Viridiofungins and xeniolide F: target oriented synthesis using different rearrangement reactions of a common substrate class

The present dissertation covers the total synthesis of viridiofungin triesters and studies toward the total synthesis of xeniolide F. In both cases, sigmatropic rearrangements of α-allyloxy substituted α,β-unsaturated esters are employed: for the viridiofungin ester synthesis a [2,3]-Wittig rearrangement and for the xeniolide F synthesis a catalytic asymmetric Claisen rearrangement CAC. For both rearrangement reactions the historical development, main characteristic and important variations are discussed. The viridiofungin triester synthesis represents a convergent and highly flexible route toward these natural products. The [2,3]-Wittig rearrangement allowed the diastereoselective synthesis of the polar head group with two adjacent stereogenic centers. The E-configured double bond was formed by a Julia-Kocienski olefination. During the studies toward the total synthesis of xeniolide F a new, diastereoselective strategy for the generation of allyl vinyl ethers with E-configured vinyl ether double bond was established employing rhodium catalyzed OH-insertion and an E-selective Horner-Wadsworth-Emmons olefination. Under the conditions of the catalytic asymmetric Claisen rearrangement (CAC) this highly substituted allyl vinyl ether rearranged diastero- and enantioselectively to the corresponding a-keto ester. This example clearly illustrates the high potential of the CAC as synthetic tool for natural product synthesis.In der vorliegenden Arbeit wird die Totalsynthese von Tirestern der Viridiofungine A, A2 und A4 sowie die Synthese eines Schlüsselintermediates für die Totalsynthese von Xeniolid F dargestellt. In beiden Fällen wird ausgehend von einem α-allyloxysubstituierten α,β-ungesättigten Ester eine Umlagerungsreaktion als Schlüsselschritt eingesetzt: im Falle der Viridiofunginester eine diastereoselektive [2,3]-Wittig-Umlagerung, bei den Arbeiten zur Totalsynthese von Xeniolid F eine diastero- und enantioselektive, katalytische Claisenumlagerung. Für beide Umlagerungsreaktionen werden ausführlich die theoretischen Hintergründe sowie die historische Entwicklung und wichtige Varianten besprochen. Mit der Viridiofungintriestersynthese wird eine konvergente und bezüglich der lipophilen Seitenkette sehr flexible Syntheseroute vorgestellt. Die [2,3]-Wittig-Umlagerung konnte dabei erfolgreich für die diastereoselektive Synthese der hochsubstituierten, polaren Kopfgruppe der Viridiofunginester mit zwei benachbarten stereogenen Zentren (davon eines quartär) eingesetzt werden. Zur Bildung der E-konfigurierten Doppelbindung wurde die Julia-Kocienskie-Olefinierung ausgenutzt. Bei den Arbeiten zur Totalsynthese von Xeniolid F wurde eine neuartige Strategie zur diastereoselektiven Synthese eines Allylvinylethers mit E-konfigurierter Vinyletherdoppelbindung eingesetzt. Die Horner-Wadsworth-Emmons-Olefinierung (HWE-Olefinierung) generierte dabei E-selektiv die Vinyletherdoppelbindung. Das für die HWE-Olefinierung benötigte Phosphonat wurde durch rhodiumkatalysierte OH-Insertion aus einem Allylalkohol und einem Diazaphosphonoacetat hergestellt. Der hochsubstituierte Allylvinylether wurde unter den Bedingungen der katalytisch asymmetrischen Claisenumlagerung umgesetzt und führte mit exzellenter Diastereo- und Enantioselektivität zum entsprechenden α-Ketoester. Anhand dieses Beispiels konnte das Potential der katalytisch asymmetrischen Claisenumlagerung zum Aufbau von hochfunktionalisierten Bausteinen für die Naturstoffsynthese verdeutlicht werden

Fysieke belasting van brandweerlieden

Tijdens dit onderzoek is de fysieke belasting van brandweermannen tijdens uitrukken en sporttrainingen in kaart gebracht met het Zephyr Bioharness. Vervolgens is er gekeken naar de mate van overeenkomst tussen de uitrukken en de sporttrainingen

Locating epistemic value

Many epistemologists are attracted to the idea that knowledge is valuable in a way that stands out when compared to the value of other doxastic attitudes. Some philosophers, including Linda Zagzebski, Jonathan Kvanvig, Richard Swinburne, and Duncan Pritchard have objected to contemporary theories of knowledge on the grounds that the analyses these theories offer fail to sufficiently distinguish knowledge from mere true belief. One particularly clear instance of this is the Swamping Problem for Process Reliabilism. Goldman and Olsson try to respond to the Swamping Problem on behalf of Reliabilism. In what follows, I first try to motivate and defend an approach to epistemic value. Then I review the Swamping Problem and evaluate Goldman and Olsson’s response to it. Finding their response unsatisfying, I suggest that we try to satisfy Zagzebski et al. by introducing a theory of understanding which answers to the intuitions many endorse about epistemic value.Philosoph

(3S,4S,5S)-4-Hydr­oxy-3-methyl-5-[(2S,3R)-3-methyl­pent-4-en-2-yl]-4,5-dihydro­furan-2(3H)-one

The title compound, C11H18O3, was synthesized to prove the relative configuration of the corresponding acyclic C1—C8 stereopentade. Mol­ecules are linked via O—H⋯O hydrogen bonds, forming a chain along the b axis

Abetalipoproteinemia: two case reports and literature review

Abetalipoproteinemia (ABL, OMIM 200100) is a rare, autosomal recessive disorder, characterized by fat malabsorption, acanthocytosis and hypocholesterolemia in infancy. Later in life, deficiency of fat-soluble vitamins is associated with development of atypical retinitis pigmentosa, coagulopathy, posterior column neuropathy and myopathy. ABL results from mutations in the gene encoding the large subunit of microsomal triglyceride transfer protein (MTP; OMIM 157147). To date at least 33 MTP mutations have been identified in 43 ABL patients. We describe the clinical progress of two patients, both currently in the fifth decade of life, who were diagnosed with ABL as children and were treated with high oral doses of fat soluble vitamins, including vitamin E over the last three decades. Treatment appears to have been associated with arrest of the neuropathy and other complications in both patients. Because pharmacologic inhibition of MTP is being developed as a novel approach to reduce plasma cholesterol for prevention of cardiovascular disease, defining the long-term clinical features of patients with a natural deficiency in MTP might provide some insight into the possible effects of such treatments. We review the range of clinical, biochemical and molecular perturbations in ABL

Genetic determinants of statin intolerance

BACKGROUND: Statin-related skeletal muscle disorders range from benign myalgias – such as non-specific muscle aches or joint pains without elevated serum creatinine kinase (CK) concentration – to true myositis with >10-fold elevation of serum CK, to rhabdomyolysis and myoglobinuria. The genetic basis of statin-related muscle disorders is largely unknown. Because mutations in the COQ2 gene are associated with severe inherited myopathy, we hypothesized that common, mild genetic variation in COQ2 would be associated with inter-individual variation in statin intolerance. We studied 133 subjects who developed myopathy on statin monotherapy and 158 matched controls who tolerated statins without incident or complaint. RESULTS: COQ2 genotypes, based on two single nucleotide polymorphisms (SNP1 and SNP2) and a 2-SNP haplotype, all showed significant associations with statin intolerance. Specifically, the odds ratios (with 95% confidence intervals) for increased risk of statin intolerance among homozygotes for the rare alleles were 2.42 (0.99 to 5.89), 2.33 (1.13 to 4.81) and 2.58 (1.26 to 5.28) for SNP1 and SNP2 genotypes, and the 2-SNP haplotype, respectively. CONCLUSION: These preliminary pharmacogenetic results, if confirmed, are consistent with the idea that statin intolerance which is manifested primarily through muscle symptoms is associated with genomic variation in COQ2 and thus perhaps with the CoQ10 pathway

An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol

An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol has been devised. This new route increases the throughput and yield of the diene product by circumventing a low yielding preparation of boronic acid intermediate as well as removing the need to use multi-gram quantities of highly toxic thallium salts. In the process of developing this new route, a higher yielding preparation of ( E)-3-hydroxyprop-1-enylboronic acid was also achieved. (c) 2007 Elsevier Ltd. All rights reserved

Calibrating spectrometers for measurements of the spectral irradiance caused by solar radiation

Measuring the spectral irradiance of solar radiation is required in many fields of science and technology. In this work, we present an in-depth discussion of the measuring procedure and required corrections for such measurements. We also describe our measurement uncertainty analysis, which is based on a Monte-Carlo procedure in accordance with the Guide to the expression of uncertainty in measurement (JCGM, Paris, 2008). For this purpose, fifteen uncertainty sources are identified, analyzed and described analytically. As a specific application example, we describe the instrumentation and procedure for determining the spectral irradiance of a solar simulator at the ISO/IEC 17 025 accredited solar cell calibration laboratory ISFH CalTeC and the corresponding measurement uncertainty analysis. Moreover, we provide a Python implementation for this calculation along with the paper. We show that for state-of-the-art instrumentation, significant uncertainty contributions arise from the reference lamp (primary calibration standard), stray light and signal-to-noise ratio. If sharp spectral features are present (which is common, e.g. for Xenon lamps), spectral bandwidth and wavelength uncertainty also contribute significantly to the overall uncertainty. © 2020 BIPM & IOP Publishing Lt

Corrigendum: Calibrating spectrometers for measurements of the spectral irradiance caused by solar radiation (2020 Metrologia 57 065027)

We correct an error in equation (60) of the original publication