Effect of 1,4-Dioxane Solvent on ß-Glucuronidation Using Methyl 1,2,3,4-Tetra-O-acetyl-ß-D-glucuronate as the Glycosyl Donor.

A facile and selective ß-D-glucuronidation of alcohols, such as (-)-menthol, cholestanol, (+)- and (-)-borneols, and 2-adamantanol, using commercially available methyl 1,2,3,4-tetra-O-acetyl-ß-D-glucuronate as the glycosyl donor and trimethylsilyl bis(trifluoromethanesulfonyl)imide (Tf2NTMS) (0.5 equivalent) as the activator in 1,4-dioxane at 60 °C gave products in moderate yields. The addition of MS4A increased the ß : α ratios of D-glucuronides when cholestanol, (+)-borneol, and 2-adamantanol were used as the acceptor substrate.

Synthesis of 2-Substituted Indoles via Migration Reaction of 3-Substituted Indoles with Triflic Acid.

This study showcases the 1,2-migration reactions of alkyl and aryl groups on the indole molecule. Trifluoromethanesulfonic acid effectively facilitates the migration of the substituent from C3- to C2-position of the indole structure. The resulting C2-substituted indoles offer a valuable pathway for the synthesis of natural products and medicinal compounds.

Regioselective One-Pot Synthesis of Vicinal Bisphosphine Derivatives from Nitroalkenes by Hydrophosphinylation/Elimination/Hydrophosphinylation.

Herein, a facile method is developed for the synthesis of vicinal bisphosphine derivatives based on a cascade of hydrophosphinylation, elimination, and hydrophosphinylation of secondary phosphine oxides with nitroalkenes. This cascade reaction provides step-economy access to a series of vicinal bisphosphine derivatives with high to excellent yields (up to 99%). This method was further extended to prepare, in one-pot, regioselective vicinal bisphosphine derivatives that incorporated two different phosphorus functional groups.

Vicinal All-Carbon Quaternary Stereocenter Construction with Trifluoromethyl Groups via Organocatalytic Asymmetric Cascade Michael/Michael Reaction.

A thiourea organocatalyst efficiently promoted the asymmetric cascade Michael/Michael reactions between isatin-derived trifluoromethylacrylate and α-alkylidene succinimide, resulting in high yields of spirooxindole derivatives. These compounds exhibit vicinal all-carbon quaternary stereocenters and bear a trifluoromethyl group, with excellent enantioselectivities reaching up to 99 % ee. This work represents the first successful organocatalyst application for the direct construction of vicinal all-carbon quaternary stereocenters, featuring a trifluoromethyl group.

Fluorescent Rotary Switches: Four- vs Three-Substituted Phthalimide Boron Difluoride Schiff Base Complexes.

The influence of the substitution pattern in phthalimide boron difluoride Schiff base complexes as fluorescent molecular rotors has been investigated. Due to their ground-state zwitterionic structures, they have exhibited negative solvatochromism in absorption and blue-green emission with moderate to satisfactory photoluminescence quantum yields in solution. Ground-state and excited-state theoretical calculations and time-resolved emission spectroscopy revealed that the excited-state rotation is triggered by planar-induced charge transfer, resulting in switched emission toward the green region. Fluorescence lifetime measurements and species-associated emission spectra exhibited two emitting excited species in equilibrium via a planar transition-state barrier. The substitution pattern models showed different behavior in solid-state mechanochromic switching and were analyzed by subcell unit packing obtained from X-ray structure data. We have attempted to gain in-depth insight into the fluorescence mechanism and photoluminescence properties associated with the substitution pattern of the phthalimide motif in order to understand the structure-property-function relationship.

Facile Preparation of L-Iduronic Acid and α-L-Iduronidation Using Methyl 1,2,3,4-Tetra-O-acetyl-α-L-iduronate as Glycosyl Donor.

Methyl 1,2,3,4-tetra-O-acetyl-α-L-iduronate was prepared from methyl 1,2,3,4-tetra-O-ß-D-glucuronate in two steps: Ferrier's photobromination and subsequent radical reduction with tris(trimethylsilyl)silane. The obtained methyl 1,2,3,4-tetra-O-acetyl-α-L-iduronate was a good glycosyl donor for the L-iduronidation when bis(trifluoromethanesulfonic)imide was employed as the activator. The reaction afforded the α-isomer as the major product, the configuration of which is the same as that of the L-iduronic acid unit in heparin and heparan sulfate.

Multiple cavitary lung lesions from colorectal cancer responding to chemotherapy.

Lung metastasis is an uncommon cause of multiple cavitary lung lesions. Herein, we report a case of multiple cavitary lung lesions of colorectal cancer that responded to chemotherapy. An 81-year-old woman was referred to our hospital for abdominal pain. Computed tomography revealed multiple cavitary lung lesions. The patient was diagnosed with lung metastases from colorectal cancer with a lower gastrointestinal endoscopy and bronchoscopy. Following chemotherapy, the cavitary lung lesions shrank. Lung metastases from colorectal cancer may appear as multiple cavitary lung lesions, which may be misdiagnosed as infections. Clinicians should consider lung metastases when multiple cavitary lung lesions are detected.

Simultaneous determination of deuterium-labeled ergosterol and brassicasterol in stroke-prone spontaneously hypertensive rats by ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry.

A previous study has shown that brassicasterol-d1 was detected in the serum of stroke-prone spontaneously hypertensive rats after oral administration of ergosterol-d1. To quantitatively evaluate the serum concentration of brassicasterol-d1, an ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for the simultaneous determination of picolinyl ester-derivatized ergosterol-d1 and brassicasterol-d1. The separation was performed on an ODS column (Waters Acquity UPLC BEH C18) with a mobile phase consisting of methanol and water containing 0.1% acetic acid (95/5, v/v). Linear calibration curves in the presence of the serum were obtained in a concentration range of 0.04-8 µg mL-1. Recovery rates of 95.6-119% were obtained with an RSD (n = 6) of less than 7.5%. The method was applied to the determination of time-concentration curves of ergosterol-d1 and brassicasterol-d1 in stroke-prone spontaneously hypertensive rats, showing a pharmacokinetic profile of ergosterol-d1 where the peak serum concentration of brassicasterol-d1 was 3-fold higher than that of ergosterol-d1.

Synthesis of Chiral α-Substituted ß-Aminophosphine Derivatives through Asymmetric Hydrophosphinylation Utilizing Secondary Phosphine Sulfides.

The organocatalytic enantioselective hydrophosphinylation of various secondary phosphine sulfides with aromatic and aliphatic nitroalkenes is presented in this study. The reaction produced chiral ß-nitrophosphine sulfides with excellent yields and enantioselectivities (up to 99% yield and 99% ee). Furthermore, the chiral ß-nitrophosphine sulfides can be easily converted into α-substituted ß-aminophosphine, which is a family of useful P, N-ligands and phosphine catalysts.

A Facile α-Glucuronidation Using Methyl 1,2,3,4-Tetra-O-acetyl-D-glucuronate as Glycosyl Donor.

Some terpenyl 2,3,4-tri-O-acetyl-α-D-glucuronide methyl esters were facilely synthesized from commercially available methyl 1,2,3,4-tetra-O-acetyl-ß-D-glucuronate and terpenoid alcohols in the presence of bis(trifluoromethanesulfonyl)imide (Tf2NH) in dichloromethane (DCM) in good yields. The predominant α-selectivity at the anomer position is caused via transition state in which the neighboring group participation of the methoxycarbonyl group at C-6 stabilizes the oxonium intermediate by forming 1C4 conformation. The intermediate accelerates the glucuronidation reaction despite the use of the acetyl group, which is not a good activating group in general glycosylation reactions, as the activating group.

Solvent-Triggered Long-Range Proton Transport in 7-Hydroxyquinoline Using a Sulfonamide Transporter Group.

The ability of long-range proton transport by substitution of 7-hydroxyquinoline at the eighth position with sulfonamide and sulfonylhydrazone rotor units to act as a crane-arm has been studied. Different proton transport pathways triggered by different stimuli have been established depending on the structure of the crane-arms. Solvent-driven proton switching from OH to the quinoline nitrogen (Nquin) site, facilitated by a sulfonamide transporter group in polar protic and aprotic solvents, has been confirmed by optical (absorption and fluorescence) and NMR spectroscopies as well as by single-crystal X-ray structure analysis. Photoinduced long-range proton transport to the Nquin site upon 340 nm UV light irradiation has been estimated in sulfonylhydrazone, which is not sensitive to solvent-driven switching. Both compounds have exhibited acid-triggered switching by trifluoroacetic acid due to the formation of a stable six-membered intramolecular hydrogen bonding interaction between the protonated Nquin and crane-arm. The structures of acid-switched form were confirmed by NMR spectroscopy and single-crystal X-ray structure analysis. The behavior of the compounds suggests a big step forward in the advanced proton pump-switching architecture because they cover three distinct driving forces in the switching process: solvent, light, and acid.

Asymmetric Henry Reaction of Trifluoromethyl Enones with Nitromethane Using a N,N-Dibenzyl Diaminomethylenemalononitrile Organocatalyst.

A novel N,N-dibenzyl diaminomethylenemalononitrile organocatalyst efficiently promoted asymmetric Henry reactions of trifluoromethyl enones with nitromethane, affording corresponding highly functionalized products in high yields with excellent enantioselectivities (up to 90% ee). This study is the first to report the successful example of the asymmetric 1,2-additions of nitromethane to trifluoromethyl enones.

Diaminomethylenemalononitrile as a Chiral Single Hydrogen Bond Catalyst: Application to Enantioselective Conjugate Addition of α-Branched Aldehydes.

An improved diaminomethylenemalononitrile organocatalyst, bearing a N,N-disubstituted structure, promoted enantioselective conjugate addition reaction of α-branched aldehydes with vinyl sulfone, affording adducts with excellent enantioselectivities (up to 96% ee). Mechanistic studies revealed that the diaminomethylenemalononitrile motif holds the vinyl sulfone substrate using a single hydrogen bond accompanied by multiple weak interactions, including electrostatic C-H⋅⋅⋅O interactions.

Acylhydrazone Subunits as a Proton Cargo Delivery System in 7-Hydroxyquinoline.

The reimagined concept of long-range tautomeric proton transfer using crane subunits is shown by designing and synthesising two new acylhydrazones containing a 7-hydroxyquinoline (7-OHQ) platform. The acylhydrazone subunits attached to the 7-OHQ at the 8th position act as crane arms for delivering proton cargo to the quinoline nitrogen. Light-induced tautomerization to their keto forms leads to Z/E isomerization of the C=C axle bond, followed by proton delivery to the quinoline nitrogen by the formation of covalent or hydrogen bonds. The axle's being either an imine or ketimine bond is the structural difference between the studied compounds. The -CH3 group in the latter provides steric strain, resulting in different proton transport pathways. Both compounds show long thermal stability in the switched state, which creates a tuneable action of bidirectional proton cargo transport by using different wavelengths of irradiation. Upon the addition of acid, the quinoline nitrogen is protonated; this results in E/Z configuration switching of the acylhydrazone subunits. This was proven by single-crystal X-ray structure analysis and NMR spectroscopy.

Alpha-dystroglycan binding peptide A2G80-modified stealth liposomes as a muscle-targeting carrier for Duchenne muscular dystrophy.

Safe and efficient gene therapy for the treatment of Duchenne muscular dystrophy (DMD), a genetic disorder, is required. For this, the muscle-targeting delivery system of genes and nucleic acids is ideal. In this study, we focused on the A2G80 peptide, which has an affinity for α-dystroglycan expressed on muscle cell membranes, as a muscle targeted nanocarrier for DMD and developed A2G80-modified liposomes. We also prepared A2G80-modified liposomes coated with long- and short-chain PEG, called A2G80-LSP-Lip, to improve the blood circulation of liposomes using microfluidics. The liposomes had a particle size of approximately 80 nm. A2G80-LSP-Lip showed an affinity for the muscle tissue section of mice by overlay assay. When the liposomes were administered to DMD model mice (mdx mice) via the tail vein, A2G80-LSP-Lip accumulated efficiently in muscle tissue compared to control liposomes. These results suggest that A2G80-LSP-Lip can function as a muscle-targeting liposome for DMD via systemic administration, and may be a useful tool for DMD treatment.

Asymmetric Direct Vinylogous Conjugate Addition of Substituted Furanone Derivatives to Benzoyl Acrylonitrile: Stereoselective Synthesis Toward Bicyclic γ-Lactams.

A diaminomethylenemalononitrile organocatalyst efficiently promotes the asymmetric direct vinylogous conjugate additions of α-angelica lactones to benzoyl acrylonitrile derivatives, resulting in the corresponding addition products bearing vicinal tertiary and quaternary stereogenic centers with excellent enantioselectivities (up to 99% ee). This report is the first successful example of the asymmetric conjugate additions of α-angelica lactone to benzoyl acrylonitriles. The chiral γ,γ-disubstituted γ-butenolides obtained can be readily transformed to the bicyclic γ-lactam derivative as a valuable synthetic intermediate.

Asymmetric Conjugate Addition of Phosphonates to Enones Using Cinchona-Diaminomethylenemalononitrile Organocatalysts.

Asymmetric conjugate additions of phosphonates to trans-crotonophenone and chalcone derivatives using a diaminomethylenemalononitrile organocatalyst resulted in the generation of the corresponding chiral γ-ketophosphonates in high yields with excellent enantioselectivities (up to 95% ee). This report is the first successful example of asymmetric 1,4-additions of phosphonate to α,ß-unsaturated ketones using an organocatalyst.

Synthesis of Chiral γ,γ-Disubstituted γ-Butenolides via Direct Vinylogous Aldol Reaction of Substituted Furanone Derivatives with Aldehydes.

An organocatalyzed method for synthesizing chiral γ,γ-disubstituted γ-butenolides via direct vinylogous aldol reactions of γ-substituted ß,γ-butenolides with aldehydes is reported. This reaction is catalyzed by a squaramide-sulfonamide organocatalyst to afford a range of anti-aldol adducts possessing vicinal quaternary and tertiary stereocenters with high to excellent enantioselectivities (reaching 95% ee). This is the first report of a successful stereoselective direct vinylogous aldol reaction of aldehydes with γ-substituted ß,γ-butenolides.

Cinchona-Diaminomethylenemalononitrile Organocatalyst for the Highly Enantioselective Hydrophosphonylation of Ketones and Enones.

The use of diaminomethylenemalononitrile (DMM) organocatalyst to promote the challenging 1,2-hydrophosphonylation of simple ketones and enones, which are also called α,ß-unsaturated ketones, is proposed and validated. This reaction provided the corresponding chiral α-hydroxy phosphonates in high to excellent yields and with enantioselectivity up to 96% ee.

Stereoselective conjugate addition of ketones to alkylidene malonates using thiourea-sulfonamide organocatalyst.

In this study, stereoselective conjugate addition of ketones to alkylidene malonates using organocatalyst has been developed. The reaction in the presence of 20 mol% of a novel thiourea-sulfonamide organocatalyst afforded conjugate adducts in moderate to high yields (up to 81%) under mild reaction conditions. Excellent diastereoselectivity (up to 98:2 dr) and enantioselectivity (up to 88% ee) were achieved.