Spectroscopie RMN | EPFL Graph Search

vignette|redresse|Spectromètre RMN avec passeur automatique d'échantillons utilisé en chimie organique pour la détermination des structures chimiques. vignette|redresse|Animation présentant le principe de la Résonance Magnétique Nucléaire (RMN). La spectroscopie RMN est une technique qui exploite les propriétés magnétiques de certains noyaux atomiques. Elle est basée sur le phénomène de résonance magnétique nucléaire (RMN), utilisé également en sous le nom d’. Les applications les plus importantes pour la chimie organique sont la RMN du proton et du carbone 13 effectuée sur des solutions liquides. Mais la RMN est aussi applicable à tout noyau possédant un spin non nul, que ce soit dans les solutions liquides ou dans les solides. Certains gaz comme le xénon peuvent aussi être mesurés lorsqu'ils sont absorbés dans des matériaux poreux par exemple. Contrairement à la spectroscopie RMN des solutions qui est utilisée de manière routinière dans les laboratoires académiques ou industriel

Copper-Catalyzed 1,2-Methoxy Methoxycarbonylation of Alkenes with Methyl Formate and Synthetic Studies Towards the Total Synthesis of Koumine, Voacafricine A and Voacafricine B

Balázs Budai

The development of an unusual oxidative alkene difunctionalization using methyl formate and syn-thetic studies towards alkaloid natural products provide the basis of the thesis. The first chapter details the development of a method that forges methoxycarbonyl radical direct-ly from its most accessible precursor: methyl formate. Although the aforementioned transfor-mation was documented in the literature, no synthetically useful method was developed at the time. We were able to identify conditions that transform methyl formate and simple styrene de-rivatives to value added ï¢-methoxy alkanoates and cinnamic acid derivatives under copper cataly-sis. We also demonstrated that by tethering nucleophilic moieties to the styrene substrates, we could access medicinally important heterocycles such as pyrrolidines, tetrahydrofurans and ï§-lactones. Our method proved to be scalable on each classes of substrates. Mechanistic studies re-vealed that methyl formate has an unprecedented double role in the transformation. It acts as a precursor for methoxycarbonyl radical; furthermore, it is the direct source of the ï¢-methoxy func-tion in the synthesis of ï¢-methoxy alkanoates. A ternary ï¢-diketiminato-Cu(I)-styrene complex, fully characterized by NMR spectroscopy and X-ray crystallographic analysis is capable of catalyz-ing the same transformation. We hypothesize that pre-coordination of electron-rich double bond to copper might play an important role in the polarity-mismatched addition between nucleophilic methoxycarbonyl radical and electron rich olefins. Synthetic studies toward the total synthesis of koumine is discussed in the second chapter. Our synthetic strategy features an oxidative ring closing, Fukuyama indole synthesis and an enantiose-lective Diels-Alder cycloaddition for the construction of the core of koumine skeleton. We designed a rapid route to access 1,2-dihydropyridine derivatives and these compounds were examined as dienes in the Diels-Alder cycloaddition reaction. Despite our efforts, we were unable to effect the [4+2] cycloaddition, which eventually lead us to decide to discontinue our campaign. In chapter three, our synthetic efforts toward voacafricine A and voacafricine B is presented. In our pursuit towards the natural products, we devised and followed a divergent and potentially en-antioselective strategy. We successfully developed a synthetic route to reach the key intermediate in five steps. Despite our efforts, we were not able to construct the remaining F ring of the natural product. Our conformational analysis of advanced intermediates suggest that epimerization of the C14 stereocenter potentially unlocks the desired reactivity and enables us to reach the target mol-ecules. Work towards the total synthesis of voacafricine A and voacafricine B is underway and may focus on the conformational manipulation of advanced intermediates to allow the elaboration of the F ring and complete the synthesis.

EPFL2020

Brain metabolism during Chronic Hepatic Encephalopathy studied by in vivo 1H and 31P MRS

Veronika Rackayová

Magnetic resonance spectroscopy (MRS) is a powerful tool increasingly used in biomedical research and also in clinical practice. This thesis focused on the improvements of in vivo 31P MRS and 31P magnetization transfer methods at high magnetic field (9.4T). Then, in vivo 31P MRS was combined with 1H MRS to longitudinally study neurometabolic changes during chronic hepatic encephalopathy (CHE) in adult and developing brain using a well-recognized animal model of cholestatic chronic liver disease and HE type C â bile duct ligated (BDL) rats. CHE is neuro-psychiatric disorder caused by chronic liver disease (CLD), with not well-understood molecular mechanisms, inducing important and sometimes lethal brain changes. In a next step, potential protective treatments (probiotics and high creatine diet) were tested. To the best of our knowledge such a detailed approach was not yet published. Firstly, we showed by in vivo 1H MRS in hippocampus that adult BDL rats suffered from increase in brain glutamine, decrease in metabolites involved in osmoregulation including creatine, decrease in neurotransmitters and ascorbate and we were able to show the importance of early metabolic changes compared to late changes thanks to longitudinal measurements. 31P MRS study in larger brain volume found only mild perturbation of energy metabolism such as non-significant trend in ATP decrease in adult BDL rats. Secondly, studies in young BDL rats at two developmental stages by 1H MRS in the hippocampus revealed similar changes that the one observed in adult brain during CHE. However almost all the neurometabolic changes were more profound or appeared earlier in the evolution of the disease in young BDL rats. A new surface 1H-31P double-tuned coil was built and several optimizations and development were done to improve the spectral resolution, SNR and localization, including implementation of 1H-31P NOE enhancement and 1H decoupling in static 31P MRS, optimization of localization method and also development of an optimal protocol for 31P magnetization transfer. 31P MRS study in p21 BDL rats was performed with an improved 31P MRS protocol and revealed a decreased creatine kinase rate constant 2 weeks after BDL surgery and significant changes in metabolites involved in high-phosphate metabolism, in phospholipid metabolism and also cellular redox state 6 weeks after BDL. In the last part of this thesis, some therapeutic approaches were tested. A probiotic treatment delayed some neurometabolic changes present in CHE in adult BDL rats and improved motor activity. Based on previously shown devastating effects of decreased brain creatine during brain development, we proposed the high creatine diet as a possible treatment for young BDL rats. We demonstrated that oral administration of creatine partially restored brain creatine levels and also had a positive effect on other neurometabolic changes present in CHE. In conclusion, the work done in this thesis revealed for the first time a large spectrum of neurometabolic alterations present in adult and young BDL rats suffering from CLD and CHE, together with the time evolution of these changes during the disease progression, using in vivo longitudinal 1H MRS, improved 31P MRS and 31P magnetization transfer protocols developed herein. In addition, we brought some insight on the positive effects of two innovative treatments on the progression of CHE in adult and young BDL rats.

EPFL2018

(1)H and (31)P magnetic resonance spectroscopy in a rat model of chronic hepatic encephalopathy: in vivo longitudinal measurements of brain energy metabolism

Corina Mihaela Berset, Cristina Ramona Cudalbu, Bernard Lanz, Veronika Rackayová

Chronic liver disease (CLD) leads to a spectrum of neuropsychiatric disorders named hepatic encephalopathy (HE). Even though brain energy metabolism is believed to be altered in chronic HE, few studies have explored energy metabolism in CLD-induced HE, and their findings were inconsistent. The aim of this study was to characterize for the first time in vivo and longitudinally brain metabolic changes in a rat model of CLD-induced HE with a focus on energy metabolism, using the methodological advantages of high field proton and phosphorus Magnetic Resonance Spectroscopy ((1)H- and (31)P-MRS). Wistar rats were bile duct ligated (BDL) and studied before BDL and at post-operative weeks 4 and 8. Glutamine increased linearly over time (+146 %) together with plasma ammonium (+159 %). As a compensatory effect, other brain osmolytes decreased: myo-inositol (-36 %), followed by total choline and creatine. A decrease in the neurotransmitters glutamate (-17 %) and aspartate (-28 %) was measured only at week 8, while no significant changes were observed for lactate and phosphocreatine. Among the other energy metabolites measured by (31)P-MRS, we observed a non-significant decrease in ATP together with a significant decrease in ADP (-28 %), but only at week 8 after ligation. Finally, brain glutamine showed the strongest correlations with changes in other brain metabolites, indicating its importance in type C HE. In conclusion, mild alterations in some metabolites involved in energy metabolism were observed but only at the end stage of the disease when edema and neurological changes are already present. Therefore, our data indicate that impaired energy metabolism is not one of the major causes of early HE symptoms in the established model of type C HE.

Springer Verlag2016