A practical and straightforward synthetic route through a Selectfluor-triggered tandem cyclization of o-hydroxyarylenaminone was developed to construct a variety of difluorinated 2-amino-substituted chromanones. This novel protocol features mild reaction conditions, operational simplicity, and broad substrate scope. The enamine moiety in o-hydroxyarylenaminone played dual roles to enable high efficiency in the difluorination and intramolecular cyclization, leading to the accomplishment of a new class of difluorinated 2-amino-substituted chromanones for pharmaceutical studies.

Hydrogen-bonding organocatalysts L-pyroglutamic sulphonamides were readily synthesized for the first time by fully exploiting the potentials of L-pyroglutamic acid. The newly designed catalyst was successfully applied in catalyzing asymmetric Diels–Alder cyclization of methyleneindolinones with 2-vinyl-1H-indoles to efficiently assemble carbazolespirooxindoles in excellent stereoselectivity (up to 99% ee, >20:1 dr) and yields (up to 99%). Mechanistic studies disclosed that the well-designed hydrogen-bonding modes between L-pyroglutamic sulphonamide and substrates were crucial for stereocontrol in the cyclization.

Surface-enhanced Raman-scattering-based (SERS-based) biosensing in biological fluids is constrained by nonspecific macromolecule adsorptions and disposable property of the SERS substrate. Here, novel multi-Au-nanoparticle-embedded mesoporous silica microspheres (AuNPs/mSiO2) were prepared using a one-pot method, which served as reliable substrates for SERS enhancement associated with salient features of self-filtering ability and reusability. The fabrication and physical characterization of AuNPs/mSiO2 microspheres were discussed, and SERS activity of this novel substrate was investigated by using 4-mercaptobenzoic acid (4-MBA) as Raman probe. The responses of our substrates to Raman intensities exhibited a SERS enhancement factor of 2.01 × 107 and high reproducibility (relative standard deviation of 6.13%). Proof-of-concept experiments were designed to evaluate the self-filtering ability of the substrates in bovine serum albumin (BSA) and human serum solution, separately. The results clearly demonstrate that mesoporous SiO2 can serve as a molecular sieve via size exclusion and avoid Raman signal interference of biomacromolecules in biological fluids. Subsequently, feasibility of practical application of AuNPs/mSiO2 microspheres was assessed by quantitative detection of methotrexate (MTA) in serum. The method exhibited good linearity between 1 and 110 nM with the correlation coefficients of 0.996, which proved that the obtained AuNPs/mSiO2 microspheres were good SERS substrates for determination of small biomolecules directly in biological fluids without need of manipulating samples. In addition, the substrate maintained its SERS response during multiple cycles, which was evaluated by recording Raman signals for 4-MBA before and after thermal annealing, thereby demonstrating the high thermostability and satisfactory reusability. These results offered the AuNPs/mSiO2 microspheres attractive advantages in their SERS biosensing.Keywords: human serum; mesoporous silica microspheres; methotrexate; reusable substrates; self-filtering; surface-enhanced Raman scattering (SERS);

With the aid of in situ protection by N-(2-formylphenyl)-4-methyl-benzenesulfonamide, enantioselective allylic alkylation of Morita–Baylis–Hillman carbonates with diethyl 2-aminomalonate was successfully realized. The corresponding adducts can be obtained in up to 99% yield with up to 98% ee as well as excellent regioselectivity. Besides, the adducts with opposite configurations were readily prepared by utilizing easily available and inexpensive quinine or quinidine as organocatalyst. Facile deprotection of the resulting adduct provides straightforward access to enantiopure α-methylene-γ-lactam.

Reductive dimerization of isatin and its derivatives can be regarded as a step-economical pathway to construct 3,3′-disubstituted bisoxindoles, which was unfortunately accompanied by severe direct reduction as well as low efficiency. A visible-light driven, photoredox-catalytic protocol was developed to readily furnish 3,3′-dihydroxy- (dl-, > 20:1 dr) and 3,3′-diamino-bisoxindoles (meso-, 3.5:1 to 5:1 dr) in moderate to good yields, successfully circumventing the common problem. Two vicinal quaternary carbon centers were effectively assembled under the irradiation of visible light.

A practical and straightforward synthetic route to construct a variety of 3-CF2/CF3-containing chromones via photoredox catalysis was developed. This novel protocol features a visible-light-induced radical-triggered tandem cyclization.

•A label-free optical sensing paper strip for SERS detection of BRs was fabricated.•Utilizing γ-PGA as the linker and concentrator for in situ growth AuNPs on paper.•Highly reproducibility and sensitive (RSD: 4.78%, LOD:1×10−11 M, EF:1.13×108).•Rapid detection of BRs in plant tissues: RSD values in a range of 3.0–13.8%.A surface-enhanced Raman scattering (SERS)-functionalized, gold nanoparticle (AuNPs)-immobilized paper strip was developed to realize label-free rapid detection of brassinosteroids (BRs) in plant tissues. The AuNPs paper strip was fabricated through utilizing poly(γ-glutamic acid) (γ-PGA) as the linker and concentrator for the directly immobilized AuNPs on paper, which can circumvent many drawbacks of the existing SERS substrates. An enhancement factor of 1.13×108, high reproducibility (relative standard deviation of 4.78%), highly sensitive detection limit with a correlation coefficient of 0.99 (1×10–11 M 4-mercaptophenylboronic acid), and long-term stability for the responses of the SERS-functionalized AuNPs paper strip to Raman intensities were achieved by optimizing reaction conditions including the concentrations of γ-PGA and HAuCl4/NaBH4. Ultimately, this developed paper strip was applied to the determination of BRs in plant tissues, obtaining precisions with RSD values in a range of 3.0–13.8%. The SERS-functionalized AuNPs paper strip featuring label-free rapid analysis, and high sensitivity could serve as an excellent alternative for on-site rapid detections.

An unusual temperature-dependent autoinductive reversal of enantioselectivity (TARE) was discovered in an asymmetric palladium-mediated [3+3]-annulation of 4-hydroxycoumarin with Morita–Baylis–Hillman acetate. The absolute stereochemistry of the reaction product can be readily inversed by solely modifying the reaction temperature (from 10 °C to 60 °C), affording multicyclic adducts with the opposite configurations respectively in moderate to excellent enantiopurities. Furthermore, the first reported example of palladium-mediated bidirectional asymmetric autoinduction was identified to mainly contribute to the reversal of enantioselectivity, in which the corresponding adduct actively participated in the stereocontrol during the reaction. The correlation between reaction temperature and autoinduction was established, which might broaden the horizon of stereocontrol in asymmetric catalysis.

A diversity-driven three-component 1,3-dipolar cycloaddition of isatins, amino acids and isatin-derived ketimines was developed to facilely assemble dispirooxindole-imidazolidine skeletons bearing vicinal quaternary carbon centers. This protocol features additive-free, minimal solvent usage (0.1 mL DMSO/0.2 mmol scale), wide substrate scope (34 examples), mild reaction conditions (room temperature) and high chemical yield (up to 99%).

•A novel approach for fabricating core-shell-satellite magnetic microspheres was developed.•Utilizing positively charged mSiO2 to anchor AuNPs and enrich the methotrexate.•Rapid SERS detection of methotrexate (LOD: 1 nM, linear range: 1–200 nM).An effective approach for fabricating core-shell-satellite magnetic microspheres was developed to form a sub-10 nm positively charged mesoporous silica (mSiO2) interlayer, which was applied to enrich samples and create sufficient hotspots between the inner Fe3O4@Ag core and outer assembled gold nanoparticles (AuNPs) satellites. Based on the prepared Fe3O4@Ag/mSiO2/AuNPs (FASA) as SERS substrates, a sensitive and label-free detection of methotrexate in serum was successfully realized. The positively charged mSiO2 interlayer exhibited strong capability in enriching methotrexate through the electrostatic interaction. The intraparticle plasmonic coupling between the inner Ag shell and the outside AuNPs satellites, and magnetism-induced aggregation greatly enhanced the SERS activity of methotrexate. The diluted serum containing different concentrations of methotrexate was employed as real samples and the minimum detected concentration of methotrexate was as low as 1 nM with a linear response range from 1 to 200 nM. This sensitive and label-free SERS detection of methotrexate based on FASA offers great potential for practical applications in medicine and biotechnology.Download high-res image (231KB)Download full-size image

An unusual ligand-to-palladium-ratio-dependent reversal of enantioselectivity was systematically observed in the asymmetric Pd-catalysed [3+3]-annulation of Morita–Baylis–Hillman acetate with 4-hydroxycoumarin or 1,3-cyclohexanedione. The absolute configurations of the annulation products can be readily inverted by simply modifying the L/Pd ratio from 1:3 to 2:1.

An unusual ligand-to-palladium-ratio-dependent reversal of enantioselectivity was systematically observed in the asymmetric Pd-catalysed [3+3]-annulation of Morita–Baylis–Hillman acetate with 4-hydroxycoumarin or 1,3-cyclohexanedione. The absolute configurations of the annulation products can be readily inverted by simply modifying the L/Pd ratio from 1:3 to 2:1.

A concise and facile approach for the construction of 2-hydroxy-2-substituted indol-3-ones was developed through an oxidative cyclization of 2-aminophenyl-1,3-dione. Using CAN and TEMPO as oxidants, C2-quaternary 2-hydroxy-indolin-3-ones were efficiently installed in moderate to excellent yields (up to 99%). Moreover, this developed protocol was further applied to synthetic studies towards natural product matemone by starting from readily available 2-amino-4-bromobenzoic acid, and the precursor for matemone was efficiently installed.

Highly diastereo- and enantioselective conjugate additions of azlactones to enolizable cyclic and linear enones were conducted by employing proline aryl sulfonamide as the organocatalyst in trifluorotoluene. The conjugate adducts bearing contiguous quaternary and tertiary stereocenters were obtained in moderate to good yields with excellent diastereoselectivities and moderate to good enantioselectivities. This developed protocol filled in the substrate gap for the organocatalytic conjugate addition of azlactone to enones.

An intramolecular [3 + 2]-annulation of amide-linked donor–acceptor cyclopropane with in situ-generated imine is described. As a result, diverse hexahydropyrrolo[3,2-c]quinolinones, as the tricyclic core of martinellines, were efficiently assembled in good to excellent yield (up to 93%) with a good diastereomeric ratio (up to 98:2).

An acid-promoted self-1,3-dipolar cycloaddition of ketimines derived from isatins and benzylamines was successfully developed to assemble unprecedented dispirooxindole–imidazolidine ring systems. Generally, excellent diastereoselectivities (only a single stereoisomer formed) and good yields (up to 94%) were obtained. Consequently, this self-1,3-dipolar cycloaddition protocol offers facile access to a novel dispiroheterocyclic skeleton.

A Michael-Michael-acetalization cascade between 4-(2-hydroxyphenyl)but-3-en-2-ones and α,β-unsaturated aldehydes via a novel dual activation mode promoted by pyrrolidine was successfully established. Consequently, various novel tetrahydro-6-hydroxyl-6H-benzo[c]chromen-9-one derivatives were prepared in excellent diastereoselectivities and moderate to good yields. Further diverse modification of the resulting tricyclic scaffolds provided a facile pathway to achieve a variety of tetrahydro-6-hydroxyl-6H-benzo[c]chromen-9-one analogs.

A series of novel 2,3- or 2,5-dispirooxindole-piperazine ring systems were efficiently constructed through the acid-promoted self-1,3-dipolar [3+3] cyclizations of azomethine ylides derived from isatin with various primary or cyclic secondary amines. Interestingly, the regioselectivity of this self-[3+3] cyclization could be effectively tuned by varying the structural features of substrates. The unprecedented 2,5-dispirooxindole-piperazine skeleton was achieved in good diastereoselectivity by employing 1,2,3,4-tetrahydroisoquinoline, while using pyrrolidine or glycine methyl ester furnished the 2,3-dispirooxindole-piperazine scaffold in excellent diastereoselectivity (only a single isomer formed).

A facile approach to the stereoselective synthesis of spiroimidazolidinones was described. A variety of novel polycyclic spiroimidazolidinones derived from isatin were prepared by employing easily available 2-pyridyl prolinamide as a chiral scaffold. Interestingly, the N-2-pyridyl motif played a vital role in improving the diastereoselectivity of this protocol. As a result, excellent diastereoselectivities (>20:1 dr) and good to excellent yields (60–96%) were achieved under extremely mild reaction conditions.

•A CCC–SPE–CCC system was developed.•Trapping conditions of SPE were optimized.•Five intractable compounds were separated by baseline through adopting recycling CCC.•11 compounds with large polarity difference were separated by running CCC only once.A counter-current chromatography (CCC)–solid phase extraction (SPE)–CCC system with high preparative capacity was used to realize rapid one-run systematic separation of natural products, in which two six-port valves and the SPE cartridge served as the interface. In the orthogonal separation system, equal column volumes of TEB-300A and TEB-300B were employed for the first dimension (1st-D) and second dimension (2nd-D), respectively. An optimized solid-phase column (25 mm × 10 mm i.d.) packed with Oasis HLB materials acted as the trapping SPE column. The analyte-focusing effect of the trapping column associated with the considerable preparative capacities of 1st-D and 2nd-D using totally different solvent systems significantly facilitated this one-run systematic separation of natural product. Therefore, this proposed approach was successfully applied to isolate chemical compounds from the crude extract of Rhizoma Chuanxiong. As a result, 11 compounds with widely different polarities were separated by running CCC for only one time. More importantly, this hyphenated strategy could serve as a rapid and efficient systematic pathway for the separation of natural products.

•Twin-column R-HPLC was used for improving enantioseparation for the first time.•Experimental comparison of two R-HPLC methods was reported for the first time.•Performance of two R-HPLC methods was evaluated on the enantioseperation.•Intractable four stereoisomers of isoxazolidines were separated by baseline.A long-neglected recycling high performance liquid chromatography (R-HPLC) strategy was adopted to improve the enantioseparation efficiency in this work. Taking intractable isoxazolidine mixtures as the example, two different R-HPLC methods including single-column and twin-column based strategy were applied to improve the enantioseparation efficiency. Under the optimized conditions, these two methods present distinct separation results: the conceptually simple and commonly used single-column based R-HPLC led to severe peak broadening and degraded separation efficiency; on the contrary, the enantioseparation was significantly improved by adopting the relatively complicated twin-column strategy. This observed difference might be mainly attributed to less peak spreading and sample mixing of the latter, as a result of avoiding redirecting the effluent back to LC pump.

A series of novel dispirooxindole derivatives, 3-acetyl-5-phenyl-pyrrolo(spiro-[2.3′]-1′-benzyl-oxindole)-spiro-[4.3″]-1″-benzyl-oxindoles, were synthesized via 1,3-dipolar cycloaddition of the azomethine ylide with 3-acetonylideneoxindole in high regioselectivities and yields. An unusual regioselectivity was observed in this 1,3-dipolar cycloaddition, leading to the construction of novel dispirooxindole skeleton. The substituent effects on the regioselectivity were also investigated.

An organocatalyzed approach to the asymmetric synthesis of 2-aryl-2,3-dihydro-4-quinolones using amino-acid derived sulfonamides as organocatalysts, which can be easily prepared starting from l-proline, l-alanine, and l-phenylalanine, has been developed in high yields (up to 92%) and with moderate to good enantioselectivities (up to 74% ee). Additionally, opposite enantioselectivities for primary and secondary amino acid sulfonamides have also been observed.N-2,4,6-Tris-(methylbenzene)sulfoneyl-l-proline amideC14H20N2O3S[α]D25=+67.7 (c 1, CHCl3)Source of chirality: Chiral poolAbsolute configuration: (S)N-2,4,6-Tris-(methylbenzene)sulfoneyl-l-alanine amideC12H18N2O3S[α]D25=-34.5 (c 1, MeOH)Source of chirality: Chiral poolAbsolute configuration: (S)N-2,4,6-Tris-(isopropylbenzene)sulfoneyl-l-alanine amideC18H30N2O3S[α]D25=-25.2 (c 1, MeOH)Source of chirality: Chiral poolAbsolute configuration: (S)N-4-Dodecylbenzenesulfoneyl-l-alanine amideC21H36N2O3S[α]D25=-77.4 (c 1, CHCl3)Source of chirality: Chiral poolAbsolute configuration: (S)N-2,4,6-Tris-(methylbenzene)sulfoneyl-l-phenylalanine amideC18H22N2O3S[α]D25=-64.4 (c 1, MeOH)Source of chirality: Chiral poolAbsolute configuration: (S)N-2,4,6-Tris-(isopropylbenzene)sulfoneyl-l-phenylalanine amideC12H34N2O3S[α]D25=-46.2 (c 1, MeOH)Source of chirality: Chiral poolAbsolute configuration: (S)N-4-Dodecylbenzenesulfoneyl-l-phenylalanine amideC27H40N2O3S[α]D25=-98.2 (c 1, MeOH)Source of chirality: Chiral poolAbsolute configuration: (S)2-Phenyl-2,3dihydroquinolin-4-(1H)-oneC15H13NO[α]D25=-19.4 (c 0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)2-(2-Hydroxypheneyl)-2,3-dihydroquinolin-4(1H)-oneC15H13NO2[α]D25=-31.8 (c 0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)2-(4-Hydroxypheneyl)-2,3-dihydroquinolin-4(1H)-oneC15H13NO2[α]D25=-23.1 (c 0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)2-(4-Bromopheneyl)-2,3-dihydroquinolin-4(1H)-oneC15H12BrNO[α]D25=-17.4 (c 0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)2-(3-Methoxypheneyl)-2,3-dihydroquinolin-4(1H)-oneC16H15NO2[α]D25=-23.2 (c 0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)2-(3-Chloropheneyl)-2,3-dihydroquinolin-4(1H)-oneC15H12CINO[α]D25=-15.4 (c0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)2-(4-(Dimethylamino)pheneyl)-2,3-dihydroquinolin-4(1H)-oneC17H18N2O[α]D25=-19.3 (c 0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)2-(4-Nitropheneyl)-2,3-dihydroquinolin-4(1H)-oneC15H12N2O3[α]D25=-19.4 (c 0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)2-(Isobutyl)-2,3-dihydroquinolin-4(1H)-oneC13H17NO[α]D25=-25.2 (c0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)2-(Pyridin-2-yl)-2,3-dihydroquinolin-4(1H)-oneC14H12N2O[α]D25=-19.6 (c 0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)2-(4-(1H-Indol-3-yl)phenyl)-2,3-dihydroquinolin-4(1H)-oneC17H14N2O[α]D25=-11.2 (c0.5, CHCl3)Source of chirality: Asymmetric synthesisAbsolute configuration: (R)

An unusual temperature-dependent autoinductive reversal of enantioselectivity (TARE) was discovered in an asymmetric palladium-mediated [3+3]-annulation of 4-hydroxycoumarin with Morita–Baylis–Hillman acetate. The absolute stereochemistry of the reaction product can be readily inversed by solely modifying the reaction temperature (from 10 °C to 60 °C), affording multicyclic adducts with the opposite configurations respectively in moderate to excellent enantiopurities. Furthermore, the first reported example of palladium-mediated bidirectional asymmetric autoinduction was identified to mainly contribute to the reversal of enantioselectivity, in which the corresponding adduct actively participated in the stereocontrol during the reaction. The correlation between reaction temperature and autoinduction was established, which might broaden the horizon of stereocontrol in asymmetric catalysis.

An acid-promoted self-1,3-dipolar cycloaddition of ketimines derived from isatins and benzylamines was successfully developed to assemble unprecedented dispirooxindole–imidazolidine ring systems. Generally, excellent diastereoselectivities (only a single stereoisomer formed) and good yields (up to 94%) were obtained. Consequently, this self-1,3-dipolar cycloaddition protocol offers facile access to a novel dispiroheterocyclic skeleton.