Of the more than 100 casbane diterpenes known to date, only the eponymous parent hydrocarbon casbene itself has ever been targeted by chemical synthesis. Outlined herein is a conceptually new ...approach that brings not a single but a variety of casbane derivatives into reach, especially the more highly oxygenated and arguably more relevant members of this family. The key design elements are a catalyst‐controlled intramolecular cyclopropanation with or without subsequent equilibration, chain extension of the resulting stereoisomeric cyclopropane building blocks by chemoselective hydroboration/cross‐coupling, and the efficient closure of the strained macrobicyclic framework by ring‐closing alkyne metathesis. A hydroxy‐directed catalytic trans‐hydrostannation allows for late‐stage diversity. These virtues are manifested in the concise total syntheses of depressin, yuexiandajisu A, and ent‐pekinenin C. The last compound turned out to be identical to euphorhylonal A, the structure of which had clearly been misassigned.
A cornucopia: Sessile soft corals as well as certain higher plants produce a multitude of casbane diterpenes with different oxygenation patterns. A new synthetic approach to this family of natural products (see structural framework) was designed that allows a large subset to be encompassed, yet is short, efficient, and selective. Key to success was a combination of catalytic cyclopropanation, alkyne metathesis, and trans‐hydrometalation chemistry.
Wind and solar power are known to be highly influenced by weather events and may ramp up or down abruptly. Such events in the power production influence not only the availability of energy, but also ...the stability of the entire power grid. By analysing significant amounts of data from several regions around the world with resolutions of seconds to minutes, we provide strong evidence that renewable wind and solar sources exhibit multiple types of variability and nonlinearity in the time scale of seconds and characterise their stochastic properties. In contrast to previous findings, we show that only the jumpy characteristic of renewable sources decreases when increasing the spatial size over which the renewable energies are harvested. Otherwise, the strong non-Gaussian, intermittent behaviour in the cumulative power of the total field survives even for a country-wide distribution of the systems. The strong fluctuating behaviour of renewable wind and solar sources can be well characterised by Kolmogorov-like power spectra and q-exponential probability density functions. Using the estimated potential shape of power time series, we quantify the jumpy or diffusive dynamic of the power. Finally we propose a time delayed feedback technique as a control algorithm to suppress the observed short term non-Gaussian statistics in spatially strong correlated and intermittent renewable sources.
Enantioselective Total Synthesis of Secalonic Acid E Ganapathy, Dhandapani; Reiner, Johannes R.; Löffler, Lorenz E. ...
Chemistry : a European journal,
November 16, 2015, Volume:
21, Issue:
47
Journal Article
Peer reviewed
The first enantioselective synthesis of a secalonic acid containing a dimeric tetrahydroxanthenone skeleton is described, using a Wacker‐type cyclization of a methoxyphenolic compound to form a ...chiral chroman with a quaternary carbon stereogenic center with >99 % ee. Further steps are a Sharpless dihydroxylation and a Dieckmann condensation to give a tetrahydroxanthenone. A late‐stage one‐pot palladium‐catalyzed Suzuki‐dimerization reaction leads to the 2,2′‐biphenol linkage to complete the enantioselective total synthesis of secalonic acid E in 18 steps with 8 % overall yield.
The first enantioselective total synthesis of a secalonic acid has been accomplished through a Wacker‐type cyclization using a chiral 2,2‐bis(oxazolyl)‐1,1′‐binaphthyl (BOXAX) ligand with >99 % ee. Dimerization was achieved through a Suzuki reaction leading to the 2,2′‐biphenol linkage with 84 % yield.
A convergent, nine‐step (LLS), enantioselective synthesis of α‐cyclopiazonic acid and related natural products is reported. The route features a) an enantioselective aziridination of an imine with a ...chiral sulfur ylide; b) a bioinspired (3+2)‐cycloaddition of the aziridine onto an alkene; and c) installation of the acetyltetramic acid by an unprecedented tandem carbonylative lactamization/N−O cleavage of a bromoisoxazole.
A convergent, nine‐step (longest linear sequence), enantioselective synthesis of α‐cyclopiazonic acid is reported featuring a) an enantioselective aziridination; b) a bioinspired (3+2)‐cycloaddition; and c) an unprecedented tandem carbonylative lactamization/N−O cleavage of a bromoisoxazole to install the acetyltetramic acid.
Combined liver/kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) since orthotopic liver transplantation replaces the deficient ...liver‐specific AGT enzyme, thus restoring normal metabolic oxalate production. However, primary hyperoxaluria type 2 (PH2) is caused by deficient glyoxylate reductase/hydroxypyruvate reductase (GRHPR), and this enzyme is widely distributed throughout the body. Though the relative abundance and activity of GRHPR in various tissues is not clear, some evidence suggests that the majority of enzyme activity may indeed reside within the liver. Thus the effectiveness of liver transplantation in correcting this metabolic disorder has not been demonstrated. Here we report a case of 44‐year‐old man with PH2, frequent stone events, and end‐stage renal disease; he received a combined liver/kidney transplant. Although requiring confirmation in additional cases, the normalization of plasma oxalate, urine oxalate, and urine glycerate levels observed in this patient within a month of the transplant that remain reduced at the most recent follow‐up at 13 months suggests that correction of the GRHPR deficiency in PH2 can be achieved by liver transplantation.
In this case report, urine oxalate and glycerate excretion normalize after combined kidney–liver transplantation in a 44‐year‐old man with type 2 primary hyperoxaluria.
In this paper, a new box-counting method to achieve a highly specific topological fingerprinting of architecture in relation to the position of the observer and in the context of its surroundings is ...proposed. Central to this method is the use of 360-degree spherical panoramas as a basis for fractal measurement. Thus, a number of problems of the comparative analysis of the fractal dimension in the field of architecture are explicitly and implicitly addressed, first and foremost being the question of choosing image boundaries while considering adjacent vegetation, urban elements, and other visually present objects for Gestalt analysis of a specific building. Second, the problem of distance and perspective as part of the aesthetic experience based on viewer and object location were taken into account and are addressed. The implications of the use of a spherical perspective as described in this research are also highly relevant for other methods of aesthetic measures in architecture, including those implementing collaborative design processes guided by digital tools and machine learning, among others.
Prolyl isomerization is recognized as one of the key regulatory mechanisms, which plays a crucial role in cell signaling, ion channel gating, phage virus infection, and molecular timing. This ...isomerization is usually slow but often accelerated by an enzyme, called peptidyl–prolyl isomerase (PPIase). In the current project, we investigate using single-molecule force spectroscopy (SMFS) the impact of a bacterial PPIase, SlyD, on the cis–trans isomerization of the proline 2225 (P2225) in an isolated 20th domain of a cytoskeletal mechanosensing protein filamin-A (FlnA20). To explore the FlnA20–PPIase interaction, we have used multiple SMFS modes, like constant velocity, constant distance, and jumping trap experiments. In our previous study, we reported the unique nature of the P2225, which is conserved in all naturally occurring filamins and can slowly (minutes) interconvert between cis–trans isomers, in absence of any PPIase. Our current results show a staggering 25-fold acceleration of the trans-to-cis isomerization rate in the presence of saturating SlyD concentration (7.25 μM) compared to the unenzymatic condition. A SlyD concentration-dependent depletion of the trans isomeric lifetime was also observed. Additionally, we observed that SlyD stabilizes the cis-isomer in the native state of FlnA20 by ∼2 k BT. This is the first single-molecule observation of the cis–trans isomerization catalysis by a PPIase in a mechanosensing protein.
Rh2(MEPY)4 is a versatile catalyst for asymmetric synthesis but its preparation requires purification by chromatography on surface‐modified silica. A higher yielding procedure based on a more ...convenient work‐up is presented herein. Moreover, a much improved method for the preparation of BiRh(OTfa)4 is described, which makes this heterobimetallic complex readily available. Subsequent exchange of the trifluoroacetate ligands opens access to a so far underappreciated family of (chiral) paddlewheel complexes. While BiRh complexes comprising four carboxylate ligands are highly adequate for intermolecular asymmetric cyclopropanation reactions, BiRh(MEPY)4 as the heterobimetallic cousin of Rh2(MEPY)4 was found to be surprisingly unreactive; DFT calculations uncover the reasons for this inertia.
The family of the toll-like receptors comprises a minimum of 10 members identified in humans so far. These transmembrane receptors act as important signaling intermediates between the host and the ...invading pathogens. The following review describes the complexities encountered by researchers studying toll-like receptor (TLR) expression changes during bacterial infections. Mutations in some of the TLRs, most prominently TLR4 and TLR2, have been associated with increased susceptibility to infectious diseases. While it is tempting to correct the phenotypic effect of such mutations, in vitro and in vivo research has shown that TLR activity and function comprises a complex regulatory network. Heterodimer formation, synergy, and cross-tolerance have previously been described. More recently, interdependence of TLR2 and TLR4 expression has been identified. In addition, TLR expression follows a specific timeline that may be dependent on the invading pathogen. Lastly, mutations in invading pathogens have been shown to alter the expression profile of TLR2 and TLR4, indicating that therapies against bacterial pathogens will have to target multiple TLRs. Despite the complexities involved in TLR function, the significant progress made in our understanding of the role these proteins play in human diseases also indicates their potential value as therapeutic agents.
About 70% of patients with primary membranous nephropathy (MN) have circulating anti‐phospholipase A2 receptor (PLA2R) antibodies that correlate with disease activity, but their predictive value in ...post‐transplant (Tx) recurrent MN is uncertain. We evaluated 26 patients, 18 with recurrent MN and 8 without recurrence, with serial post‐Tx serum samples and renal biopsies to determine if patients with pre‐Tx anti‐PLA2R are at increased risk of recurrence as compared to seronegative patients and to determine if post‐Tx changes in anti‐PLA2R correspond to the clinical course. In the recurrent group, 10/17 patients had anti‐PLA2R at the time of Tx versus 2/7 patients in the nonrecurrent group. The positive predictive value of pre‐Tx anti‐PLA2R for recurrence was 83%, while the negative predictive value was 42%. Persistence or reappearance of post‐Tx anti‐PLA2R was associated with increasing proteinuria and resistant disease in 6/18 cases; little or no proteinuria occurred in cases with pre‐Tx anti‐PLA2R and biopsy evidence of recurrence in which the antibodies resolved with standard immunosuppression. Some cases with positive pre‐Tx anti‐PLA2R were seronegative at the time of recurrence. In conclusion, patients with positive pre‐Tx anti‐PLA2R should be monitored closely for recurrent MN. Persistence or reappearance of antibody post‐Tx may indicate a more resistant disease.
This case series of patients with end‐stage primary membranous nephropathy undergoing renal transplant uses serial posttransplant protocol biopsies and serum collections to describe the changes in anti‐PLA2R antibodies and tissue staining for the PLA2R antigen before and after transplant, and to correlate these changes with clinical outcomes.
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