Improved Process for the Synthesis of 3-(3-Trifluoromethylphenyl)propanal for More Sustainable Production of Cinacalcet HCl.

Cinacalcet (I), sold as hydrochloride salt, is a calcimimetic drug which has been approved for the treatment of secondary hyperparathyroidism in patients with chronic renal disease and for the treatment of hypercalcemia in patients with parathyroid carcinoma. Here, an improved method for the synthesis of 3-(3-trifluoromethylphenyl)propanal (II), a key intermediate for the preparation of I, is described. The protocol required a Mizoroki-Heck cross-coupling reaction between 1-bromo-3-(trifluoromethyl)benzene and acroleine diethyl acetal, catalyzed by Pd(OAc)2 in the presence of nBu4NOAc (tetrabutylammonium acetate), followed by the hydrogenation reaction of the crude mixture of products in a cascade process. Palladium species, at the end of the reaction, were efficiently recovered as Pd/Al2O3. The procedure was developed under conventional heating conditions as well as under microwave-assisted conditions. The obtained mixture of 1-(3,3-diethoxypropyl)-3-(trifluoromethyl)benzene (III), impure for ethyl 3-(3-trifluoromethylphenyl) propanoate (IV), was finally treated, under mild conditions, with potassium diisobutyl-tert-butoxyaluminum hydride (PDBBA) to obtain after hydrolysis 3-(3-trifluoromethylphenyl)propanal (II), in an excellent overall yield and very high purity. Microwave conditions permitted a reduction in reaction times without affecting selectivity and yield. The final API was obtained through reductive amination of (II) with (R)-(+)-1-(1-naphthyl)ethylamine (V) using a catalyst prepared by us with a very low content of precious metal.

Cascading One-Pot Synthesis of Biodegradable Uronic Acid-Based Surfactants from Oligoalginates, Semi-Refined Alginates, and Crude Brown Seaweeds.

The present article describes a one-pot and cascade mode process using biocompatible/biodegradable reagents, for simply obtaining surfactant compositions comprising mixtures of d-mannuronic acid and l-guluronic acid directly from oligoalginates or semi-refined alginates (mixtures of alginate, cellulose, hemicellulose, laminaran, and fucan). Simple treatments of partial purification of the reaction crudes (elimination of the salts and/or the residual fatty alcohols) or isolation of the surfactant compositions result in sugar-based compounds having performance levels appropriate to applications in detergency. In addition, the challenging extension of this cascading one-pot synthesis technology to crude milled brown seaweeds was successfully carried out to provide promising surface-active compositions made up of alkyl uronate and alkyl glycoside monosaccharides.

Organocatalytic Dynamic Kinetic Resolution Enabled Asymmetric Synthesis of Phosphorus-Containing Chiral Helicenes.

The catalytic asymmetric synthesis of phosphorus-containing helicenes remains a formidable challenge, presumably due to the lack of rational design of substrates, right choice of reactions together with highly effective catalysis systems. Herein, we disclosed an efficient and practical DKR-involving (dynamic kinetic resolution) cascade strategy toward synthesizing a novel family of phosphorus-installing helicenes by peptide-mimic phosphonium salt (PPS) catalysis. The sequential process of PPS-catalyzed phospha-Michael attack and copper salt-facilitated aromatization led to the formation of unprecedented phosphorus-containing oxa[5]helicene scaffolds. A wide variety of substrates bearing an assortment of functional groups were compatible with this protocol, furnishing the expected helical compounds in high yields and excellent stereoselectivities. Additionally, the helical products could be conveniently elaborated to promising phosphine ligands with perfectly retained helical chirality, which turned out to be highly efficient chiral ligands in transition metal-catalyzed reactions. These findings not only expand the current library of phosphorus-containing helicenes but also offer insights to explore other challenging scaffolds with molecular chirality.

Transformation of Pectins into Non-Ionic or Anionic Surfactants Using a One-Pot and Cascade Mode Process.

The present article describes the one-pot synthesis of double- and single-tailed surfactants by a cascade process that involves the hydrolysis/butanolysis of pectins into butyl galacturonate monosaccharides followed by transesterification/transacetalisation processes with fatty alcohols, and subsequent aqueous basic and acid treatments. The cascade mode allows the depolymerisation to proceed more efficiently, and the purification conditions are optimised to make the production of single-tailed surfactants more manufacturable. These products in a pure form or as mixtures with alkyl glycosides resulting from butanolysis and transglycosylation of pectin-derived hexoses, exhibit attractive surface-tension properties, especially for the n-oleyl ᴅ-galactosiduronic acid products. In addition, a readily biodegradability and an absence of aquatic ecotoxicity are shown for the galacturonic acid derivatives possessing an oleyl alkyl chain at the anomeric position.

One-Pot Generation of Bicyclo[3.1.0]hexanols and Cyclohexanones by Double Interrupted Nazarov Reactions.

Organoaluminum-mediated double interrupted Nazarov cyclization to access bicyclo[3.1.0]hexanols via nucleophilic methyl attack followed by Simmons-Smith-type electrophilic cyclopropanation is reported. These alcohols can undergo ring opening to afford cyclohexanones or cyclohexenones, broadening the range of scaffolds available via interrupted Nazarov reaction beyond the usual cyclopentanoid products. Throughout the sequence, a total of four new C-C bonds are formed, along with four new stereogenic centers.

Disintegration of the agricultural by-product wheat bran under subcritical conditions.

BACKGROUND: The disintegration of destarched wheat bran in water and sulfuric acid (pH 3) under subcritical conditions (275-300 °C) and at short reaction times (1-4 min) was investigated. A cascade process comprising a stepwise separation of the liquid was applied to reduce the formation of undesired degradation products. RESULTS: The highest degree of biomass disintegration (67% dry mass solubilization) was achieved by application of a cascade process at 275 °C (pH 3). Regarding the dissolution of carbohydrates (monomeric and oligomeric form), the total glucose yields remained below 60%, while the total xylose and arabinose yields were about 76% and 67%. Approximately 74% of the protein and 95% of the mineral fraction could be extracted. The application of the cascade process enabled a substantially reduced formation of degradation products. CONCLUSION: When operating hydrothermally and subcritically in order to avoid some problematic aspects of a biorefinery, an extensive disintegration and monomerization of wheat bran and its constituents remains difficult even under the tested conditions (300 °C, pH 3). However, the applied cascade process proved to be useful to increase the yields and to substantially reduce the formation of undesired degradation products. Despite this fact, increased water consumption has to be conceded. © 2018 Society of Chemical Industry.

Improved salt removal and power generation in a cascade of two hydraulically connected up-flow microbial desalination cells.

A novel two chamber up-flow microbial desalination cell (UMDC) was designed for evaluating desalination of real seawater with simultaneous wastewater treatment and energy generation. Two UMDCs were hydraulically connected in continuous flow mode (cascade mode) and operated at ten different hydraulic retention times (HRTs) [120 h to 12 h] and salt retention times (SRTs) [40 h to 4 h] for improved performance of chemical oxygen demand (COD) and salt removal. These UMDCs were operated at different combinations of high power (higher external resistance) and high current (low external resistance) mode to find the most suitable conditions for obtaining higher COD removal, salt removal, power production and current generation. The optimum HRT and SRT were 60 h and 40 h, respectively. The highest salt removal achieved was 72% at SRT of 40, while the highest COD removal was 83% at a HRT of 60 h. A maximum current density of 2.375 A/m2 was obtained, while the maximum power density was 5.879 W/m2. The obtained results give an overlook for the scale up of UMDCs in the future. In the entire system, membrane fouling is still a major problem. As the operation time increases, this resulted in low power generation and low salt removal efficiency. The UMDCs can function as sustainable and alternative solution for real wastewater treatment and seawater desalination with resource recovery and power production.

Direct Synthesis of Highly Substituted Pyrroles and Dihydropyrroles Using Linear Selective Hydroacylation Reactions.

Rhodium(I) catalysts incorporating small bite-angle diphosphine ligands, such as (Cy2 P)2 NMe or bis(diphenylphosphino)methane (dppm), are effective at catalysing the union of aldehydes and propargylic amines to deliver the linear hydroacylation adducts in good yields and with high selectivities. In situ treatment of the hydroacylation adducts with p-TSA triggers a dehydrative cyclisation to provide the corresponding pyrroles. The use of allylic amines, in place of the propargylic substrates, delivers functionalised dihydropyrroles. The hydroacylation reactions can also be combined in a cascade process with a Rh(I) -catalysed Suzuki-type coupling employing aryl boronic acids, providing a three-component assembly of highly substituted pyrroles.

Methodology for assessing pipeline failure probability due to a debris flow in the near field.

Aboveground transmission oil pipelines can cross debris flow-prone areas. Currently, there are no available methodologies to assess pipeline failure status with the different pipeline arrangements (location, direction, and segment lengths) and different operating conditions. For solving the research gap, this study proposes a novel methodology to simulate the cascade processes of debris flow propagation, the impact of debris flow on pipelines, and pipeline failure. With consideration of different pipeline arrangement and operating conditions. We introduce the polar coordinate system to set up locations and directions scenarios for the first time. Also, we use the 3-D debris flow simulation model (DebrisInterMixing solver in OpenFOAM) coupled with a modified pipeline mechanical model considering operating conditions for the first time. The proposed methodology shows the different trends of pipeline failure probability with the increase of pipeline segment length for the different pipeline locations and directions. The result shows, for the pipelines of 30° the tensile stress has a more moderate increase rate with the increase of pipeline segment length, and the pipeline failure probability keeps 0 at the 5-m location. At 5 m and 15 m locations, the failure probabilities of the pipelines of 60° and 90° start to increase when the segment length is 13-14 m, while for other pipelines the segment length is 17-19 m. The findings of this study can support the decisions of government authorities, stakeholders, and operators for risk assessment, prioritization of hazard mitigation measures and emergency planning, or concerning decisions regarding pipeline siting during the design, routing, construction, operation, and maintenance stage.

Organelle-inspired supramolecular nanomedicine to precisely abolish liver tumor growth and metastasis.

Organelles are responsible for the efficient storage and transport of substances in living systems. A myriad of extracellular vesicles (EVs) acts as a bridge to exchange signaling molecules in cell-cell communication, and the highly dynamic tubulins and actins contribute to efficient intracellular substance transport. The inexhaustible cues of natural cargo delivery by organelles inspire researchers to explore the construction of biomimetic architectures for "smart" delivery carriers. Herein, we report a 10-hydroxycamptothecin (HCPT)-peptide conjugate HpYss that simulates the artificial EV-to-filament transformation process for precise liver cancer therapy. Under the sequential stimulus of extracellular alkaline phosphatase (ALP) and intracellular glutathione (GSH), HpYss proceeds via tandem self-assembly with a morphological transformation from nanoparticles to nanofibers. The experimental phase diagram elucidates the influence of ALP and GSH contents on the self-assembled nanostructures. In addition, the dynamic transformation of organelle-mimetic architectures that are formed by HpYss in HepG2 cells enables the efficient delivery of the anticancer drug HCPT to the nucleus, and the size-shape change from extracellular nanoparticles (50-100 nm) to intracellular nanofibers (4-9 nm) is verified to be of key importance for nuclear delivery. Nuclear targeting of HpYss amplifies apoptosis, thus significantly enhancing the inhibitory effect of HCPT (>10-fold) to HepG2 cells. Benefitting from the spatiotemporally controlled nanostructures, HpYss exhibited deep penetration, enhanced accumulation, and long-term retention in multicellular spheroid and xenograft models, potently abolishing liver tumor growth and preventing lung metastasis. We envision that our organelle-mimicking delivery strategy provides a novel paradigm for designing nanomedicine to cancer therapy.

Transformation of Cellulose into Nonionic Surfactants Using a One-Pot Catalytic Process.

Alkyl glucosides surfactants are synthesized by a cascade process that involves the methanolysis of cellulose into methyl glucosides followed by the transacetalization with n-octanol. The first step was performed using methanol as solvent and acid catalysts (such as, inorganic acids, heteropolyacids, ionexchange resins, or modified carbon materials). Subsequently, long-chain alkyl glucosides are obtained in the second step by transacetalization, which involves the reaction of methyl glucosides with a fatty alcohol using the same acid catalyst. The overall process was performed under mild conditions. Amorphous sulfonated carbon catalyst achieved the best results for the complete conversion of cellulose in methanol at 200 °C with methyl α,ß-glucopyranosides yields higher than 80 %. Moreover, this material containing -SO3 H groups is ideal to perform the second step to obtain octyl and decyl glucosides in yields higher than 73 % at 120 °C. In addition, the sulfonated carbon catalyst (C-SO3 H) can be reused with only a slightly decrease of its activity after four consecutive cycles.

Efficient cascade synthesis of ampicillin from penicillin G potassium salt using wild and mutant penicillin G acylase from Alcaligenes faecalis.

To avoid isolation and purification of the intermediate 6-aminopenicillanic acid (6-APA), a two-enzyme two-step cascade synthesis of ampicillin from penicillin G was established. In purely aqueous medium, penicillin G hydrolysis and ampicillin synthesis were catalyzed by immobilized wild-type and mutagenized penicillin G acylases from Alcaligenes faecalis (Af PGA), respectively (Fig. 1). The ßF24 G mutant Af PGA (the 24th Phenylalanine of the ß-subunit was replaced by Glycine) was employed for its superior performance in enzymatic synthesis of ampicillin. By optimizing the reaction conditions, including enzyme loading, temperature, initial pH and D-PGME/6-APA ratio, the conversion of the second step of ampicillin synthesis reached approximately 90% in 240 min and less than 1.7 mole D-PGME were required to produce 1 mole ampicillin. Overall, in a 285 min continuous two-step procedure, an ampicillin yield of 87% was achieved, demonstrating the possibility of improving the cascade synthesis of ampicillin by mutagenized PGA, providing an economically efficient and environmentally benign procedure for semi-synthetic penicillins antibiotics synthesis.

Synthesis of ß-Hydroxysulfides from Thiophenols and Disulfides with tert-Butyl Hydroperoxide as the Oxidant and Reactant.

In this Communication, we developed a new procedure for the synthesis of ß-hydroxysulfides from thiophenols or diaryl disulfides with TBHP as the oxidant. In the presence of zinc iodide or potassium iodide, with TBHP as the oxidant and pre-reactant, thiophenols and diaryl disulfides reacted with the methyl group of tBuOH smoothly and selectivity to give the corresponding 2-methyl-1-(arylthio)propan-2-ols as the terminal products in moderate to good yields.