93139-85-6

Enantioselective desymmetrization by direct monofunctionalization of prochiral diols is a powerful strategy to prepare valuable synthetic intermediates in high optical purity. Boron acids can activate diols toward nucleophilic additions; however, the design of stable chiral catalysts remains a challenge and highlights the need to identify new chemotypes for this purpose. Herein, the discovery and optimization of a bench-stable chiral 9-hydroxy-9,10-boroxarophenanthrene catalyst is described and applied in the highly enantioselective desymmetrization of 2-aryl-1,3-diols using benzylic electrophiles under operationally simple, ambient conditions. Nucleophilic activation and discrimination of the enantiotopic hydroxy groups on the diol substrate occurs via a defined chairlike six-membered anionic complex with the hemiboronic heterocycle. The optimal binaphthyl-based catalyst 1g features a large aryloxytrityl group to effectively shield one of the two prochiral hydroxy groups on the diol complex, whereas a strategically placed "methyl blocker"on the boroxarophenanthrene unit mitigates the deleterious effect of a competing conformation of the complexed diol that compromised the overall efficiency of the desymmetrization process. This methodology affords monoalkylated products in enantiomeric ratios equal or over 95:5 for a wide range of 1,3-propanediols with various 2-aryl/heteroaryl groups.

An efficient method for photocatalytic perfluoroalkylation of vinyl-substituted all-carbon quaternary centers involving 1,2-aryl migration has been developed. The rearrangement reactions use fac-Ir(ppy)3, visible light and commercially available fluoroalkyl halides and can generate valuable multisubstituted perfluoroalkylated compounds in a single step that would be challenging to prepare by other methods. Mechanistically, the photoinduced alkyl radical addition to an alkene leads to the migration of a vicinal aryl substituent from its adjacent all-carbon quaternary center with the concomitant generation of a C-radical bearing two electron-withdrawing groups that is further reduced by a hydrogen donor to complete the domino sequence.

A concise and catalyst-free aryltrifluoromethylative cyclization of unactivated alkenes has been developed herein. The use of PhICF3Cl as a powerful trifluoromethylating agent allows easy transformations. A set of trifluoroethylated carbocycles and aza-hereocycles were efficiently synthesized in good yield and selectivity. A broad substrate scope, mild reaction conditions, and easy operation would make this method well-suited for applications.

Described herein are methods of oxidative coupling of aryl boron reagents with sp3-carbon nucleophiles, and ambient decarboxylative arylation of malonate half-esters via oxidative catalysis.

Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.

A new Janus-type dianionic bis(maloNHC) (1) was synthesized and characterized by NMR spectroscopy. The utility of this extended biscarbene for the construction of homobimetallic systems has been demonstrated by its coordination to two coinage metals. The resulting zwitterionic metal complexes of the type [(Ph3P)M(1)M(PPh3)] (M = Au, Ag) have been fully characterized. The X-ray crystallography shows that the new ligand positions the two metal centers at a distance of 24.2 ?, the longest distance reported to date for any related NHC ligand.

Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study factors that control conformation. Whereas one might expect an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation similar to that in axial phenylcyclohexane, a series of studies including X-ray crystallography, NOE measurements, and DFT calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to position an ortho-hydrogen to participate in a stabilizing, nonclassical CH···O hydrogen bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of anancomeric 2-tert-butyl-5-aryl-1,3-dioxane isomers demonstrates that remote substituents on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents decrease the conformational energy of the aryl group, while electron-donating substituents increase the conformational energy of the group. This effect is correlated in a very linear way to Hammett substituent parameters. In short, the strength of the CH···O hydrogen bond may be tuned in a predictable way in response to the electron-withdrawing or electron-donating ability of substituents positioned remotely on the aryl ring. This effect may be profound: a 3,5-bis-CF3 phenyl group at C(5) in 1,3-dioxane displays a pronounced preference for the axial orientation. The results are relevant to broader conformational issues involving heterocyclic systems bearing aryl substituents.

Reported is a versatile new oxidative method for the arylation of activated methylene species. Under mild reaction conditions (RT to 40 C), Cu(OTf)2 mediates the selective coupling of functionalized aryl boron species with a variety of stabilized sp3-nucl

Reported is a versatile new oxidative method for the arylation of activated methylene species. Under mild reaction conditions (RT to 40°C), Cu(OTf)2mediates the selective coupling of functionalized aryl boron species with a variety of stabilized sp3-nucleophiles. Tertiary malonates and amido esters can be employed as substrates to generate quaternary centers. Complementing either traditional cross-coupling or SNAr protocols, the transformation is chemoselective in the presence of halogen electrophiles, including aryl bromides and iodides. Substrates bearing amide, sulfonyl, and phosphonyl groups, which are not amenable to coupling under mild Hurtley-type conditions, are suitable reaction partners.

The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.

The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.

A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof: wherein Z represents nitrogen atom, C-F or the like; R1 represents a C1-C3 alkyl group; Y represents oxygen atom or N-R7; R2, R3, R4, R5, R6 and R7 each independently represents hydrogen atom, a C1-C6 alkyl group, or a group represented by the formula (II): which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.

A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.

The present invention provides a preventive or therapeutic agent for hyperlipidemia, comprising as an active ingredient a heterocyclic compound of the formula [1], or a pharmaceutically acceptable salt thereof: R1-Het-D-E??[1] wherein: R1

The Lewis acid-promoted reactions of chiral 2-aryl-3-azido-1-propanols with 4-substituted cyclohexanones lead to iminium ethers and ultimately caprolactams (following a hydrolysis step). In this study, it is shown that these reactions afford variable ratios of products, depending on the electronic nature of the phenyl group. These results are interpreted in the context of a cation?π stabilizing effect in the product-determining reaction intermediate. Remarkably, the best selectivity was obtained when an azidopropanol reagent containing a quaternary center was used; a control experiment showed that the high selectivity observed in this result depended upon the free rotation of the pseudoaxial aromatic group in the intermediate that affords the major product. Copyright