Rhodium(I)-Catalyzed Direct Enantioselective C-H Functionalization of Indoles.

A highly regiospecific vinylogous carbene insertion protocol for direct asymmetric C-H functionalization of indoles with arylvinyldiazoacetates has been developed. Under the catalysis of simple Rh(I)/chiral diene complexes, the reaction occurs solely at the vinylogous position of the vinylcarbenoid with exceptional E selectivity and enantiocontrol. It provides an efficient way to obtain an interesting class of chiral indole scaffolds bearing an α,ß-unsaturated ester unit and a gem-diaryl carbon stereocenter in good yields (≤99%) with excellent enantioselectivities (≤96%) at room temperature.

Rhodium(I) Carbene-Promoted Enantioselective C-H Functionalization of Simple Unprotected Indoles, Pyrroles and Heteroanalogues: New Mechanistic Insights.

A rhodium(I)-diene catalyzed highly enantioselective C(sp2 )-H functionalization of simple unprotected indoles, pyrroles, and their common analogues such as furans, thiophenes, and benzofurans with arylvinyldiazoesters has been developed for the first time. This transformation features unusual site-selectivity exclusively at the vinyl terminus of arylvinylcarbene and enables a reliable and rapid synthetic protocol to access a distinctive class of diarylmethine-bearing α,ß-unsaturated esters containing a one or two heteroarene-attached tertiary carbon stereocenter in high yields and excellent enantioselectivities under mild reaction conditions. Mechanistic studies and DFT calculations suggest that, compared to the aniline substrate, the more electron-rich indole substrate lowers the C-C addition barrier and alters the rate-determining step to the reductive elimination, leading to different isotope effect.

[Tanshinone IIa attenuates vascular calcification through inhibition of NF-κB and ß-catenin signaling pathways].

Tanshinone IIa is a key ingredient extracted from the traditional Chinese medicine Salvia miltiorrhiza (Danshen), and is widely used to treat various cardiovascular diseases. Vascular calcification is a common pathological change of cardiovascular tissues in patients with chronic kidney disease, diabetes, hypertension and atherosclerosis. However, whether Tanshinone IIa inhibits vascular calcification and the underlying mechanisms remain largely unknown. This study aims to investigate whether Tanshinone IIa can inhibit vascular calcification using high phosphate-induced vascular smooth muscle cell and aortic ring calcification model, and high dose vitamin D3 (vD3)-induced mouse models of vascular calcification. Alizarin red staining and calcium quantitative assay showed that Tanshinone IIa significantly inhibited high phosphate-induced vascular smooth muscle cell and aortic ring calcification. qPCR and Western blot showed that Tanshinone IIa attenuated the osteogenic transition of vascular smooth muscle cells. In addition, Tanshinone IIa also significantly inhibited high dose vD3-induced mouse aortic calcification and aortic osteogenic transition. Mechanistically, Tanshinone IIa inhibited the activation of NF-κB and ß-catenin signaling in normal vascular smooth muscle cells. Similar to Tanshinone IIa, inhibition of NF-κB and ß-catenin signaling using the chemical inhibitors SC75741 and LF3 attenuated high phosphate-induced vascular smooth muscle cell calcification. These results suggest that Tanshinone IIa attenuates vascular calcification at least in part through inhibition of NF-κB and ß-catenin signaling, and Tanshinone IIa may be a potential drug for the treatment of vascular calcification.

Stereodivergent Synthesis of Enantioenriched 2,3-Disubstituted Dihydrobenzofurans via a One-Pot C-H Functionalization/Oxa-Michael Addition Cascade.

A one-pot rhodium-catalyzed C-H functionalization/organocatalyzed oxa-Michael addition cascade reaction has been developed. This methodology enables the stereodivergent synthesis of diverse 2,3-disubstituted dihydrobenzofurans with broad functional group compatibility in good yields with high levels of stereoselectivity under exceptionally mild conditions. The full complement of stereoisomers of chiral 2,3-disubstituted dihydrobenzofurans and 3,4-disubstituted isochromans could be accessed at will by appropriate permutations of the two chiral catalysts. The current work provides a rare example of two chiral catalysts independently controlling two contiguous stereogenic centers subsequently via a two-step reaction in a single operation.

Regiospecific and Enantioselective Arylvinylcarbene Insertion of a C-H Bond of Aniline Derivatives Enabled by a Rh(I)-Diene Catalyst.

Asymmetric insertion of an arylvinylcarbenoid into the C-H bond for direct enantioselective C(sp2)-H functionalization of aniline derivatives catalyzed by a rhodium(I)-diene complex was developed for the first time. The reaction occurred exclusively at the uncommon vinyl terminus site with excellent E selectivity and enantioselectivities, providing various chiral γ,γ-gem-diarylsubstituted α,ß-unsaturated esters with broad functional group compatibility under simple and mild conditions. It provides a rare example of the asymmetric C-H insertion of arenes with selective vinylogous reactivity. Synthesis applications of this protocol were featured by several versatile product transformations. Systematic DFT calculations were also performed to elucidate the reaction mechanism and origin of the uncommon enantio- and regioselectivity of the Rh(I)-catalyzed C(sp2)-H functionalization reaction. The measured and computed inverse deuterium kinetic isotope effect supports the C-C bond-formation step as the rate-determining step. Attractive interactions between the chiral ligand and substrates were also proposed to control the enantioselectivity.

Enantioselective Synthesis of gem-Diaryl Benzofuran-3(2H)-ones via One-Pot Asymmetric Rhodium/Palladium Relay Catalysis.

An asymmetric dual-metal relay catalysis strategy that combines Rh/chiral sulfur-olefin-catalyzed enantioselective 1,2-addition with a Pd-catalyzed intramolecular C-O coupling has been developed. The method allows rapid and efficient synthesis of quaternary carbon-containing gem-diaryl benzofuran-3(2H)-ones in good yields in a highly enantioselective manner (up to 99% ee) through a simple one-pot cascade reaction.

Rhodium(I)-Catalyzed Highly Enantioselective Insertion of Carbenoid into Si-H: Efficient Access to Functional Chiral Silanes.

The first rhodium(I)-catalyzed enantioselective Si-H insertion reaction of α-diazoesters and α-diazophosphonates has been developed. The use of a C1-symmetric chiral diene ligand enabled the asymmetric reaction to proceed under exceptionally mild conditions and give versatile chiral α-silyl esters and phosphonates with excellent enantioselectivities (up to 99% ee). The mechanism and stereochemical pathway of this novel Rh(I)-carbene-directed Si-H insertion was investigated by deuterium kinetic isotope effect experiments and DFT calculations.

A new versatile approach to synthesise enantioenriched 3-hydroxyoxindoles, 1,3-dihydroisobenzofuran and 3-isochromanone derivatives by a rhodium-catalyzed asymmetric arylation-cyclization sequence.

A novel arylation-cyclization strategy for the highly enantioselective synthesis of titled heterocycles with a quaternary stereogenic center has been developed.

Involvement of transcription factor activator protein-2alpha in doxazosin-induced HeLa cell apoptosis.

AIM: To investigate the pro-apoptotic effects of alpha1-adrenergic inhibitor doxazosin in HeLa cells and the potential involvement of transcription factor activator protein-2alpha (AP-2alpha) in doxazosin-induced apoptosis. METHODS: The HeLa cells were exposed to various concentrations of doxazosin for 16 h. Apoptosis was detected using a DNA fragmentation assay, Hoechst 33258 staining, and flow cytometric analysis. The expression of AP-2alpha and caspase-3 was detected by relative quantitative RT-PCR and Western blot assays, respectively. After the respective transfections of the HeLa cells with AP-2alpha overexpressing constructs and an antisense oligonucleotide against AP-2alpha, apoptosis was assessed by flow cytometric analysis, and the expression of AP-2alpha and caspase-3 was detected by relative quantitative RT-PCR and Western blot assays. The colorimetric assay was performed to detect the caspase-3 activity. RESULTS: Treatment with various concentrations of doxazosin for 16 h increased the apoptotic rate and total cell death rate of the HeLa cells in a dose-dependent manner and upregulated the expression of AP-2alpha and caspase-3 in a dose-dependent manner. A dose-dependent increase was observed in the caspase-3 activity. Overexpressing AP-2alpha led to the increased rate of doxazosin-induced apoptosis and the total cell death, whereas doxazosin-induced apoptosis and the total cell death in HeLa cells decreased by antisense AP-2alpha. Furthermore, overexpressing AP-2alpha increased the expression and activity of caspase-3, whereas antisense AP-2alpha in part abolished the increased effects of doxazosin on caspase-3 expression and activity. CONCLUSION: Doxazosin induces apoptosis in HeLa cells in a dose-dependent manner, and transcription factor AP-2alpha is functionally involved in doxazosin-induced HeLa cell apoptosis.