The rate and enantioselectivity of chiral NHC-catalyzed asymmetric acylation of alcohols with an adjacent H-bond donor functionality are remarkably enhanced in the presence of a carboxylate cocatalyst. The degree of the enhancement is correlated with the basicity of the carboxylate. With a cocatalyst and a newly developed electron-deficient chiral NHC, kinetic resolution and desymmetrization of cyclic diols and amino alcohols were achieved with extremely high selectivity (up to s = 218 and 99% ee, respectively) at a low catalyst loading (0.5 mol %). This asymmetric acylation is characterized by a unique preference for alcohols over amines, which are not converted into amides under the reaction conditions.

Purpose The clinical features of patients with advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) have not fully been elucidated. This study aimed to investigate the clinical features of these patients, particularly with idiopathic pulmonary fibrosis (IPF).Methods Data on 218 patients with pathologically confirmed diagnoses of NSCLC who had been treated with chemotherapy and/or molecular targeted therapy were retrospectively analyzed for progression-free survival (PFS), overall survival (OS), responses to first-line therapy, and incidence of acute exacerbations (AEs).ResultsFifty-three of the 218 patients were diagnosed with ILD, and 34 of them with IPF. The frequency of epidermal growth factor receptor (EGFR) mutation was significantly lower in ILD and IPF patients than in non-ILD patients (2 or 0 vs. 32 %, respectively). Median PFS and OS were significantly shorter in both ILD and IPF patients than in non-ILD patients (118, 92, and 196 days for PFS, and 267, 223, and 539 days for OS, respectively). Multivariate analysis showed that poor performance status, absence of EGFR mutation, and presence of IPF were poor prognostic factors for PFS and OS. Disease control rate (DCR) was significantly lower in ILD and IPF patients than in non-ILD patients regardless of the presence of EGFR mutation (67 or 53 vs. 85 %, respectively). The incidence of AEs of ILD was significantly higher during chemotherapy with docetaxel-containing regimens (seven of 38; 18.4 %).ConclusionsBoth IPF and ILD were associated with lower EGFR positivity, lower DCR, and shorter PFS and OS in advanced NSCLC patients.

We report asymmetric dearomatization of phenols using Ag carbenoids from α-diazoacetamides. The Ag catalyst promoted intramolecular dearomatization of phenols, whereas a Rh or Cu catalyst caused C-H insertion and a Büchner reaction. Studies indicated Ag carbenoids have a carbocation-like character, making their behavior and properties unique. Highly enantioselective transformations using Ag carbenoids have not been reported. We achieved a Ag carbenoid-mediated chemo- and highly enantioselective phenol dearomatization with substrate generality for the first time.

Background: Oral administration of tolvaptan, a vasopressin V2 receptor antagonist, significantly reduces deterioration of renal function, which has recently been highlighted as an exacerbating factor for adverse events in patients with acute heart failure. In the present study we tested the hypothesis that concomitant administration of tolvaptan with a conventional diuretic is beneficial for perioperative body fluid management in patients who have undergone cardiac surgery. Methods and Results:In all, 280 patients who underwent cardiac surgery were prospectively randomized to concomitant treatment with tolvaptan and a conventional diuretic (tolvaptan group; 147 patients) or treatment with a conventional diuretic alone (control group; 133 patients). Groups were compared in terms of the time required to restore preoperative body weight and the incidence of worsening renal function (WRF), defined as an increase in the serum creatinine level ≥0.3 mg/dL. The time required to restore preoperative body weight was significantly shorter in the tolvaptan than control group (mean [±SD] 3.97±1.95 vs. 5.02±2.83 days, respectively; P<0.001). The incidence of WRF was significantly lower in the tolvaptan than control group (n=11 [7.5%] vs. n=25 [18.8%], respectively; P=0.011). Conclusions:Administration of tolvaptan with conventional diuretics in the early postoperative period after cardiac surgery could be beneficial in maintaining urine output without affecting renal function and may thus help avoid WRF.

Adipose stem cells (ASCs) are a source of regenerative cells available for autologous transplantation to hearts. We compared protective actions of ASC sheets on rat myocardial infarction (MI) in comparison with those of skeletal myoblast cell sheets. Their effects on infarcted hearts were evaluated by biological, histochemical as well as physiological analyses. ASC sheets secreted higher concentrations of angiogenic factors (HGF, VEGF, and bFGF; P < 0.05) under normoxic and hypoxic conditions than those of myoblast cell sheets, associated with reduction of cell apoptosis (P < 0.05). Like myoblast cell sheets, ASC sheets improved cardiac function (P < 0.05) and decreased the plasma level of ANP (P < 0.05) in MI hearts. ASC sheets restored cardiac remodeling characterized by fibrosis, cardiac hypertrophy and impaired angiogenesis (P < 0.05), which was associated with increases in angiogenic factors (P < 0.05). In isolated perfused rat hearts, ASC sheets improved both systolic and diastolic functions, which was comparable to cardiac functions of myoblast cell sheets, while both cell sheets failed to restore cardiac contractile response to either isoproterenol, pimobendan or dibutyryl cAMP. These results indicated that ASC sheets improved cardiac function and remodeling of MI hearts mediated by their paracrine action and this improvement was comparable to those by myoblast cell sheets.

An asymmetric dearomatization of indoles bearing α-diazoacetamide functionalities was developed for synthesizing high-value spiro scaffolds. A silver phosphate chemoselectively catalyzed the sterically challenging dearomatization, whereas more typically used metal catalysts for carbene transfer reactions, such as a rhodium complex, were not effective and instead resulted in a Büchner ring expansion or cyclopropanation. Mechanistic studies indicated that the spirocyclization occurred through a silver-assisted asynchronous concerted process and not via a silver–carbene intermediate. Analyses based on natural bond orbital population and a distortion/interaction model indicated that the degree of C–Ag mutual interaction is crucial for achieving a high level of enantiocontrol. In addition, an oxidative disconnection of a C­(sp3)–C­(sp2) bond in the product provided unconventional access to the corresponding chiral spirooxindole.

Arene dearomatization is a straightforward method for converting an aromatic feedstock into functionalized carbocycles. Enantioselective dearomatizations of chemically inert arenes, however, are quite limited and underexplored relative to those of phenols and indoles. We developed a method for diazo-free generation of silver-carbene species from an ynamide and applied it to the dearomatization of nonactivated arenes. Transiently generated norcaradiene could be trapped by intermolecular [4 + 2] cycloaddition, synthesizing polycycles with five consecutive stereogenic centers. This protocol constitutes the first highly enantioselective reaction based on the diazo-free generation of silver-carbene species. Mechanistic investigations revealed a dearomatization followed by two different classes of pericyclic reactions, as well as the origin of the chemo- and enantioselectivity.

Säure statt Base: Die kinetische Racematspaltung von sekundären Alkoholen durch Acylierung wurde nicht wie üblich unter basischen Bedingungen, sondern mithilfe eines chiralen Brønsted‐Säure‐Katalysators erzielt. Eine Bandbreite von funktionellen Gruppen wie Aldehyde, Carbonsäuren und Enoate wird toleriert. Der Selektivitätsfaktor (s) beträgt bis zu 215 bei Umgebungstemperatur.