Natural pigment chlorophyll was used as a green photosensitizer for the first time in a visible-light photoredox catalysis for the efficient synthesis of tetrahydroquinolines from N,N-dimethylanilines and maleimides in an air atmosphere. The reaction involves direct cyclization via an sp3 C–H bond functionalization process to afford products in moderate to high yields (61–98%) from a wide range of substrates with a low loading of chlorophyll under mild conditions. This work demonstrates the potential benefits of chlorophyll as photosensitizer in visible light catalysis.

Bio-catalytic bis-Michael reaction for the construction of quaternary carbon centers is reported. Glucoamylase from Aspergillus niger (AnGA) was used as a sustainable and eco-friendly catalyst. Various highly substituted trans-cyclohexanones with a quaternary carbon center were obtained with yields of up to 92%. As a novel case of enzyme promiscuity, this work provides a bio-catalytic alternative for construction of quaternary carbon centers.Glucoamylase from Aspergillus niger (AnGA) catalyzed the bis-Michael addition of (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones with active methylene compounds to form various highly substituted trans-cyclohexanones with a quaternary carbon center

A novel strategy combining visible-light and enzyme catalysis in one pot for the synthesis of 1,3-oxazine derivatives from α- or β-naphthols and ethyl N-aryl glycinates is described for the first time. Various 1,3-oxazine derivatives were prepared with yields of up to 69% under mild reaction conditions by a simple operation. This approach consists of sequential enzymatic hydrolysis and visible-light excited decarboxylation of ethyl N-aryl glycinates, oxidation of α-amino radicals, Mannich reaction, transimination and intramolecular cyclization. This work provides a novel alternative method for the synthesis of 1,3-oxazine derivatives.

The visible-light driven reaction for the synthesis of tetrahydroquinoline derivatives via tandem radical cyclization of N,N-dimethylanilines with 2-benzylidenemalononitriles has been developed. Corresponding products were obtained with yields of up to 74% under mild conditions by using Rose Bengal as a triplet sensitizer, which is inexpensive, environmentally-friendly and easily acquired. This work demonstrates the potential benefits of Rose Bengal for the production of tetrahydroquinoline derivatives.Download high-res image (133KB)Download full-size image

We report an example of Rose Bengal-photosensitized oxidation of tertiary amines for the synthesis of bis-1,3-dicarbonyl compounds. This protocol employs Rose Bengal as a visible-light absorbing photocatalyst without the need of a transition metal, and air as a green oxidant. Various functional groups were well tolerated to afford products with yields of up to 80% under mild reaction conditions.Download high-res image (134KB)Download full-size image

•Pepsin-catalyzed vinylogous Michael addition was described.•The novel reaction also expands the field of organic synthesis.•This work promotes the development of enzyme catalytic promiscuity.A pepsin catalyzed vinylogous Michael addition of deconjugated butenolides and maleimides in water has been successfully achieved, and γ,γ-disubstituted butenolides were obtained in up to 98% yields with up to 99:1 dr.A vinylogous Michael addition of deconjugated butenolides to maleimides catalyzed by pepsin from porcine gastric mucous in water has been developed.Download high-res image (139KB)Download full-size image

The direct asymmetric Michael addition of malonates and enones was promoted by protease from Streptomyces griseus for the first time. Yields of up to 84% with enantioselectivities of up to 98% enantiomeric excess (ee) were achieved under optimized conditions.Protease from Streptomyces griseus (SGP) was used for the first time as a biocatalyst in asymmetric Michael reaction of malonates.

AbstractAn efficient strategy for constructing (R)-3-alkyl-3-hydroxyindolin-2-one derivatives catalyzed by a structurally simple and easily prepared primary amine catalyst under mild conditions has been developed. Various isatins and ketones were tolerated, and the desired products were obtained in up to 99 % yield and up to 99 % ee. The biologically active natural product (R)-convolutamydine A was synthesized in 96 % yield and 95 % ee.

Pepsin from porcine gastric mucosa was used as a sustainable and environmentally friendly biocatalyst in the domino Knoevenagel/Michael/Michael reaction for the synthesis of spirooxindole derivatives in methanol. A wide range of isatins and α,β-unsaturated ketones reacting with malononitrile provided the corresponding products in yields of up to 99% with diastereoselectivities of up to >99:1 dr. This pepsin-catalyzed domino reaction provided a novel case of enzyme catalytic promiscuity.

A highly enantioselective Mannich reaction between 3-substituted-2H-1,4-benzoxazines and acetone catalyzed by lipase from wheat germ type I (WGL) is described. Enantioselectivity of up to 95% ee was achieved in DMSO at 25 °C. This research provides a new and simple method for the synthesis of β-amino ketone derivatives and promotes the development of enzyme-catalyzed Mannich reactions.

An unprecedented enzyme-catalyzed asymmetric domino aza-Michael/aldol reaction of 2-aminobenzaldehyde and α,β-unsaturated aldehydes is achieved. Pepsin from porcine gastric mucosa provided mild and efficient access to diverse substituted 1,2-dihydroquinolines in yields of 38%–97% with 6%–24% enantiomeric excess (ee). This work not only provides a novel method for the synthesis of dihydroquinoline derivatives, but also promotes the development of enzyme catalytic promiscuity.Pepsin from porcine gastric mucosa is used as a catalyst in the domino aza-Michael/aldol reaction for the synthesis of 1,2-dihydroquinolines.

The novel catalytic promiscuity of pepsin from porcine gastric mucosa for the asymmetric catalysis of the domino thia-Michael/aldol condensation reaction in MeCN and buffer was discovered for the first time. Broad substrate specificity was tested, and a series of corresponding products were obtained with enantioselectivities of up to 84% ee. This specific catalysis was demonstrated by using recombinant pepsin and control experiments with denatured and inhibited pepsin. The reaction was also shown to occur in the active site by site-directed mutagenesis (the Asp32Ala mutant of pepsin), and a possible mechanism was proposed.

The three-component one-pot Povarov reaction for the synthesis of tetrahydroquinoline derivatives was catalyzed by α-chymotrypsin from bovine pancreas (BPC) for the first time. The products were obtained in moderate to good yields with a wide range of substrates. Based on the control and comparison experiments of natural and promiscuous activities, a tentative mechanism was discussed. Molecular docking and energy calculation of quantum chemistry were used to explain the experimental results in theory. As a novel case of enzyme catalytic promiscuity, this work expands the application of BPC. Exploring the untapped catalytic promiscuity of natural enzymes may also provide useful information about enzyme evolution.

Enzyme catalytic promiscuity, in which the active site of an enzyme has the ability to catalyze more than one chemical transformation, has received widespread attention as more catalytic promiscuities of existing enzymes have been discovered. In this field, hydrolases have been mainly studied due to their commercial availability, high stability, broad substrate scope and high catalytic efficiency in media containing organic solvents. In this study, we review the hydrolase-catalyzed asymmetric carbon–carbon bond-forming reactions for the preparation of enantiomerically enriched compounds in organic synthesis. To date, these hydrolase-catalyzed asymmetric reactions include the direct asymmetric aldol, Michael, Mannich and Morita–Baylis–Hillman reactions. The hydrolase-catalyzed non-enantioselective examples were not included.

α-Amylase from hog pancreas displayed catalytic promiscuity in three-component reaction for the synthesis of 3,3′-disubstituted oxindoles and spirooxindole pyrans. The reactions between isatins, malononitrile and active methyl or active methylene compounds (acetone, nitromethane, indole, acetylacetone, 4-hydroxylcoumarin and dimedone) offered corresponding products via Knoevenagel/Michael reactions or Knoevenagel/Michael/cyclization reactions in one pot with high to excellent yields of up to 98% under mild reaction conditions. The α-amylase showed a broad spectrum of adaptability to various substrates. A possible mechanism of the α-amylase catalyzed three-component reaction was proposed.

The powder of a crude extract from earthworms was used as a catalyst in three-component cascade Mannich-Michael reaction for the preparation of isoquinuclidine (azabicyclo[2.2.2]octane) derivatives. The influences of mole ratio of substrates, solvents, water contents, catalyst loading, temperature, and reaction time on the reaction were investigated. The developed system had excellent substrate adaptability. Various isoquinuclidines were obtained in yields of up to 99% with ratio of endo/exo of up to 76:24. This method provided a good example to use naturally existing catalyst for organic synthesis.

The catalytic promiscuity of pepsin from porcine gastric mucous was observed in catalysis of the direct asymmetric aldol reactions of aromatic aldehydes with acetones, which were substituted by hydroxy-, dihydroxy-, methoxy- and benzyloxy- for the synthesis of diol compounds in acetonitrile. This biocatalysis was also applicable to the aldol reactions of cyclic or hetereocyclic ketones with aromatic aldehydes. Yields of up to 87%, diastereoselectivities of up to >99/1 dr and enantioselectivities of up to 75% ee were achieved.

A green one-pot multicomponent reaction for the synthesis of 3-indole derivatives was developed via l-proline-catalyzed condensation between indoles, aldehydes, and malononitrile. The process was carried out in ethanol at room temperature, and the desired products were obtained in good to excellent yields of up to 98%. Pyrrole as the nucleophile and 2,2,2-trifluoroacetophenone as the electrophile can also work in this transformation. The salient features of this protocol were environmental friendliness, simplicity of the procedure, ready accessibility of the catalyst, high yield, and mild reaction conditions.

A simple, efficient, eco-friendly and catalyst-free procedure was developed for the construction of trisubstituted tetrahydrothiophenes via sulfa-Michael/aldol (Henry) cascade reaction in water. The protocol, simply utilizing readily-available starting materials under clean reaction conditions, provided an alternative and highly attractive approach to a series of tetrahydrothiophene derivatives from a wide range of substrates in good yields (up to 93%) with excellent diastereoselectivities (up to >99:1).

A highly efficient, bifunctional prolinamide catalyst, which consists of chiral proline and trans-cyclohexanediamine moieties, was prepared and evaluated in the direct asymmetric aldol reactions of various ketones and aldehydes. The catalyst displayed impressive catalytic activity toward heterocyclic ketones containing oxygen, sulfur, or nitrogen, which have not been sufficiently explored. The substrate scope also covered cyclic and acyclic ketones. With heterocyclic ketones or cyclohexanone, the aldol reactions gave products in high yields and with respectable enantioselectivities (87–99% ee) and diastereoselectivities (up to >99:1 anti/syn). The catalyst could be recycled and reused up to seven times resulting in good yields and with good selectivities. This catalyst is also efficient in large-scale reactions with the enantioselectivities remaining at the same level as in the experimental scale reactions.(R)-N-((1R,2R)-2-(3,4,5-Trimethoxybenzamido)cyclohexyl)pyrrolidine-2-carboxamideC21H31N3O5[α]D20 = −69.1 (c 0.3, CHCl3)Source of chirality: the precursorAbsolute configuration: (R)-N-(1R,2R)(S)-3-((R)-Hydroxy(2-nitrophenyl)methyl)dihydro-2H-pyran-4(3H)-oneC12H13NO5[α]D20 = −7.3 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-Hydroxy(3-nitrophenyl)methyl)dihydro-2H-pyran-4(3H)-oneC12H13NO5[α]D20 = −7.9 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-Hydroxy(4-nitrophenyl)methyl)dihydro-2H-pyran-4(3H)-oneC12H13NO5[α]D20 = −18.1 (c 1.0, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)4-((R)-Hydroxy((S)-4-oxotetrahydro-2H-pyran-3-yl)methyl)benzonitrileC13H13NO3[α]D20 = −6.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(4-Chlorophenyl)(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC12H13ClO3[α]D20 = −7.8 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(2-Chlorophenyl)(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC12H13ClO3[α]D20 = −8.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(4-Bromophenyl)(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC12H13BrO3[α]D20 = −7.3 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(3-Bromophenyl)(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC12H13BrO3[α]D20 = −8.0 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(4-Fluorophenyl)(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC12H13FO3[α]D20 = −8.5 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-Hydroxy(p-tolyl)methyl)dihydro-2H-pyran-4(3H)-oneC13H16O3[α]D20 = −6.3 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-Hydroxy(phenyl)methyl)dihydro-2H-pyran-4(3H)-oneC12H14O3[α]D20 = −9.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-Furan-2-yl(hydroxy)methyl)dihydro-2H-pyran-4(3H)-oneC10H12O4[α]D20 = −10.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-Hydroxy(thiophen-2-yl)methyl)dihydro-2H-pyran-4(3H)-oneC10H12O3S[α]D20 = −9.8 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-Hydroxy(2-nitrophenyl)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13NO4S[α]D20 = +35.8 (c 1.0, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-Hydroxy(3-nitrophenyl)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13NO4S[α]D20 = +26.8 (c 0.8, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-Hydroxy(4-nitrophenyl)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13NO4S[α]D20 = +17.6 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)4-((R)-Hydroxy((S)-4-oxotetrahydro-2H-thiopyran-3-yl)methyl)benzonitrileC13H13NO2S[α]D20 = +14.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(4-Fluorophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13FO2S[α]D20 = +15.7 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(4-Chlorophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13ClO2S[α]D20 = +16.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(2-Chlorophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13ClO2S[α]D20 = +18.8 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(4-Bromophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13BrO2S[α]D20 = +20.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(3-Bromophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H13BrO2S[α]D20 = +19.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((R)-(2,4-Dichlorophenyl)(hydroxy)methyl)dihydro-2H-thiopyran-4(3H)-oneC12H12Cl2O2S[α]D20 = +24.5 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-3-((S)-1-Hydroxy-2-methylpropyl)dihydro-2H-thiopyran-4(3H)-oneC9H16O2S[α]D20 = −33.6 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′S)(S)-tert-Butyl 3-((R)-hydroxy(2-nitrophenyl)methyl)-4-oxopiperidine-1-carboxylateC17H22N2O6[α]D20 = −72.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-tert-Butyl 3-((R)-hydroxy(3-nitrophenyl)methyl)-4-oxopiperidine-1-carboxylateC17H22N2O6[α]D20 = −75.1 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-tert-Butyl 3-((R)-hydroxy(4-nitrophenyl)methyl)-4-oxopiperidine-1-carboxylateC17H22N2O6[α]D20 = −76.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-tert-Butyl 3-((R)-(4-fluorophenyl)(hydroxy)methyl)-4-oxopiperidine-1-carboxylateC17H22FNO4[α]D20 = −70.3 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-tert-Butyl 3-((R)-(4-chlorophenyl)(hydroxy)methyl)-4-oxopiperidine-1-carboxylateC17H22ClNO4[α]D20 = −68.5 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-tert-Butyl 3-((R)-(2-chlorophenyl)(hydroxy)methyl)-4-oxopiperidine-1-carboxylateC17H22ClNO4[α]D20 = −79.6 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-tert-Butyl 3-((R)-(4-bromophenyl)(hydroxy)methyl)-4-oxopiperidine-1-carboxylateC17H22BrNO4[α]D20 = −74.6 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-tert-Butyl 3-((R)-(3-bromophenyl)(hydroxy)methyl)-4-oxopiperidine-1-carboxylateC17H22BrNO4[α]D20 = −83.7 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (3S,1′R)(S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclohexanoneC13H15NO4[α]D20 = +10.4 (c 1.0, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)(S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclohexanoneC13H15NO4[α]D20 = +12.6 (c 0.8, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexanoneC13H15NO4[α]D20 = +8.6 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)4-((R)-Hydroxy((S)-2-oxocyclohexyl)methyl)benzonitrileC14H15NO2[α]D20 = +9.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)(S)-2-((R)-Hydroxy(2-methoxyphenyl)methyl)cyclohexanoneC14H18O3[α]D20 = +11.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)(S)-2-((R)-Hydroxy(3-methoxyphenyl)methyl)cyclohexanoneC13H15NO4[α]D20 = +9.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)(S)-2-((R)-Hydroxy(4-methoxyphenyl)methyl)cyclohexanoneC14H18O3[α]D20 = +12.1 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)(S)-2-((R)-(4-Chlorophenyl)(hydroxy)methyl)cyclohexanoneC14H15ClO2[α]D20 = +15.3 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)(S)-2-((R)-(4-Bromophenyl)(hydroxy)methyl)cyclohexanoneC13H15BrO2[α]D20 = +18.2 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)(S)-2-((R)-(4-Fluorophenyl)(hydroxy)methyl)cyclohexanoneC13H15FO2[α]D20 = +11.5 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclopentanoneC12H13NO4[α]D20 = +15.1 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (2S,1′R)(R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-oneC10H11NO4[α]D20 = +18.4 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (4R)(1R,2S)-1-Hydroxy-2-methyl-1-(4-nitrophenyl)pentan-3-oneC12H15NO4[α]D20 = +20.1 (c 0.5, CHCl3)Source of chirality: chiral catalystAbsolute configuration: (1R,2S)

Eco-friendly, highly efficient and large-scalable Henry reactions of aromatic aldehydes and nitroalkanes catalyzed by glucoamylase from Aspergillus niger (AnGA) are described. The reactions were carried out at 30 °C in the mixed solvents of ethanol and water, and the corresponding β-nitro alcohols were obtained in yields of up to 99%. Only 3 mg of enzyme was sufficient to catalyze the reaction of 1 mmol aldehydes. The natural activity and promiscuous activity of AnGA were compared under different conditions. Experiments demonstrated that the product of the Henry reaction could inhibit AnGA at 80 °C. This enzymatic Henry reaction showed a broad substrate scope, and could be facilely enlarged to gram scale. The possible mechanism was also discussed.

The direct asymmetric aldol reaction of aromatic aldehydes with cyclic or acyclic ketones was catalyzed by proteinase from Aspergillus melleus (AMP) in acetonitrile in the presence of water. A wide range of substrates could be transformed into the corresponding aldol products in yields up to 89%, enantioselectivities up to 91% ee and diastereoselectivities up to >99:1 (anti/syn). This work provided an example of enzyme catalytic promiscuity that widens the applicability of this biocatalyst in organic synthesis without the need for additional cofactors or special equipment.

The new promiscuous activity of lipase from porcine pancreas, type II (PPL II), has been observed to catalyze the direct asymmetric aldol reaction of heterocyclic ketones with aromatic aldehydes. PPL II showed favorable catalytic activity and had a good adaptability to different substrates in the reaction. The enantioselectivities of up to 87% ee and diastereoselectivities of up to 83:17 (anti/syn) were achieved. It is interesting that PPL II possesses the function of aldolase in organic solvents.

The synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives by NiCl2-catalyzed novel one-pot four-component condensation reaction of phthalimide, hydrazine, malononitrile (or ethyl cyanoacetate), and aromatic aldehydes was reported. This work provides a simple, efficient, and eco-friendly method for the construction of pyrazolo[1,2-b]phalazine-5,10-dione derivatives.

The direct three-component aza-Diels–Alder reaction of aromatic aldehyde, aromatic amine, and 2-cyclohexen-1-one was catalyzed by hen egg white lysozyme for the first time. Under the optimized conditions investigated in this paper, the enzyme-catalyzed aza-Diels–Alder reaction gave yields up to 98% and stereoselectivity of endo/exo ratios up to 90:10.

The unnatural ability of nuclease p1 from Penicillium citrinum was first discovered to catalyze asymmetric aldol reactions between aromatic aldehydes and cyclic ketones under solvent-free conditions. The excellent enantioselectivities of up to 99% ee and high diastereoselectivities of up to >99:1 (anti/syn) were achieved. This nuclease p1 catalyzed reaction provided a novel case for new activities of existing enzymes, which widens the applicability of this biocatalyst in organic synthesis.

An efficient and general two-step halogenation procedure to prepare diethyl α,α-bromofluorophosphonates was described, which included bromination by PPh3, 2,3-dichloro-5,6-dicyanobenzquinone (DDQ) and n-Bu4NBr, and electrophilic fluorination by N-fluorobisbenzenesulfonimide (NFSI). Both aromatic and aliphatic α,α-bromofluorophosphonates could be prepared by this method.Graphical abstractAn efficient and general two-step halogenation procedure to prepare diethyl α,α-bromofluorophosphonates was described. Both aromatic and aliphatic α,α-bromofluorophosphonates could be prepared by this method.Highlights► A general procedure for preparation diethyl α,α-bromofluorophosphonates was described. ► Both aromatic and aliphatic α,α-bromofluorophosphonates could be prepared. ► The electronic effect and steric effect of substrates were investigated.

A general procedure for the preparation of 4-substituted-3-halo-2-quinolones (halo = F, Cl, Br) utilizing 2-halo diethylphosphonoacetic acids (halo = F, Cl, Br) and o-aminophenylketones as the starting materials is described. The title compounds are obtained by an intramolecular Horner–Wadsworth–Emmons olefination of halogen-containing N-acyl-o-aminophenylketones. The transformation process is generally applicable under mild conditions.A general and efficient procedure for the preparation of 4-substituted-3-halo-2-quinolones by an intramolecular Horner–Wadsworth–Emmons olefination under mild conditions.

•Papain-catalyzed aldol reaction was described.•17 examples of aldol products were obtained by this reaction.•The novel reaction also expands the field of organic synthesis.•This work promotes the development of enzyme catalytic promiscuity.Papain from Carica papaya demonstrated catalytic promiscuity was first discovered to catalyze the synthesis of trifluoromethyl carbinol derivatives via aldol reaction between α,α,α-trifluoromethyl ketones and aliphatic ketones in a mixed solvent of DMF and water. The best results of the corresponding aldol products with up to 99% yield and 30% ee were achieved.Download full-size imagePapain was used for the first time as a biocatalyst in aldolreaction between α,α,α-trifluoromethyl ketones and aliphatic ketones.

Unnatural catalytic activity of trypsin from porcine pancreas for direct asymmetric aldol reaction was discovered. The reactions between aromatic aldehydes and various ketones gave products in moderate yields and enantioselectivities in the presence of a small amount of water. The influences of solvent, water content, temperature, mole ratio of substrates, and enzyme concentration were investigated. The mechanism of trypsin-catalyzed aldol reaction was discussed. This enzymatic promiscuity widens the application of trypsin to new chemical transformations.Graphical abstractDownload full-size imageHighlights► Unnatural catalytic activity of trypsin from porcine pancreas for direct asymmetric aldol reaction was discovered. ► Mechanism of trypsin-catalyzed aldol reaction was hypothesized. ► This enzymatic promiscuity widens the application of trypsin to new chemical transformations.

•Acylase I from A melleus showed catalytic promiscuity in asymmetric Mannich reaction.•It displayed good adaptability to different substrates.•The selectivities up to 89% ee, 90:10 dr and yields up to 82% were obtained.•This work offered a novel case of enzyme catalytic promiscuity.Acylase I from Aspergillus melleus (AMA) displayed catalytic promiscuity towards one-pot asymmetric Mannich reaction in acetonitrile for the first time. AMA showed favourable catalytic activity with good adaptability to different substrates. The activity and stereoselectivity of the enzyme could be improved by adjusting solvent, pH, water content, temperature, molar ratio of substrates and enzyme loading. The enantioselectivities up to 89% ee, diastereoselectivities up to 90:10 dr (syn/anti) and yields up to 82% were achieved. This work offered a novel case of enzyme catalytic promiscuity and a potential synthetic method for organic chemistry.Download full-size image

•Pepsin-catalyzed Morita–Baylis–Hillman (MBH) reaction was described.•15 examples of MBH products were obtained by this reaction.•The novel reaction also expands the field of organic synthesis.•This work promotes the development of enzyme catalytic promiscuity.Pepsin from porcine gastric mucous shown catalytic promiscuity was first discovered to catalyze the Morita–Baylis–Hillman (MBH) reaction between aromatic aldehydes with 2-cyclohexen-1-one or 2-cyclopenten-1-one in a two-phase medium of phosphate buffer/cyclohexane in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO). The best results of the corresponding MBH products up to 77% yield and 38% ee were achieved.Pepsin from porcine gastric mucous shown catalytic promiscuity was first used to catalyze Morita–Baylis–Hillman reaction in combination with 1,4-diazabicyclo[2.2.2]octane (DABCO).Download full-size image

•α-Amylase (hog pancreas) was used to catalyze the synthesis of nitrocyclopropanes.•The products were obtained via Michael addition initiated ring-closure sequence.•Bromonitroalkanes and α,β-unsaturated cyclic enones were used as substrates.•Moderate to good yields (55–93%) and certain enantioselectivities were obtained.This article presents a one-pot synthesis of nitrocyclopropanes via Michael addition initiated ring-closure sequence reactions of bromonitroalkane to α,β-unsaturated enones. Moderate to favorable yields (55–93%) and certain enantioselectivities were obtained with α-amylase from hog pancreas as the catalyst. This strategy utilizes the unnatural ability of enzymes to provide a convenient and biocatalytic method for green organic synthesis.α-Amylase from hog pancreas was used for the first time to catalyze Michael addition initiated ring-closure sequence reactions for the synthesis of nitrocyclopropanes.Download high-res image (187KB)Download full-size image

•A bovine serum albumin (BSA)-catalyzed domino reaction was described.•This domino process involved Michael and intramolecular cyclization reactions.•Various 2-amino-4H-chromene derivatives were obtained by this reaction in ethanol.•This work broadens the BSA-catalyzed chemical transformations.A domino reaction for the synthesis of 2-amino-4H-chromene derivatives using bovine serum albumin (BSA) as a catalyst in ethanol was described. The domino Michael addition/intramolecular cyclization reactions of readily available 2-hydroxychalcones with malononitrile gave the desired products in yields of 31–96% under the optimized conditions. As an example of biocatalytic methods, this work not only broadens the BSA-catalyzed chemical transformations, but also could be a potential valuable tool in organic synthesis in view of the economical and sustainable catalyst and simple operation.Bovine serum albumin (BSA) was used as a catalyst in the domino Michael/intramolecular cyclization reaction for the synthesis of 2-amino-4H-chromene derivatives.Download high-res image (108KB)Download full-size image

•Chiral tertiary alcohols were obtained via asymmetric ketone–ketone aldol reaction.•Proteinase from Aspergillus melleus (AMP) was used as a sustainable biocatalyst.•Enzymatic promiscuity was used to construct chiral tertiary alcohols.•This work expands the application of natural enzyme in organic synthesis.A new enzyme-catalyzed asymmetric construction of chiral tertiary alcohols via asymmetric aldol reactions between β,γ-unsaturated α-keto esters and ketones was reported. Proteinase from Aspergillus melleus (AMP) was used as a sustainable biocatalyst. The best results can be obtained with yields of up to 90%, diastereoselectives of up to 93:7 dr, and enantioselectivities of up to 70% ee. This work not only expands the application of enzymatic promiscuity, but also provides more examples for constructing chiral tertiary alcohols.Download full-size imageChiral tertiary alcohol was obtained via asymmetric ketone–ketone aldol reaction using proteinase from Aspergillus melleus (AMP) as a sustainable biocatalyst.

The Rose Bengal sensitized intermolecular [2 + 2]-cycloaddition of 3-ylideneoxindoles for the synthesis of spirocyclic oxindoles was developed successfully under visible light irradiation conditions. The cycloaddition products were obtained in good yields (up to 93%) with excellent diastereoselectivity and regioselectivity by using a low loading of Rose Bengal (0.125 mol%) as a triplet sensitizer. This work demonstrates the potential benefits of Rose Bengal in visible light catalysis.

•Ficin from fig tree latex exhibited distinct catalytic activity in direct asymmetric aldol reactions.•Different aromatic aldehydes and cyclic or heterocyclic ketones could participate in the reaction.•The products were obtained in yields up to 44% with enantioselectivities up to 81% ee and dr up to 86:14 (anti/syn).•This methodology employed the catalytic promiscuity of ficin in asymmetric reaction for the first time.Ficin from fig tree latex displayed a promiscuous activity to catalyze the direct asymmetric aldol reactions of heterocyclic ketones with aromatic aldehydes. Ficin showed good substrate adaptability to different heterocyclic ketones containing nitrogen, oxygen or sulfur. The enantioselectivities up to 81% ee and diastereoselectivities up to 86:14 (anti/syn) were achieved under the optimized reaction conditions.Download full-size image

A new function of BLAP (alkaline protease from Bacillus licheniformis) was first discovered to catalyze direct aldol reactions between aromatic aldehydes and cyclic ketones in an organic medium in the presence of water. The products were obtained in yields of 28–92% with 22–99% ee.Download full-size imageResearch Highlights► The enzyme-catalyzed direct aldol reaction was observed. ► BLAP (alkaline protease from Bacillus licheniformis) was used in DMSO/H2O at 20 °C. ► The yields of 28–92% with 22–99% ee were achieved. ► BLAP showed a wide substrate tolerance for aromatic aldehydes and cyclic ketones.

Primary natural amino acid l-tryptophan was used, for the first time, as a catalyst in Knoevenagel condensations of aliphatic, aromatic, hetero-aromatic and α,β-unsaturated aldehydes with less reactive acetylacetone and ethyl acetoacetate. The reactions were carried out at room temperature and gave good yields. It is a convenient entry for preparation of functionalized trisubstituted alkenes and α,β,γ,δ-unsaturated carbonyl compounds.

A novel strategy combining visible-light and enzyme catalysis in one pot for the synthesis of 1,3-oxazine derivatives from α- or β-naphthols and ethyl N-aryl glycinates is described for the first time. Various 1,3-oxazine derivatives were prepared with yields of up to 69% under mild reaction conditions by a simple operation. This approach consists of sequential enzymatic hydrolysis and visible-light excited decarboxylation of ethyl N-aryl glycinates, oxidation of α-amino radicals, Mannich reaction, transimination and intramolecular cyclization. This work provides a novel alternative method for the synthesis of 1,3-oxazine derivatives.

A highly enantioselective Mannich reaction between 3-substituted-2H-1,4-benzoxazines and acetone catalyzed by lipase from wheat germ type I (WGL) is described. Enantioselectivity of up to 95% ee was achieved in DMSO at 25 °C. This research provides a new and simple method for the synthesis of β-amino ketone derivatives and promotes the development of enzyme-catalyzed Mannich reactions.

Pepsin from porcine gastric mucosa was used as a sustainable and environmentally friendly biocatalyst in the domino Knoevenagel/Michael/Michael reaction for the synthesis of spirooxindole derivatives in methanol. A wide range of isatins and α,β-unsaturated ketones reacting with malononitrile provided the corresponding products in yields of up to 99% with diastereoselectivities of up to >99:1 dr. This pepsin-catalyzed domino reaction provided a novel case of enzyme catalytic promiscuity.