Studies Toward the Synthesis of Exiguaquinol

This dissertation describes our efforts to develop a total synthesis of the biologically active marine natural product exiguaquinol. Chapter 1 focuses on the isolation and structure elucidation of exiguaquinol, its biological significance as a Helicobacter pylori MurI inhibitor, and its proposed biogenesis from halenaquinol sulfate. In addition, synthetic efforts yielding related furanosteroid natural products halenaquinone and xestoquinone are discussed.Chapter 2 details our synthesis of the tetracyclic core scaffold of exiguaquinol. While several functional groups were omitted in this endeavor, this model system was targeted in order to test the feasibility of our proposed strategy. Through a desymmetrizing aldol reaction, a thermal sulfoxide elimination, and a 5-exo reductive Heck cyclization, the tetracyclic core was prepared in 14 steps from commercially available starting materials. In the end, an unexpected stereochemical outcome involving the N-acyl hemiaminal was uncovered, which could be explained through a favorable internal hydrogen bonding arrangement between the alcohol and the C9 ketone. This phenomenon was simulated computationally by the Houk group for further understanding.In Chapter 3, our efforts to apply this strategy to the first total synthesis of exiguaquinol are disclosed. After preparing the necessary naphthaldehyde, the pentacyclic framework was assembled using the strategy developed previously for the tetracyclic core. Although we were able to access exiguaquinol des-sulfate, the final regioselective sulfation was ultimately unsuccessful. Further studies regarding the regioselective installation of sulfate groups will be necessary to provide exiguaquinol

Dynamic Nuclear Polarization NMR Spectroscopy of Microcrystalline Solids

Dynamic nuclear polarization (DNP) solid-state NMR has been applied to powdered microcrystalline solids to obtain sensitivity enhancements on the order of 100. Glucose, sulfathiazole, and paracetamol were impregnated with bis-nitroxide biradical (bis-cyclohexyl-TEMPO-bisketal, bCTbK) solutions of organic solvents. The organic solvents were carefully chosen to be nonsolvents for the compounds, so that DNP-enhanced solid-state NMR spectra of the unaltered solids could be acquired. A theoretical model is presented that illustrates that for externally doped organic solids characterized by long spin-lattice relaxation times (T-1(H-1) > 200 s), H-1-H-1 spin diffusion can relay enhanced polarization over micrometer length scales yielding substantial DNP enhancements (epsilon). epsilon on the order of 60 are obtained for microcrystalline glucose and sulfathiazole at 9.4 T and with temperatures of ca. 105 K. The large gain in sensitivity enables the rapid acquisition of C-13-C-13 correlation spectra at natural isotopic abundance. It is anticipated that this will be a general method for enhancing the sensitivity of solid-state NMR experiments of organic solids

DNP enhanced NMR spectroscopy for pharmaceutical formulations

International audienceDynamic nuclear polarization (DNP) enhanced solid-state NMR spectroscopy at 9.4 T is demonstrated for the detailed atomic-level characterization of commercial pharmaceutical formulations. To enable DNP experiments without major modifications of the formulations, the gently ground tablets are impregnated with solutions of biradical polarizing agents. The organic liquid used for impregnation (here 1,1,2,2-tetrachloroethane) is chosen so that the active pharmaceutical ingredient (API) is minimally perturbed. DNP enhancements (ε) of between 40 and 90 at 105 K were obtained for the microparticulate API within four different commercial formulations of the over-the-counter antihistamine drug cetirizine dihydrochloride. The different formulations contain between 4.8 and 8.7 wt % API. DNP enables the rapid acquisition with natural isotopic abundances of one- and two-dimensional 13C and 15N solid-state NMR spectra of the formulations while preserving the microstructure of the API particles. Here this allowed immediate identification of the amorphous form of the API in the tablet. API-excipient interactions were observed in high-sensitivity 1H-15N correlation spectra, revealing direct contacts between povidone and the API. The API domain sizes within the formulations were determined by measuring the variation of ε as a function of the polarization time and numerically modeling nuclear spin diffusion. Here we measure an API particle radius of 0.3 μm with a single particle model, while modeling with a Weibull distribution of particle sizes suggests most particles possess radii of around 0.07 μm

Dynamic Nuclear Polarization NMR Spectroscopy of Microcrystalline Solids

International audienceDynamic nuclear polarization (DNP) solid-state NMR has been applied to powdered microcrystalline solids to obtain sensitivity enhancements on the order of 100. Glucose, sulfathiazole, and paracetamol were impregnated with bis-nitroxide biradical (bis-cyclohexyl-TEMPO-bisketal, bCTbK) solutions of organic solvents. The organic solvents were carefully chosen to be nonsolvents for the compounds, so that DNP-enhanced solid-state NMR spectra of the unaltered solids could be acquired. A theoretical model is presented that illustrates that for externally doped organic solids characterized by long spin-lattice relaxation times (T-1(H-1) > 200 s), H-1-H-1 spin diffusion can relay enhanced polarization over micrometer length scales yielding substantial DNP enhancements (epsilon). epsilon on the order of 60 are obtained for microcrystalline glucose and sulfathiazole at 9.4 T and with temperatures of ca. 105 K. The large gain in sensitivity enables the rapid acquisition of C-13-C-13 correlation spectra at natural isotopic abundance. It is anticipated that this will be a general method for enhancing the sensitivity of solid-state NMR experiments of organic solids

Monolayer doping of silicon through grafting a tailored molecular phosphorus precursor onto cxide-passivated silicon surfaces

The authors thank S. Deleonibus (DRT/LETI), M. Sanquer (DSM/INAC), and L. Vandroux (DRT/LETI) for their continuous support, as well as V. Loup, P. Besson, M. Danielou, S. Kerdiles, A. Andre, L. Andreutti, and J.P. Barnes from CEA/LETI/Minatec; and K. Szeto from C2P2-LCOMS. ETH Zurich, CPE Lyon and UCBL are also acknowledged for their scientific support and the access to the process and characterization facilities.International audienceMonolayer doping (MLD) of silicon substrates at the nanoscale is a powerful method to provide controlled doses of dopants and defect-free materials. However, this approach requires the deposition of a thick SiO2 cap layer to limit dopant evaporation during annealing. Here, we describe the controlled surface doping of thin oxide-passivated silicon wafers through a two-step process involving the grafting of a molecular phosphorus precursor containing a polyhedral oligomeric silsesquioxane (POSS) scaffold with silica-like architecture and thermal annealing. We show that the POSS scaffold favors the controlled formation of dopant-containing surface species with up to similar to 8 x 10(13) P atoms cm(-2) and efficiently avoids phosphorus evaporation during annealing for temperatures up to 800 degrees C. Silicon doping is demonstrated, in particular, by grafting the POSS phosphorus triester on SiO2/Si wafers with optimized surface preparation (thin SiO2 layer of 0.7 nm) and annealing temperature (1000 degrees C), which provides phosphorus doses of similar to 7 x 10(12) P atoms cm(-2) in the silicon substrates together with a decrease of their sheet resistance. A detailed study of the surface chemistry on SiO2 nanoparticles used as a high-surface-area model yields the grafting mechanism and the structure of the surface species. We show that the POSS scaffold is conserved upon grafting, that its size controls the final P-surface density, and that it behaves as a self-protecting ligand against phosphorus volatilization during the annealing step. We thus demonstrate that the use of custom-made dopant precursors with self-capping properties is a promising approach to tune medium to low doping doses in technologically relevant semiconductors

Dynamic nuclear polarization surface enhanced NMR spectroscopy: the design of new biradicals enables application to challenging materials

International audienceNMR spectroscopy (often in conjunction with diffraction methods) is the method of choice for characterizing surfaces whenever possible, but the detection limit of NMR is far too low to allow many modern materials to be examined. Because it provides dramatic sensitivity enhancement, solid-state Dynamic Nuclear Polarization (DNP) NMR is currently emerging as a powerful tool to study samples previously inaccessible to NMR. We have recently shown how DNP could be used to selectively enhance the NMR signals from surfaces in a wide range of materials (DNP SENS). While signal enhancements of between 20 and 50 are routinely obtained at 9.4 T and 100 K (for 29Si, 13C, or 27Al nuclei after cross-polarization from protons), these enhancement factors are still far from the predicted maximum values. Much effort is currently devoted to the development of ever more efficient polarizing agents. We will present a series of bTbK derivatives suitable for high-field DNP enhanced solid-state NMR spectroscopy. These biradicals differ by the functional groups at the vicinal position of the two nitroxides. We establish clear relationships between the DNP efficiencies of these new radicals and (i) their molecular weight, (ii) the number of methyl groups and (iii) their electron spin relaxation rates. In particular, a new radical is introduced, that yields proton enhancement of over 200 at 9.4 T and 100 K in bulk solution as well as in mesoporous materials. The temperature and spinning speed dependence of the DNP enhancement factors is also discussed for this new family of polarizing agents. These new polarizing agents are demonstrated through the application of DNP SENS to the characterization of periodic mesoporous organosilicates (POM). The rapid acquisition of high quality natural abundance 1D 13C, 15N, and 29Si, and 2D 1H-13C and 1H-29Si DNP solid-state NMR spectra was essential to distinguish outer and inner layers in these porous materials and to monitor their surface functionalization

Phenylazide Hybrid-Silica - Polarization Platform for Dynamic Nuclear Polarization at Cryogenic Temperatures

Hyperpolarization of NMR-active nuclei is key to gather high quality spectra of rare species and insensitive isotopes. We have recently established that silica-based materials containing regularly distributed nitroxyl radicals connected to the silica matrix by flexible linkers can serve as promising polarization matrices for dynamic nuclear polarization (DNP). Here we investigate the influence of the linker on the efficiency of the polarization. The materials were fully characterized and exhibit high surface areas and narrow pore size distributions with a tunable amount of phenyl azide groups over a broad range of concentrations. The phenyl azide groups can be easily functionalized via a two-step procedure with 4-carboxy-2,2,6,6-tetramethyl-1-oxylpiperidine (TEMPO) to give polarizing matrices with controllable radical content. The DNP efficiency was found to be similar as in materials with flexible linkers, both for magic angle spinning at 105 K and dissolution DNP at 4 K

Cubic three-dimensional hybrid silica solids for nuclear hyperpolarization

Mathieu Baudin is kindly acknowledged for his contribution to dissolution DNP experiments.International audienceHyperpolarization of metabolites by dissolution dynamic nuclear polarization (D-DNP) for MRI applications often requires fast and efficient removal of the radicals (polarizing agents). Ordered mesoporous SBA-15 silica materials containing homogeneously dispersed radicals, referred to as HYperPolarizing SOlids (HYPSOs), enable high polarization – P(1H) = 50% at 1.2 K – and straightforward separation of the polarizing HYPSO material from the hyperpolarized solution by filtration. However, the one-dimensional tubular pores of SBA-15 type materials are not ideal for nuclear spin diffusion, which may limit efficient polarization. Here, we develop a generation of hyperpolarizing solids based on a SBA-16 structure with a network of pores interconnected in three dimensions, which allows a significant increase of polarization, i.e. P(1H) = 63% at 1.2 K. This result illustrates how one can improve materials by combining a control of the incorporation of radicals with a better design of the porous network structures