Short and Efficient Syntheses of Protoberberine Alkaloids using Palladium-Catalyzed Enolate Arylation

A concise synthesis of the biologically active alkaloid berberine is reported, and a versatile palladium‐catalyzed enolate arylation is used to form the isoquinoline core. The overall yield of 50 % is a large improvement over the single, previous synthesis. By design, this modular route allows the rapid synthesis of other members of the protoberberine family (e.g., pseudocoptisine and palmatine) by substitution of the readily available aryl bromide and ketone coupling partners. Moreover, by combining enolate arylation with in situ functionalization, substituents can be rapidly and regioselectively introduced at the alkaloid C13 position, as demonstrated by the total synthesis of dehydrocorydaline. The avoidance of electrophilic aromatic substitution reactions to make the isoquinoline allows direct access to analogues possessing more varied electronic properties, such as the fluorine‐containing derivative synthesized here

Discovery of AZD3199, an inhaled ultralong acting β2 receptor agonist with rapid onset of action

A series of dibasic des-hydroxy β2 receptor agonists has been prepared and evaluated for potential as inhaled ultra-long acting bronchodilators. Determination of activities at the human β-adrenoreceptors demonstrated a series of highly potent and selective β2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by; onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i. t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultra-long acting inhaled β2 receptor agonist with rapid onset of action

Studies on the stereochemical assignment of 3-acylidene 2-oxindoles

The designation of E/Z-geometrical isomers in 3-acylidene 2-oxindoles by NMR spectroscopy can lead to erroneous assignment of alkene stereochemistry because of the narrow chemical shift range observed over a large series of analogues. In contrast, UV-Vis spectroscopy offers a convenient and more reliable method for alkene stereochemical assignment. A combination of X-ray crystallography and theoretical studies shows that the observed differences in UV-Vis spectroscopic behaviour relate to the twisted conformation of the Z-isomers that provides reduced conjugation and weaker hypsochromic (blue-shifted) absorbances relative to those of the E-isomers

Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp3-rich library

The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp3-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp3-rich natural product-like library

Mineral composition of two populations of leaves - green and iron chlorotic - of the same age all from the same tree

Since carefully washed Fe chlorotic leaves often contain more total Fe on the dry weight basis than do green leaves, a population of leaves of the same age representing chlorotic leaves from each of two lemon trees and green leaves also of the same age and from the same two trees were analyzed individually for mineral elements to determine, especially, the frequency distribution of Fe in the various groups of leaves (n = 47, 48, 71, 48). The chlorotic leaves from one tree had mineral composition typical of lime-induced chlorosis. The chlorotic leaves for this tree were, on the average, higher in P, K, and Fe and lower in Ca than the green leaves. For the other tree the chlorotic leaves appeared to be truly Fe deficient; P was not higher in these leaves but the mean K and Ca showed the same pattern as in the first tree. Zinc was higher in the deficient leaves than in the green ones on this tree which can be expected for true Fe deficiency. Mean zinc levels were below the critical levels. Mean manganese was below the critical level for all groups. The coefficient of variation for each element in each group was usually around 30%. Maximum-minimum data indicated that many individual leaves did not fit the patterns just described. Correlation coefficients indicated that most major patterns were consistent in spite of the variability, although there were some differences. The frequency distribution for each of most elements was much like a normal curve with usually a three-fold range for each of the elements. Many of the Fe-deficient leaves had more Fe than some of the green leaves. Analysis of an individual leaf, therefore, cannot result in accurate description of lime-induced chlorosis

Residential battery controller for solar PV impact mitigation: A practical and customer-friendly approach

The rapid adoption of residential solar photovoltaic (PV) systems combined with the falling prices of residential battery energy storage (BES) systems is paving the way for a future in which customers could locally supply most of their energy needs. However, as off-the-shelf (OTS) residential BES systems operate for the sole benefit of the customer, there are no guarantees that they will be able to charge during periods of peak solar generation; thus being unable to mitigate overvoltage and asset congestion issues resulting from reverse power flows. This work proposes a practical adaptive decentralized (AD) controller that, throughout the day, constantly adapts the charging and discharging power rate of the BES system so that reverse power flows are significantly reduced whilst still reducing customer grid imports. Its performance is assessed on a real Australian medium voltage feeder with realistically modelled low voltage networks and smart meter data. Results highlight that the proposed AD controller overcomes the limitations of the OTS by mitigating technical issues while still bringing similar reductions in electricity imports

Carving techniques of Fatimid rock crystal ewers (10-12th cent. AD)

Fatimid art is known for the production of luxury artifacts, particularly rock crystal vessels. The appearance in 2008 of the Francis Mills Ewer, which seemed to belong to a famous group of 6-8 rock crystal ewers attributed to Fatimid Egypt, prompted an investigation of the techniques used to carve them. A comparison of the carving technique of the Francis Mills Ewer with that of the other members of the group offers the best criterion for determining whether the new ewer belongs to this group. To this end, the traces of manufacture (mainly polishing and carving) were analysed on a group of fourteen artifacts. The topography of the surfaces has been measured with a confocal rugosimeter using silicon replicas. To identify and characterise the multi-scale wear signature and the traces left by the tools, a Fourier isotropic filtering technique was applied. Using these complementary methods, we were able to confirm that the Francis Mills Ewer belongs to the Fatimid group. © 2013 Elsevier B.V. All rights reserved

Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (c log P 116 μg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA2 <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom log D7.4 (2.4), high LE (0.43), and solubility (152 μg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation