cl2)Ee = 46%Source of chirality: asymmetric synthesis(R)-4-Hydroxy-4-(2′-nitrophenyl)butan-2-oneC10H11NO4[α]D20=-89.0 (c 0.34, CH2Cl2)Ee = 62%Source of chirality: asymmetric synthesis(R)-4-Hydroxy-4-(3′-nitrophenyl)butan-2-oneC10H11NO4[α]D20=+35.0 (c 1.14, CH2Cl2)Ee = 47%Source of chirality: asymmetric synthesis(R)-4-Hydroxy-4-(4′-chlorophenyl)butan-2-oneC10H11ClO2[α]D20=+24.4 (c 0.94, CH2Cl2)Ee = 36%Source of chirality: asymmetric synthesis(R)-4-Hydroxy-4-(2′-chlorophenyl)butan-2-oneC10H11ClO2[α]D20=+50.0 (c 1.07, CH2Cl2)Ee = 41%Source of chirality: asymmetric synthesis(R)-4-Hydroxy-4-(4′-fluorophenyl)butan-2-oneC10H11FO2[α]D20=+25.9 (c 1.24, CH2Cl2)Ee = 37%Source of chirality: asymmetric synthesis(R)-4-Hydroxy-4-phenylbutan-2-oneC10H12O2[α]D20=+26.5 (c 0.40, CH2Cl2)Ee = 37%Source of chirality: asymmetric synthesis(R)-4-Hydroxy-4-(4′-cyanophenyl)butan-2-oneC11H11NO2[α]D20=+27.0 (c 0.94, CH2Cl2)Ee = 36%Source of chirality: asymmetric synthesis

The phenyl glycidyl ether derivatives have been kinetically resolved with the growing cells of Bacillus alcalophilus MTCC10234 yielding (S)-epoxides with up to >99% ee and (R)-diols with up to 89% ee. The enantiomeric ratio (E) of up to 67 has been obtained for biohydrolysis process. The effect of different substituents of phenyl glycidyl ether on the biocatalytic efficiency of B. alcalophilus MTCC10234 showed preference for methyl- and chloro-substituted aryl glycidyl ether derivatives whereas nitro-derivatives were transformed at a slower rate. 2,6-Dimethylphenyl glycidyl ether which contains a bulky aryl group having methyl group on both the ortho positions was resolved with an E = 39.

α,α-Dicyanoolefins have emerged as versatile reactants, finding use as vinylogous nucleophiles, Michael acceptors and dienophiles in a variety of organic reactions. In the last few years, the reactivity of α,α-dicyanoolefins has been explored in various asymmetric transformations catalyzed by organocatalysts. In this review, we are presenting the recent advances in asymmetric organocatalytic transformations involving α,α-dicyanoolefins.

A new series of water compatible primary-tertiary diamine catalysts derived from natural primary amino acids bearing a hydrophobic side chain have been synthesized. These new primary-tertiary diamine-Brønsted acid conjugates bifunctional organocatalysts efficiently catalyzes the asymmetric direct syn selective cross-aldol reaction of different protected hydroxyacetone with various aldehydes in high yield (94%) and high enantioselectivity (up to 97% ee of syn) and dr of 91:9 (syn/anti) under mild reaction conditions.

A highly enantioselective Morita–Baylis–Hillman reaction of maleimides with isatin derived ketimines has been developed to obtain enantiomerically enriched 3-substituted-3-aminooxindoles using β-isocupreidine as an organocatalyst. Maleimide acting as a nucleophile provides products with up to 99% ee.