Impact of Catalyst Deuteration on the Reactivity of Chiral Phase-Transfer Organocatalysts.

Site-specifically deuterated organocatalysts were prepared and found to show improved reactivity over the non-deuterated analogs. Two privileged C2 -symmetric chiral binaphthyl-modified tetraalkylammonium salts were selected for this study. The stability of these phase-transfer catalysts was generally improved by site-specific deuteration, though the degree of improvement was structure dependent. In particular, a large secondary kinetic isotope effect was observed for the tetradeuterated phase-transfer catalyst. The performance of these deuterated catalysts in the asymmetric catalytic alkylation of amino acid derivatives was better than that of non-deuterated analogs at low catalyst loadings. The results suggest that catalyst deuteration is a promising strategy for enhancing the stability and performance of organocatalysts.

Bazedoxifene improves renal function and increases renal phosphate excretion in patients with postmenopausal osteoporosis.

INTRODUCTION: Because aging is a predictor of renal insufficiency in the general population, renal function is a concern in postmenopausal patients undergoing treatment for osteoporosis. Although high serum phosphate concentration is a predictor of renal insufficiency, the effect of selective estrogen receptor modulator (SERM) on renal function and phosphate homeostasis remains to be established. MATERIALS AND METHODS: We administered 20 mg/day bazedoxifene to 48 postmenopausal osteoporotic women who had been taking alfacalcidol for ≥ 6 months, and assessed lumbar spine bone mineral density (LS-BMD), renal function (by calculating estimated glomerular filtration rate using serum cystatin-C levels [eGFRcys] [range 38.0-98.2 mL/min/1.73 m2]), and phosphate homeostasis. RESULTS: LS-BMD was significantly higher 6 months after the initiation of bazedoxifene administration. eGFRcys had increased by 3 months after initiation and was stable until 12 months. Serum phosphate gradually decreased after initiation, reaching statistical significance at 6 months. The changes in serum phosphate were also significant when the maximum tubular reabsorption rate of phosphate was normalized to glomerular filtration rate (TmP/GFR), indicating that bazedoxifene treatment reduces serum phosphate by increasing the urinary excretion of phosphate. The change in eGFRcys after the initiation of bazedoxifene was significantly negatively correlated with the change in serum phosphate, suggesting that a reduction in serum phosphate improves renal function. CONCLUSION: Bazedoxifene improves renal function, possibly by increasing renal phosphate excretion, in postmenopausal osteoporotic women without severe renal insufficiency.

Transcriptional Induction of Cystathionine γ-Lyase, a Reactive Sulfur-Producing Enzyme, by Copper Diethyldithiocarbamate in Cultured Vascular Endothelial Cells.

As toxic substances can enter the circulating blood and cross endothelial monolayers to reach parenchymal cells in organs, vascular endothelial cells are an important target compartment for such substances. Reactive sulfur species protect cells against oxidative stress and toxic substances, including heavy metals. Reactive sulfur species are produced by enzymes, such as cystathionine γ-lyase (CSE), cystathionine ß-synthase, 3-mercaptopyruvate sulfurtransferase, and cysteinyl-tRNA synthetase. However, little is known about the regulatory mechanisms underlying the expression of these enzymes in vascular endothelial cells. Bio-organometallics is a research field that analyzes biological systems using organic-inorganic hybrid molecules (organometallic compounds and metal coordinating compounds) as molecular probes. In the present study, we analyzed intracellular signaling pathways that mediate the expression of reactive sulfur species-producing enzymes in cultured bovine aortic endothelial cells, using copper diethyldithiocarbamate (Cu10). Cu10 selectively upregulated CSE gene expression in vascular endothelial cells independent of cell density. This transcriptional induction of endothelial CSE required both the diethyldithiocarbamate scaffold and the coordinated copper ion. Additionally, the present study revealed that ERK1/2, p38 MAPK, and hypoxia-inducible factor (HIF)-1α/HIF-1ß pathways mediate transcriptional induction of endothelial CSE by Cu10. The transcription factors NF-κB, Sp1, and ATF4 were suggested to act in constitutive CSE expression, although the possibility that they are involved in the CSE induction by Cu10 cannot be excluded. The present study used a copper complex as a molecular probe to reveal that the transcription of CSE is regulated by multiple pathways in vascular endothelial cells, including ERK1/2, p38 MAPK, and HIF-1α/HIF-1ß. Bio-organometallics appears to be an effective strategy for analyzing the functions of intracellular signaling pathways in vascular endothelial cells.

Catalytic Transfer Hydration of Cyanohydrins to α-Hydroxyamides.

We report the palladium(II)-catalyzed transfer hydration of cyanohydrins to α -hydroxyamides by using carboxamides as water donors. This method enables selective hydration of various aldehyde- and ketone-derived cyanohydrins to afford α-mono- and α,α-disubstituted-α -hydroxyamides, respectively, under mild conditions (50 °C, 10 min). The direct conversion of fenofibrate, a drug bearing a benzophenone moiety, into a functionalized α,α-diaryl-α -hydroxyamide was achieved by means of a hydrocyanation-transfer hydration sequence. Preliminary kinetic studies and the synthesis of a site-specifically 18O-labeled α -hydroxyamide demonstrated the carbonyl oxygen transfer from the carboxamide reagent into the α -hydroxyamide product.

Copper(II) Bis(diethyldithiocarbamate) Induces the Expression of Syndecan-4, a Transmembrane Heparan Sulfate Proteoglycan, via p38 MAPK Activation in Vascular Endothelial Cells.

Proteoglycans synthesized by vascular endothelial cells are important for regulating cell function and the blood coagulation-fibrinolytic system. Since we recently reported that copper(II) bis(diethyldithiocarbamate) (Cu(edtc)2) modulates the expression of some molecules involving the antioxidant and blood coagulation systems, we hypothesized that Cu(edtc)2 may regulate the expression of proteoglycans and examined this hypothesis using a bovine aortic endothelial cell culture system. The experiments showed that Cu(edtc)2 induced the expression of syndecan-4, a transmembrane heparan sulfate proteoglycan, in a dose- and time-dependent manner. This induction required the whole structure of Cu(edtc)2-the specific combination of intramolecular copper and a diethyldithiocarbamate structure-as the ligand. Additionally, the syndecan-4 induction by Cu(edtc)2 depended on the activation of p38 mitogen-activated protein kinase (MAPK) but not the Smad2/3, NF-E2-related factor2 (Nrf2), or epidermal growth factor receptor (EGFR) pathways. p38 MAPK may be a key molecule for inducing the expression of syndecan-4 in vascular endothelial cells.

Photocatalytic Transfer Hydrogenolysis of Allylic Alcohols on Pd/TiO2 : A Shortcut to (S)-(+)-Lavandulol.

We report herein a regio- and stereoselective photocatalytic hydrogenolysis of allylic alcohols to form unsaturated hydrocarbons employing a palladium(II)-loaded titanium oxide; the reaction proceeds at room temperature under light irradiation without stoichiometric generation of salt wastes. Olefin and saturated alcohol moieties tolerated the reaction conditions. Hydrogen atoms were selectively incorporated into less sterically congested carbons of the allylic functionalities. This protocol allowed a short-step synthesis of (S)-(+)-lavandulol from (R)-(-)-carvone by avoiding otherwise necessary protection/deprotection steps.

A Fluorinated Cobalt(III) Porphyrin Complex for Hydroalkoxylation of Alkynes.

A fluorinated cobalt(III) porphyrin complex [Co(TPFPP)NTf2·2C2H5OH, where TPFPP=5,10,15,20-tetrakis(pentafluorophenyl)porphyrin, Tf=CF3SO2] promotes hydroalkoxylation of alkynes to give acetals in good to excellent yields. The acetals can be directly functionalized with nucleophiles in a one-pot procedure.

Copper diethyldithiocarbamate as an activator of Nrf2 in cultured vascular endothelial cells.

The interest in organic-inorganic hybrid molecules as molecular probes for biological systems has been growing rapidly. Such hybrid molecules exhibit unique biological activities. Herein, copper(II) bis(diethyldithiocarbamate) (Cu10) was found to activate the transcription factor NF-E2-related factor 2 (Nrf2), which is responsible for regulating antioxidant and phase II xenobiotic enzymes, in vascular endothelial cells. The copper complex rapidly accumulated within cells and induced nuclear translocation of Nrf2, leading to upregulation of the expression of downstream proteins without cytotoxic effects. However, while copper bis(2-hydroxyethyl)dithiocarbamate activated Nrf2, copper ion, diethyldithiocarbamate ligand with or without zinc or iron failed to exhibit this activity. Intracellular accumulation of Cu10 was higher than that of Cu(II) and Cu(I). While the accumulation of copper(II) bis(dimethyldithiocarbamate) was reduced by small interfering RNA (siRNA)-mediated knockdown of the copper transporter CTR1, the knockdown did not affect Cu10 accumulation, indicating that Cu10 rapidly enters vascular endothelial cells via CTR1-independent mechanisms. In addition, copper and iron complexes with other ligands tested could not activate Nrf2, suggesting that the intramolecular interaction between copper and dithiocarbamate ligand is important for the activation of the transcription factor. Cu10 induced the expression of heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, and γ-glutamylcysteine synthetase, downstream proteins of Nrf2. It was suggested that Cu10-induced activation of Nrf2 was due to proteasome inhibition as well as binding to Kelch-like ECH-associated protein 1. Since the effects of Cu10 on vascular endothelial cells are unique and diverse, the copper complex may be a good molecular probe to analyze the functions of the cells.

Hydration of terminal alkynes catalyzed by water-soluble cobalt porphyrin complexes.

Water-soluble cobalt(III) porphyrin complexes were found to promote the hydration of terminal alkynes to give methyl ketones. The alkyne hydration proceeded in good to excellent yield with 0.1 to 2 mol % cobalt catalyst 1 and was compatible with the presence of acid/base- or redox-sensitive functional groups such as alkyl silyl ethers; allyl ethers; trityl ethers; benzyl ethers; carboxylic esters; boronic esters; carboxamides; nitriles; and nitro, iodo, and acetal groups. Some of the alkyne substrates tested here are otherwise difficult to hydrate. The alkyne hydration can be performed on a gram scale, and the catalyst can be recovered by aqueous workup.

Two cases of dementias with motor neuron disease evaluated by Pittsburgh compound B-positron emission tomography.

We described the cases of two patients with dementia associated with motor neuron disease, the former with frontotemporal dementia (FTD) and the latter with Alzheimer's disease (AD), studied by the Pittsburgh compound B-positron emission tomography (PIB-PET). In the FTD patient, the PIB-PET revealed no amyloid accumulation in the cortex, whilst in the AD patient showed amyloid accumulation mainly in the frontal, parietal and lateral temporal lobes, besides the posterior cingulate gyrus and the precuneus. Thus, PIB-PET might facilitate the discrimination of different proteinopathies that cause neurodegenerative diseases, as dementia associated with ALS.

Iridium-catalyzed α-selective deuteration of alcohols.

The development of chemoselective C(sp3)-H deuteration is of particular interest in synthetic chemistry. We herein report the α-selective, iridium(iii)-bipyridonate-catalyzed hydrogen(H)/deuterium(D) isotope exchange of alcohols using deuterium oxide (D2O) as the primary deuterium source. This method enables the direct, chemoselective deuteration of primary and secondary alcohols under basic or neutral conditions without being affected by coordinative functional groups such as imidazole and tetrazole. Successful substrates for deuterium labelling include the pharmaceuticals losartan potassium, rapidosept, guaifenesin, and diprophylline. The deuterated losartan potassium shows higher stability towards the metabolism by CYP2C9 than the protiated analogue. Kinetic and DFT studies indicate that the direct deuteration proceeds through dehydrogenation of alcohol to the carbonyl intermediate, conversion of [IrIII-H] to [IrIII-D] with D2O, and deuteration of the carbonyl intermediate to give the α-deuterated product.

Preparation of a platinum nanoparticle catalyst located near photocatalyst titanium oxide and its catalytic activity to convert benzyl alcohols to the corresponding ethers.

A novel platinum nanoparticle catalyst closely located near the surface of titanium oxide, PtNP/TiO2, has been prepared. This catalyst has both the properties of a photocatalyst and a metal nanoparticle catalyst, and acquired environmentally friendly catalytic activity, which cannot be achieved by just one of these catalysts, to afford ethers from benzyl alcohols under the wavelength of 420 nm.

Effects of raloxifene treatment on the structural geometry of the proximal femur in Japanese women with osteoporosis.

The purpose of this study was to clarify the effects of 2-year treatment with raloxifene on the proximal femoral geometry among Japanese patients with osteoporosis by hip structure analysis. One hundred ninety-eight community-dwelling postmenopausal women with osteoporosis were enrolled. The structural variables were areal bone mineral density (BMD), cross-sectional area (CSA), section modulus (index of resistance to bending forces), and buckling ratio (index of cortical instability). BMD, CSA, and section modulus at the narrow neck significantly increased by 1.27, 2.67, and 3.90% at 2 years, respectively. BMD, CSA, and section modulus at the intertrochanter significantly increased by 2.55, 4.49, and 6.60% at study termination, respectively. The buckling ratio at the intertrochanter decreased by 2.36% at 1 year, but differences at 2 years became non-significant. Parameters at the shaft were qualitatively similar to those of the narrow neck and intertrochanter. The percent change of the section modulus was significantly higher than that of BMD at 2 years in all three regions. The percent changes of the section modulus is strongly correlated with the percent changes of BMD and CSA, and negative correlated with the percent changes of buckling ratio in all regions. In conclusion, Japanese osteoporotic women on raloxifene therapy have significant improvements of both BMD and geometry in the proximal femur.

S(N)2' reaction of organozinc reagents activated by catalytic tBu-P4 base in the presence of LiCl.

The tBu-P4 base was found to be an excellent catalyst for the activation of organozinc reagents. The base was used to promote the S(N)2' reaction of alpha,beta-unsaturated esters bearing a gamma-chloride in the reactions with various organozinc reagents in the presence of LiCl. The reactions proceeded in high yield with excellent chemo-and regioselectivity. The role of LiCl appears to be the activation of the gamma-chloride of the alpha,beta-unsaturated esters, which was confirmed by NMR spectroscopic study.

Acceptor-Controlled Transfer Dehydration of Amides to Nitriles.

Palladium-catalyzed dehydration of primary amides to nitriles efficiently proceeds under mild, aqueous conditions via the use of dichloroacetonitrile as a water acceptor. A key to the design of this transfer dehydration catalysis is the identification of an efficient water acceptor, dichloroacetonitrile, that preferentially reacts with amides over other polar functional groups with the aid of the Pd catalyst and makes the desired scheme exergonic, thereby driving the dehydration.

Pd/TiO2-Photocatalyzed Self-Condensation of Primary Amines To Afford Secondary Amines at Ambient Temperature.

Symmetric secondary amines were synthesized by the self-condensation of primary amines over a palladium-loaded titanium dioxide (Pd/TiO2) photocatalyst. The reactions afforded a series of secondary amines in moderate to excellent isolated yields at ambient temperature (30 °C, in cyclopentyl methyl ether). Applicability for one-pot pharmaceutical synthesis was demonstrated by a photocatalytic reaction sequence of self-condensation of an amine followed by N-alkylation of the resulting secondary amine with an alcohol.

Mixed alkylamido aluminate as a kinetically controlled base.

The mechanisms by which directed ortho metalation (DoM) and postmetalation processes occur when aromatic compounds are treated with mixed alkylamido aluminate i-Bu3Al(TMP)Li (TMP-aluminate 1; TMP = 2,2,6,6-tetramethylpiperidide) have been investigated by computation and X-ray diffraction. Sequential reaction of ArC(=O)N(i-Pr)2 (Ar = phenyl, 1-naphthyl) with t-BuLi and i-Bu3Al in tetrahydrofuran affords [2-(i-Bu3Al)C(m)H(n)C(=O)N(i-Pr)2]Li x 3 THF (m = 6, n = 4, 7; m = 10, n = 6, 8). These data advance the structural evidence for ortho-aluminated functionalized aromatics and represent model intermediates in DoM chemistry. Both 7 and 8 are found to resist reaction with HTMP, suggesting that ortho-aluminated aromatics are incapable of exhibiting stepwise deprotonative reactivity of the type recently shown to pertain to the related field of ortho zincation chemistry. Density functional theory calculations corroborate this view and reveal the existence of substantial kinetic barriers both to one-step alkyl exchange and to amido-alkyl exchange after an initial amido deprotonation reaction by aluminate bases. Rationalization of this dichotomy comes from an evaluation of the inherent Lewis acidities of the Al and Zn centers. As a representative synthetic application of this high kinetic reactivity of the TMP-aluminate, the highly regioselective deprotonative functionalization of unsymmetrical ketones both under mild conditions and at elevated temperatures is also presented.

Organozinc reagents in DMSO solvent: remarkable promotion of SN2' reaction for allene synthesis.

The S N2' reaction of propragyl mesylates with organozinc reagents was dramatically improved in DMSO solvent, and the stereoselective conversion of chiral substrates was successfully achieved using LiCl-free diorganozinc without the loss of optical purity.

Activation of organozinc reagents with t-Bu-P4 base for transition metal-free catalytic SN2' reaction.

The t-Bu-P4 base was found to be an excellent catalyst for activating organozinc reagents and was used to promote the S(N)2' reaction of alpha,beta-unsaturated esters bearing a gamma-chloride using various organozinc reagents: these reactions proceeded in high yields with excellent chemo-and regioselectivity.