The first highly enantioselective conjugate addition of 2-acetyl azaarenes to α-substituted-β-nitroacrylates was successfully realized under mild conditions by a Ni(II)-bisoxazoline complex, providing the desired adducts bearing an all-carbon quaternary stereocenter in high yield with excellent enantioselectivity. The products obtained in this system could be readily converted into optically active β2,2-amino esters, succinates, lactones, and lactams.

•Thifluzamide increased liver glycogen levels in zebrafish.•Thifluzamide reduced blood glucose levels in zebrafish.•Aerobic glycolysis in liver was inhibited by thifluzamide.•Anaerobic glycolysis in liver was inhibited by thifluzamide.•Pentose phosphate pathway in liver was stimulated by thifluzamide.Thifluzamide exerts toxic effects to zebrafish and causes liver mitochondrial damage. To better understand the further mechanism, adult zebrafish were exposed to a range of thifluzamide concentrations (0, 0.019, 0.19, and 1.90 mg/L) for 28 days. In response to 1.90 mg/L exposure, liver glycogen significantly increased and blood glucose decreased. The expression of genes related to glycometabolism showed corresponding changes. Genes related to mtDNA replication and transcription and genes participating in mitochondrial complexes showed altered expression, which might lead to the inhibition of the tricarboxylic acid cycle (TCA). Additionally, the activity of glucose-6-phosphate dehydrogenase (G6PDH) was markedly increased at 1.90 mg/L, which might result in the activation of the pentose phosphate pathway. Moreover, the activity of lactate dehydrogenase (LDH) was significantly reduced at 1.90 mg/L, which might indicate that anaerobic glycolysis was inhibited. This study suggests that the altered gene expression and enzyme activities might be responsible for changes in glycometabolism, as evidenced by the altered expression of glycometabolism-related genes, the increased amount of glycogen in the liver and the decreased blood glucose levels. Overall, thifluzamide caused dysfunctional glycometabolism and led to events that might contribute to various thifluzamide-induced abnormalities in zebrafish.

The enantioselective Mukaiyama–Mannich reaction of cyclic N-sulfonyl α-ketiminoesters and silyl enol ethers was realized for the first time using a Ni(II)-bis(oxazoline) complex. Both di- and tri-substituted silyl enol ethers as well as silyl dienol ethers generated from the corresponding aromatic ketones or α,β-unsaturated ketones were well tolerated in this reaction. The reaction proceeded smoothly under mild conditions to provide a series of enantioenriched benzofused sultams containing an α-quaternary α-amino ester and an aromatic ketone moiety. Moreover, the products can be readily converted into potentially bioactive benzosultams including aziridine and polycyclic benzosultams.

Correction for ‘Ni(II)-Catalyzed enantioselective Mukaiyama–Mannich reaction between silyl enol ethers and cyclic N-sulfonyl α-ketiminoesters’ by Lei Xie, et al., Org. Chem. Front., 2017, DOI: 10.1039/c7qo00370f.

A highly enantioselective 1, 3-dipolar cycloaddition of nitrone with α, β-unsaturated acyl phosphonate was developed for the first time by using a chiral indane-bis(oxazoline)-copper(II) complex. The reaction proceeded smoothly under mild conditions to provide isoxazolidines with multi-stereocenters in good yields with high to excellent diastereo- (>20:1 dr) and enantioselectivities (up to 99% ee). The resulting products were readily converted to multi-functional isoxazolidines or γ-amino alcohol compounds.Download high-res image (143KB)Download full-size image

The highly enantioselective 1,3-dipolar cycloaddition of nitrones with α,β-unsaturated acylcarboxylates was realized for the first time by using a chiral bis(indano-oxazoline)-based Ni complex. The reaction proceeded smoothly under mild conditions and provided isoxazolidines with three contiguous stereocenters in high yields with excellent diastereoselectivities (>20:1 dr) and enantioselectivities (up to 99 % ee). The reaction was scaled up to the gram scale, and the products were readily transformed into γ-amino alcohols and other potentially bioactive compounds.

The first example of a highly enantioselective Michael addition of 2-acetyl azaarenes with β,β-disubstituted nitroalkenes was achieved using a Ni(acac)2–bisoxazoline complex as a catalyst, which afforded chiral compounds with an all-carbon quaternary stereocenter bearing a CF3 group in good yields with excellent enantioselectivities (up to >99% ee). This reaction, featuring mild conditions, excellent enantioselectivity and broad generality, provides a new efficient strategy for the construction of trifluoromethylated all-carbon quaternary stereocenters.

A new functional polyfluorene derivative containing quinoline skeleton and quarternary ammonium group (QAG) modified side chains (PFPQ) was synthesized and characterized. The multimodal antimicrobial effect toward Gram-negative E. coli was achieved by the dark toxicity resulting from the quinoline skeleton, QAG, and light toxicity resulting from reactive oxygen species (ROS) produced by the main backbone of PFPQ under white light. The mechanism of interaction between PFPQ and bacteria was also demonstrated. PFPQ bound to E. coli mainly through electrostatic interactions causing nearly 50% bacterial death in the absence of light irradiation, and the huge capability of PFPQ to generate ROS under white light opened another bactericidal mode. The killing efficiency was more than 99% upon relatively mild irradiation under white light (400–800 nm) with a light dose of 18 J·cm–2. PFPQ with the incorporation of quinoline into the backbones will provide a new versatile strategy to achieve the multimodal antimicrobial effect to fight against resistant bacteria.Keywords: antimicrobial activity; multimodal; polyfluorene; QAG; quinoline; ROS

A convenient approach to the synthetically and biologically useful indole derivatives was developed. A cascade sequence involving Friedel–Crafts alkylation of 3-methyl indoles with β,γ-unsaturated α-ketoester followed by N-hemiacetalization were realized using heteroarylidene-tethered bis(oxazoline)-copper complexes. The pyrroloindole products with two chiral centers were obtained in high yields (85–95%) with both high diastereoselectivities (87:13–96:4 drs) and enantioselectivities (87–98% ees). A plausible mechanism was proposed.

The simple and cheap chiral catalyst, heteroarylidene-tethered Ph-bis(oxazoline)–Cu(OTf)2, can efficiently catalyze the asymmetric F–C alkylation of indoles and pyrrole with β,γ-unsaturated α-ketoesters. The 3-indolyl adducts were obtained in up to >99% ee. Moreover, the 2-pyrrolyl adducts were achieved in up to 92% ee for the first time.

A series of novel heteroarylidene malonate derived bis(thiazoline) ligands 1 and 2 were synthesized and applied to a Friedel–Crafts reaction between indole and alkylidene malonate. The Cu(OTf)2 complex of ligand 2b bearing a benzyl group afforded moderate to excellent enantioselectivity for the adducts (up to >99% ee).(S,S)-N,N-Bis(2-TBDMSO-1-iso-propyl)-2-(2-thienylmethylidene)malonamideC30H56N2O4SSi2Ee = 100%[α]D25=-49.2 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMSO-1-benzyl)-2-(2-thienylmethylidene) malonamideC38H56N2O4SSi2Ee = 100%[α]D25=-85.6 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMSO-1-phenyl)-2-(2-thienylmethylidene) malonamideC36H52N2O4SSi2Ee = 100%[α]D25=-35.0 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMS-1-iso-propyl)-2-(2-furylmethylidene) malonamideC30H56N2O5Si2Ee = 100%[α]D25=-121.2 (c 0.30, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMS-1-benzyl)furylmethylidene) malonamideC36H52N2O5Si2Ee = 100%[α]D25=-87.2 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMS-1-phenyl)-2-(2-furylmethylidene) malonamideC36H52N2O5Si2Ee = 100%[α]D25=-88.0 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMSO-1-iso-propyl)-2-(2-thienylmethylidene)thio-malonamideC30H56N2O2S3Si2Ee = 100%[α]D25=-155.5 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMSO-1-benzyl)-2-(2-thienylmethylidene) thio-malonamideC38H56N2O2S3Si2Ee = 100%[α]D25=-112.8 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMSO-1-phenyl)-2-(2-thienylmethylidene) thio-malonamideC36H52N2O2S3Si2Ee = 100%[α]D25=-62.4 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMSO-1-iso-propyl)-2-(2-furylmethylidene) thio-malonamideC30H56N2O3S2Si2Ee = 100%[α]D25=-140.5 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMSO-1-benzyl)-2-(2-furylmethylidene) thio-malonamideC38H56N2O3S2Si2Ee = 100%[α]D25=-111.2 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)(S,S)-N,N-Bis(2-TBDMSO-1-phenyl)-2-(2-furylmethylidene) thio-malonamideC36H52N2 O3S2Si2Ee = 100%[α]D25=-29.6 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S,S)Bis[(S)-4-(iso-propyl)thiazoline-2-yl]-2-thienyletheneC18H24N2S3Ee = 100%[α]D25=-89.6 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)Bis[(S)-4-benzylthiazoline-2-yl]-2-thienyletheneC26H24N2S3Ee = 100%[α]D25=+25.6 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)Bis[(S)-4-phenylthiazoline-2-yl]-2-thienyletheneC24H20N2S3Ee = 100%[α]D25=+42.0 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)Bis[(S)-4-(iso-propyl)thiazoline-2-yl]-2-furyletheneC18H24N2OS2Ee = 100%[α]D25=-44.4 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)Bis[(S)-4-benzylthiazoline-2-yl]-2-furyletheneC26H24N2OS2Ee = 100%[α]D25=-17.6 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)Bis[(S)-4-phenylthiazoline-2-yl]-2-furyletheneC24H20N2OS2Ee = 100%[α]D25=+105.4 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)

A series of novel C3 symmetric tris(thiazoline) ligands were synthesized from trimethyl nitrilotriacetate and an enantiomerically pure amino alcohol via an efficient route. Compound 7a showed moderate to good catalytic enantioselectivity for the asymmetric allylic oxidation of cycloalkenes.N,N′,N″-Tris[(1S)-(2-TBDMSO-1-phenylethyl-)]nitrilotriacetamideC48H78N4O6Si3•Ee = 100%•[α]D25=+30.0 (c 0.50, CH2Cl2)•Source of chirality: l-amino alcohol•Absolute configuration: (S)N,N′,N″-Tris[(1S)-(2-TBDMSO-1-benzylethyl-)]nitrilotriacetamideC51H84N4O6Si3Ee = 100%[α]D25=+74.4 (c 0.67, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)N,N′,N″-Tris[(1S)-(2-TBDMSO-1-iso-propylethyl-)]nitrilotriacetamideC39H85N4O6Si3Ee = 100%[α]D25=-38.1 (c 1.50, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)N,N′,N″-Tris[(1S)-(2-TBDMSO-1-iso-butylethyl-)]nitrilotriacetamideC45H97N4O6Si3Ee = 100%[α]D25=-38.8 (c 1.0, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)N,N′,N″-Tris[(1S)-(2-TBDMSO-1-phenylethyl-)]nitrilotri(thio-acetamide)C48H78N4O3S3Si3Ee = 100%[α]D25=+35.6 (c 0.50, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)N,N′,N″-Tris[(1S)-(2-TBDMSO-1-benzylethyl-)]nitrilotri(thio-acetamide)C51H85N4O3S3Si3Ee = 100%[α]D25=+103.0 (c 0.63, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)N,N′,N″-Tris[(1S)-(2-TBDMSO-1-iso-propylethyl-)]nitrilotri(thio-acetamide)C39H85N4O3S3Si3Ee = 100%[α]D25=-105.0 (c 0.50, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)N,N′,N″-Tris[(1S)-(2-TBDMSO-1-iso-butylethyl-)]nitrilotri(thio-acetamide)C42H91N4O3S3Si3Ee = 100%[α]D25=-62.8 (c 1.0, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)Tri{[2-(4S)-(4-phenyl-1,3-thiazolinyl)] methyl} amineC30H30N4S3Ee = 100%[α]D25=+126.0 (c 0.25, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)Tri{[2-(4S)-(4-benzyl-1,3-thiazolinyl)] methyl} amineC33H36N4S3Ee = 100%[α]D25=+120.0 (c 0.30, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)Tri{[2-(4S)-(4-i-propyl-1,3-thiazolinyl)] methyl} amineC21H36N4S3Ee = 100%[α]D25=-65.0 (c 0.30, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)Tri{[2-(4S)-(4-i-butyl-1,3-thiazolinyl)] methyl} amineC24H42N4S3Ee = 100%[α]D25=-95.0 (c 0.20, CH2Cl2)Source of chirality: l-amino alcoholAbsolute configuration: (S)

The first example of a highly enantioselective Michael addition of 2-acetyl azaarenes with β,β-disubstituted nitroalkenes was achieved using a Ni(acac)2–bisoxazoline complex as a catalyst, which afforded chiral compounds with an all-carbon quaternary stereocenter bearing a CF3 group in good yields with excellent enantioselectivities (up to >99% ee). This reaction, featuring mild conditions, excellent enantioselectivity and broad generality, provides a new efficient strategy for the construction of trifluoromethylated all-carbon quaternary stereocenters.

The simple and cheap chiral catalyst, heteroarylidene-tethered Ph-bis(oxazoline)–Cu(OTf)2, can efficiently catalyze the asymmetric F–C alkylation of indoles and pyrrole with β,γ-unsaturated α-ketoesters. The 3-indolyl adducts were obtained in up to >99% ee. Moreover, the 2-pyrrolyl adducts were achieved in up to 92% ee for the first time.