Rh-Catalyzed Carbonylative Cyclization of Propargylic Alcohols with Aryl Boronic Acids.

2(3H)-Furanones are tremendously important not only because of their wide occurrence in bioactive compounds but also due to their versatility in organic synthesis. Here, a straightforward approach to 2(3H)-furanones from readily available tertiary propargylic alcohols with arylboronic acids in the presence of CO using rhodium as a catalyst has been established. The method exhibits a broad substrate scope tolerating useful functional groups with a moderate to high stereoselectivity.

Modular and diverse synthesis of amino acids via asymmetric decarboxylative protonation of aminomalonic acids.

Stereoselective protonation is a challenge in asymmetric catalysis. The small size and high rate of transfer of protons mean that face-selective delivery to planar intermediates is hard to control, but it can unlock previously obscure asymmetric transformations. Particularly, when coupled with a preceding decarboxylation, enantioselective protonation can convert the abundant acid feedstocks into structurally diverse chiral molecules. Here an anchoring group strategy is demonstrated as a potential alternative and supplement to the conventional structural modification of catalysts by creating additional catalyst-substrate interactions. We show that a tailored benzamide group in aminomalonic acids can help build a coordinated network of non-covalent interactions, including hydrogen bonds, π-π interactions and dispersion forces, with a chiral acid catalyst. This allows enantioselective decarboxylative protonation to give α-amino acids. The malonate-based synthesis introduces side chains via a facile substitution of aminomalonic esters and thus can access structurally and functionally diverse amino acids.

Stereoselectivity control in Rh-catalyzed ß-OH elimination for chiral allene formation.

Stereoselectivity control and understanding in the metal-catalyzed reactions are fundamental issues in catalysis. Here we report sterically controlled rhodium-catalyzed SN2'-type substitution reactions of optically active tertiary propargylic alcohols with arylmetallic species affording the non-readily available enantioenriched tetrasubstituted allenes via either exclusive syn- or anti-ß-OH elimination, respectively, under two sets of different reaction parameters. Detailed mechanistic experiments and density functional theory (DFT) studies reveal that the exclusive anti-Rh(I)-OH elimination is dictated by the simultaneous aid of in situ generated boric acid and ambient water, which act as the shuttle in the hydroxy relay to facilitate the Rh(I)-OH elimination process via a unique ten-membered cyclic transition state (anti-TS2_u). By contrast, the syn-Rh(III)-OH elimination in C-H bond activation-based allenylation reaction is controlled by a four-membered cyclic transition state (syn-TS3) due to the steric surroundings around the Rh(III) center preventing the approach of the other assisting molecules. Under the guidance of these mechanistic understandings, a stereodivergent protocol to construct the enantiomer of optically active tetrasubstituted allenes from the same starting materials is successfully developed.

Ti-Catalyzed Diastereoselective Cyclopropanation of Carboxylic Derivatives with Terminal Olefins.

Cyclopropanols and cyclopropylamines not only serve as important structural motifs in medicinal chemistry but also show diverse reactivities in organic synthesis. Owing to the high ring strain energy, the development of a general protocol from stable and readily available starting materials to afford these cyclopropyl derivatives remains a compelling challenge. Herein, we describe that a Ti-based catalyst can effectively promote the diastereoselective syntheses of cyclopropanols and cyclopropylamines from widely accessible carboxylic derivatives (acids, esters, amides) with terminal olefins. To the best of our knowledge, this method represents the first example of direct converting alkyl carboxylic acids into cyclopropanols. Distinct from conventional studies in Ti-mediated cyclopropanations with reactive alkyl Grignard reagents as nucleophiles or reductants, this protocol utilizes Mg and Me2SiCl2 to turn over the Ti catalyst. Our method exhibits broad substrate scope with good functional group compatibility and is amenable to late-stage synthetic manipulations of natural products and biologically active molecules.

Chirality memory of α-methylene-π-allyl iridium species.

Chirality is one of the most important types of steric information in nature. In addition to central chirality, axial chirality has been catching more and more attention from scientists. However, although much attention has recently been paid to the creation of axial chirality and the chirality transfer of allenes, no study has been disclosed as to the memory of such an axial chirality. The reason is very obvious: the chiral information is stored over three carbon atoms. Here, the first example of the memory of chirality (MOC) of allenes has been recorded, which was realized via an optically active alkylidene-π-allyl iridium intermediate, leading to a highly stereoselective electrophilic allenylation with amines. Specifically, we have established the transition metal-mediated highly stereoselective 2,3-allenylation of amines by using optically active 2,3-allenyl carbonates under the catalysis of a nonchiral iridium(iii) complex. This method is compatible with sterically bulky and small substituents on both amines and 2,3-allenyl carbonates and furnishes the desired optically active products with a high efficiency of chirality transfer. Further mechanistic experiments reveal that the isomerization of the optically active alkylidene-π-allyl iridium intermediate is very slow.

A palladium-catalyzed approach to allenic aromatic ethers and first total synthesis of terricollene A.

A palladium-catalyzed C-O bond formation reaction between phenols and allenylic carbonates to give 2,3-allenic aromatic ethers with decent to excellent yields under mild reaction conditions has been described. A variety of synthetically useful functional groups are tolerated and the synthetic utility of this method has been demonstrated through a series of transformations of the allene moiety. By applying this reaction as the key step, the total syntheses of naturally occurring allenic aromatic ethers, eucalyptene and terricollene A (first synthesis; 4.5 g gram scale), have been accomplished.

Pd-Catalyzed Enantioselective Syntheses of Trisubstituted Allenes via Coupling of Propargylic Benzoates with Organoboronic Acids.

Enabled by the newly developed ligand, Ming-Phos, the first example of palladium-catalyzed highly enantioselective coupling of racemic propargylic benzoates with organoboronic acids for chiral allenes synthesis has been developed. Excellent asymmetric induction has been achieved with a decent substrate scope. Synthetic potentials for the construction of polycyclic compounds with multiple chiral centers have been demonstrated.

C1qTNF-related protein-6 protects against doxorubicin-induced cardiac injury.

The clinical use of doxorubicin (DOX) is limited by its toxic effect. However, there is no specific drug that can prevent DOX-related cardiac injury. C1qTNF-related protein-6 (CTRP6) is a newly identified adiponectin paralog with many protective functions on metabolism and cardiovascular diseases. However, little is known about the effect of CTRP6 on DOX-induced cardiac injury. The present study aimed to investigate whether CTRP6 could protect against DOX-related cardiotoxicity. To induce acute cardiotoxicity, the mice were intraperitoneally injected with a single dose of DOX (15 mg/kg). Cardiomyocyte-specific CTRP6 overexpression was achieved using an adenoassociated virus system at 4 weeks before DOX injection. The data in our study demonstrated that CTRP6 messenger RNA and protein expression were decreased in DOX-treated hearts. CTRP6 attenuated cardiac atrophy induced by DOX injection and inhibited cardiac apoptosis and improved cardiac function in vivo. CTRP6 also promoted the activation of protein kinase B (AKT/PKB) signaling pathway in DOX-treated mice. CTRP6 prevented cardiomyocytes from DOX-induced apoptosis and activated the AKT pathway in vitro. CTRP6 lost its protection against DOX-induced cardiac injury in mice with AKT inhibition. In conclusion, CTRP6 protected the heart from DOX-cardiotoxicity and improves cardiac function via activation of the AKT signaling pathway.

Combined value of red blood cell distribution width and global registry of acute coronary events risk score on predicting long-term major adverse cardiac events in STEMI patients undergoing primary PCI.

The combined value of RDW and GRACE risk score for cardiovascular prognosis in ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) has not been fully investigated. This study was designed to explore the combined value of RDW and GRACE risk score on predicting long-term major adverse cardiac event (Mace) in STEMI patients undergoing primary PCI. This study included 390 STEMI patients. The primary endpoint at the (33.5 ± 7.1) months follow-up was composed of cardiac death and nonfatal myocardial infarction. The relationship between clinical parameters and clinical outcomes was evaluated using Cox regression model and receiver operating characteristic (ROC) analysis. Mace occurred in 126 (32.3%) patients including 54 (13.8%) cardiac deaths and 72 (18.5%) nonfatal myocardial infarctions. Patients in Mace group had significantly higher RDW and GRACE score than the patients in non-Mace group. According to the Cox model, RDW and GRACE score were the most important independent predictors of Mace and cardiac death. The best cut-off value for RDW to predict the occurrence of primary events was 13.25% (AUC = 0.694, 95% CI:0.639-0.750, P < 0.001) and that for GRACE score was 119.5 (AUC = 0.721, 95% CI:0.666-0.777, P < 0.001). The combination of RDW and GRACE score were more valuable (AUC = 0.775, 95% CI: 0.727-0.824, P < 0.001). Kaplan-Meier analysis provided significant prognostic information with the highest risk for cardiac death (Log-Rank χ2 = 24.684, P < 0.001) in group with both high RDW (> 13.25%) and high GRACE score (> 119.5). The combination of RDW level and GRACE score may be valuable and simple independent predictors of Mace and cardiac death in STEMI patients undergoing primary PCI. They may be useful tools for risk stratification and may indicate long-term clinical outcomes.

Rhodium-Catalyzed Regio- and Stereoselective [2 + 2] Cycloaddition of Allenamides.

A highly regio- and stereoselective Rh-catalyzed intermolecular head-to-head [2 + 2] cycloaddition of allenamides was developed. The intermolecular cycloadducts, trans-dimethylenecyclobutane-1,2-diamine derivatives, were achieved in good yields with high regioselectivity and stereoselectivity.

The prognostic value of lymph nodes count on survival of patients with node-negative gastric cancer.

The retrieved lymph node (LN) count has been validated as a prognostic factor in various cancers. However, the interaction between LN counts and patients' prognosis in gastric cancer with negative-LN metastasis is not fully studied. Surveillance, Epidemiology, and End Results Program (SEER)-registered gastric cancer patients were used for analysis in this study. Patients operated on for gastric cancer at N0 stage between 2004 and 2012 were identified from the SEER database. The association between the LN counts and survival was assessed using the Cox proportional hazards model. Patients were stratified into 1-4, 5-13, and > 13 subgroups according to LN count cut-off values determined by X-tile program, with the 5-year cause specific survival (CSS) rate of 64.8%, 72.5%, and 79.4%, respectively. LN count was also validated as an independently prognostic factor in multivariate Cox analysis (P < 0.001). In addition, nomograms including LN counts on CSS were established according to all significant factors, and the c-index was 0.703 (95% CI: 0.672-0.734). Further study indicated that patients with no LN metastasis had a decreased risk of death for each patient with LN examined up to approximately 14 LNs. Collectively, our study firmly demonstrated that the number of the retrieved LNs count was an independent prognostic factor for gastric cancer with no LN metastasis. The higher the LN count, the better the survival would be; the best CSS was observed on the LN count more than 14.

Correlation between plasma lipoprotein-associated phospholipase A2 and peripheral arterial disease.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a recently identified and potentially useful plasma biomarker for cardiovascular diseases. However, its role in peripheral arterial disease (PAD) remains unclear. The objective of this study was to assess the independent association of Lp-PLA2 and other inflammatory markers with the reduced ankle-brachial blood pressure index (ABI), a marker of PAD. We performed a cross-sectional study in 982 individuals aged ≥40 years who were recruited from the First Affiliated Hospital of Zhengzhou University. PAD was defined as an ABI <0.9 in at least one leg. The individuals were further divided into two groups, 145 with PAD and 837 without PAD. Following adjustment for traditional cardiovascular risk factors, the odds ratios of PAD when comparing the highest to the lowest quartiles were 3.24 (95% CI, 1.68-3.94) for Lp-PLA2, 2.14 (95% CI, 1.07-3.11) for homocysteine, 1.93 (95% CI, 1.02-4.01) for fibrinogen, 2.26 (95% CI, 1.32-5.74) for apolipoprotein B and 1.3 (95% CI, 0.75-2.49) for high-sensitivity C-reactive protein (hsCRP). When Lp-PLA2 and inflammatory markers were simultaneously included in the full model, the corresponding odds ratios were 1.81 (95% CI, 1.14-3.68) for Lp-PLA2, 1.15 (95% CI, 0.49-2.69) for homocysteine, 1.21 (95% CI, 0.88-5.57) for fibrinogen, 0.98 (95% CI, 0.51-3.85) for apolipoprotein B and 1.23 (95% CI, 1.12-3.51) for hsCRP. Lp-PLA2 levels were significantly and independently associated with PAD following adjustment for other inflammatory markers. These findings reflect the potential role of circulating Lp-PLA2 as a marker of atherosclerosis.

Myeloperoxidase and risk of recurrence of atrial fibrillation after catheter ablation.

BACKGROUND: Myeloperoxidase (MPO) has been associated with the development of atrial fibrillation (AF), but its impact on the recurrence of AF after catheter ablation has not been explored. This study investigated the effect of plasma MPO on recurrence after catheter ablation of paroxysmal AF. METHODS AND RESULTS: Two hundred eighty-eight consecutive patients with paroxysmal AF and who underwent circumferential pulmonary vein isolation were prospectively enrolled. After a mean ± SD follow-up of 516 ± 204 (91-910) days, the recurrence rates were 16.9%, 25.7%, 29.7%, and 38.0% from the lowest MPO quartile to the highest MPO quartile, respectively (P = 0.023). After adjustment for age, sex, left atrial diameter, high-sensitivity C-reactive protein, and pulmonary vein isolation, there was an increased risk of recurrence in the subjects with the highest MPO quartile compared with those with the lowest quartile (hazard ratio, 3.18; 95% confidence interval, 2.12-5.23; P = 0.024). As a continuous variable, MPO was also an independent predictor of recurrence (hazard ratio, 2.12; 95% confidence interval, 1.71-3.27; P = 0.032). CONCLUSIONS: Patients with high MPO levels were at an increased risk of AF recurrence after catheter ablation.