Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.

Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis.

Rh(I)-catalyzed direct arylation of azines.

The Rh(I)-catalyzed direct arylation of azines has been developed. Quinolines and 2-substituted pyridines couple with aryl bromides to efficiently afford ortho-arylated azine products using the commercially available and air-stable catalyst [RhCl(CO)2]2. Electron-deficient and electron-rich aromatic bromides couple in good yields, and hydroxyl, chloro, fluoro, trifluoromethyl, ether, and ketone functionalities are compatible with the reaction conditions.

Why are a(3) ions rarely observed?

It has been determined experimentally that a(3) ions are generally not observed in the tandem mass spectroscopic (MS/MS) spectra of b(3) ions. This is in contrast to other b(n) ions, which often have the corresponding a(n) ion as the base peak in their MS/MS spectra. Although this might suggest a different structure for b(3) ions compared to that of other b(n) ions, theoretical calculations indicate the conventional oxazolone structure to be the lowest energy structure for the b(3) ion of AAAAR, as it is for other b(n) ions of this peptide.

Rh(I)-catalyzed direct arylation of pyridines and quinolines.

A Rh(I)-catalyzed direct arylation of pyridine and quinoline heterocycles has been developed. The method provides rapid entry into an important class of substituted heterocycles employing inexpensive and readily available starting materials.

Rh(I)-catalyzed arylation of heterocycles via C-H bond activation: expanded scope through mechanistic insight.

A practical, functional group tolerant method for the Rh-catalyzed direct arylation of a variety of pharmaceutically important azoles with aryl bromides is described. Many of the successful azole and aryl bromide coupling partners are not compatible with methods for the direct arylation of heterocycles using Pd(0) or Cu(I) catalysts. The readily prepared, low molecular weight ligand, Z-1-tert-butyl-2,3,6,7-tetrahydrophosphepine, which coordinates to Rh in a bidentate P-olefin fashion to provide a highly active yet thermally stable arylation catalyst, is essential to the success of this method.

Copper-catalyzed electrophilic amination of organozinc nucleophiles: documentation of O-benzoyl hydroxylamines as broadly useful R2N(+) and RHN(+) synthons.

[reaction: see text] This paper details new copper-catalyzed electrophilic amination reactions of diorganozinc reagents using O-benzoyl hydroxylamines as electrophilic nitrogen sources that may be accessed in one step. Simple and functionalized aryl, heteroaryl-, benzyl, n-alkyl, sec-alkyl, and tert-alkyl nucleophiles couple with R2NOC(O)Ph and RHNOC(O)Ph reagents in the presence of catalytic quantities of copper salts to provide tertiary and secondary amines, respectively, in generally good yields. In many cases, the product may be isolated analytically pure after a simple extractive workup.

Copper-catalyzed electrophilic amination of functionalized diarylzinc reagents.

The copper-catalyzed electrophilic amination of functionalized diarylzinc reagents with O-acyl hydroxylamines allows for the preparation of functionalized tertiary arylamines in high yields, and is noteworthy for the mild reaction conditions employed. The functionalized diarylzinc reagents were prepared via an iodine/magnesium exchange of the corresponding aryl iodide followed by transmetalation of the resultant Grignard species with ZnCl(2).

Copper-catalyzed electrophilic amination of diorganozinc reagents.

The copper-catalyzed electrophilic amination of diorganozinc reagents employing O-acyl N,N-dialkyl hydroxylamine derivatives as aminating agents is described. This reaction offers a general method for the preparation of tertiary amines in high yields and is noteworthy for its convenience both in terms of reaction conditions employed (room temperature, View Article and Find Full Text PDF