Isomerization of E-Cinnamamides into Z-Cinnamamides Using a Recycling Photoreactor.

The photocatalytic synthesis of thermodynamically less-stable Z-alkenes has received considerable research attention in recent years. In this study, a recycling photoreactor was applied to the photoisomerization of E-alkenes (cinnamamide and Weinreb amide derivatives) to produce Z-alkenes. The closed-loop recycling system comprises an immobilized photosensitizer to achieve rapid photoisomerization and a high-performance liquid chromatography instrument for separation of the Z/E diastereomers. After 4-10 cycles, the desired pure Z-alkenes were obtained efficiently. In the photoreactor system, a photosensitizer (thioxanthone) was covalently immobilized on silica gel via amide bonding, which led to an enhanced photocatalytic activity compared to the parent thioxanthone. This recycling photoreactor shows promise as an alternative system for the production of Z-alkenes.

Conversion of Racemic Alkyl Aryl Sulfoxides into Pure Enantiomers Using a Recycle Photoreactor: Tandem Use of Chromatography on Chiral Support and Photoracemization on Solid Support.

Chiral sulfoxides are valuable in the fields of medicinal chemistry and organic synthesis. A recycle photoreactor utilizing the concept of deracemization, where a racemate is converted into a pure enantiomer, is developed and successfully applied in the syntheses of chiral alkyl aryl sulfoxides. The recycling system consists of rapid photoracemization using an immobilized photosensitizer and separation of the enantiomers via chiral high-performance liquid chromatography, and the desired pure chiral sulfoxides are obtained after 4-6 cycles. The key to the success of the system is the photoreactor site, wherein the photosensitizer 2,4,6-triphenylpyrylium is immobilized on the resin and irradiated (405 nm) to enable the rapid photoracemizations of the sulfoxides. As the green recycle photoreactor requires no chiral components, it should be a useful alternative system for application in producing chiral compounds.

Synthesis and structure-activity relationships of 2-acylamino-4,6-diphenylpyridine derivatives as novel antagonists of GPR54.

GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor has an essential role to modulate sex-hormones including GnRH. Though antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis, small molecule GPR54 antagonists have not been reported. We have synthesized a series of 2-acylamino-4,6-diphenylpyridines to identify potent GPR54 antagonists. Detailed structure-activity relationship studies led to compound 9l with an IC(50) value of 3.7nM in a GPR54 binding assay, and apparent antagonistic activity in a cellular functional assay.

Optical study on electronic transport properties of single-walled carbon nanotubes at high temperature.

The transport properties of single-walled carbon nanotubes (SWNTs) above room temperature are studied in this work. The infrared optical properties of SWNTs were investigated to clarify their conduction mechanism at high temperature. We present reflectivity spectra of SWNT mats in the infrared region between 0.08 eV and 0.8 eV under Ar gas flow at temperatures between 330 K and 840 K. These spectra have the typical appearance of the metallic reflectivity. Examination within the framework of the Drude-Lorentz model was performed to work out the electric resistivity for each reflectivity spectrum. It was found that the resistivity of SWNTs increases superlinearly with increasing the temperature from 330 K to 690 K, which can be explained by the quasi-1D metallic term model very well. However, the resistivity at higher temperatures than 690 K exhibited the tendency of saturation and deviated from the quasi-1D metallic term model. This behavior could be attributed to the thermal excitation of free carriers in the semiconducting SWNTs included in the mats.

Further development of a robust workup process for solution-phase high-throughput library synthesis to address environmental and sample tracking issues.

During further improvement of a high-throughput, solution-phase synthesis system, new workup tools and apparatus for parallel liquid-liquid extraction and evaporation have been developed. A combination of in-house design and collaboration with external manufacturers has been used to address (1) environmental issues concerning solvent emissions and (2) sample tracking errors arising from manual intervention. A parallel liquid-liquid extraction unit, containing miniature high-speed magnetic stirrers for efficient mixing of organic and aqueous phases, has been developed for use on a multichannel liquid handler. Separation of the phases is achieved by dispensing them into a newly patented filter tube containing a vertical hydrophobic porous membrane, which allows only the organic phase to pass into collection vials positioned below. The vertical positioning of the membrane overcomes the hitherto dependence on the use of heavier-than-water, bottom-phase, organic solvents such as dichloromethane, which are restricted due to environmental concerns. Both small (6-mL) and large (60-mL) filter tubes were developed for parallel phase separation in library and template synthesis, respectively. In addition, an apparatus for parallel solvent evaporation was developed to (1) remove solvent from the above samples with highly efficient recovery and (2) avoid the movement of individual samples between their collection on a liquid handler and registration to prevent sample identification errors. The apparatus uses a diaphragm pump to achieve a dynamic circulating closed system with a heating block for the rack of 96 sample vials and an efficient condenser to trap the solvents. Solvent recovery is typically >98%, and convenient operation and monitoring has made the apparatus the first choice for removal of volatile solvents.

TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties.

Crystalline 1 (TAK-599) is a novel N-phosphono prodrug of anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporin 2a (T-91825) that has high affinity for penicillin-binding protein (PBP) 2' (IC(50); 0.90 microg/mL) and shows potent in vitro anti-MRSA activity (MIC against MRSA N133; 1.56 microg/mL), comparable to that of vancomycin (1.56 microg/mL). Although 2a had insufficient water solubility (2.3 mg/mL) for parenteral administration, 1 showed excellent water solubility (>100 mg/mL, pH 7) as well as good chemical stability in the solid state and solution. In pharmacokinetic studies, when 1 was administered intravenously to rats and monkeys, it was rapidly converted into 2a in the blood. These results show that 1 (TAK-599) is a highly promising parenteral cephalosporin targeted for MRSA infection.