Development of Amino Acid-Derived Ligands for Enantioselective Synthesis of Amines and Alcohols

Thesis advisor: Amir H. HoveydaChapter One Development of Simple Organic Molecules as Catalysts for Enantioselective Allyl Additions to N-Phosphinoylaldimines and Isatins A new catalytic protocol for the enantioselective addition of organoborates to imines and carbonyls is described. This novel method, which does not require transition metals utilizes a modular and easily accessed aminophenol to dictate the stereochemistry of the products. Allyl-additions to N-phosphinoylaldimines and isatins, as well as allenyl-additions to isatins are studied and literature relevant to these transformations is discussed. Additionally, two separate methods for obtaining "crotyl-type" addition products to aldimines; one requiring α-chiral allylboronates and the other requiring a zinc-alkoxide, are discussed. Studies to elucidate the mechanism of this catalytic protocol are also contained in this chapter. Chapter Two Enantioselective Additions to Fluorinated Ketones: A Platform for Studying the Interaction Between Organofluorine and a Small Molecule Utilizing the new protocol discussed in Chapter One, allyl- and allenyl-groups are added enantioselectively to ketones containing a fluorinated substituent. Myriad tertiary alcohols are synthesized, demonstrating the value of this method. This study also allows for examining how organofluorine containing compounds bind to other organic molecules, which is a current topic of intense interest in the field of medicinal chemistry. Mechanistic studies support the idea that, in many cases, the fluorine of the substrate is electrostatically attracted to the ammonium-ion in the catalyst. Chapter Three Enantioselective Additions of Organoboronates to Ketones and Alphaketoesters Promoted by an Aminophenol Containing Catalyst Modification of the aminophenol disclosed in Chapter One allows for increased enantioselectivity for the allyl-addition to both simple ketones (such as acetophenone) and alphaketoesters. For simple ketones, a critical component of the optimal catalyst is replacing the tert-butyl group ortho to the phenol with the sterically large triphenylsilyl group. For alphaketoesters, this tert-butyl group was replaced with the sterically smaller metyl group. Rationale for why these contradictory changes in the catalyst structure lead to higher enantioselectivity for reactions with these two classes of ketones is discussed. Chapter Four Ag-Catalyzed Enantioselective Vinylogous Mannich Reactions of γ-Substituted Siloxyfurans with Aldimines A previously disclosed Ag-catalyzed enantioselective vinylogous Mannich reaction (EVM) with α-, β-, and unsubstituted siloxyfurans is extended to include γ-substituted siloxyfurans. This method, which generates a tertiary stereogenic center concurrent with an adjacent to a quaternary stereogenic center, requires a rarely used 2-thiomethylaniline N-protecting group for the aldimines.Thesis (PhD) — Boston College, 2014.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Chemistry

Kepler-20: A Sun-like Star with Three Sub-Neptune Exoplanets and Two Earth-size Candidates

We present the discovery of the Kepler-20 planetary system, which we initially identified through the detection of five distinct periodic transit signals in the Kepler light curve of the host star 2MASSJ19104752+4220194. We find a stellar effective temperature Teff=5455+-100K, a metallicity of [Fe/H]=0.01+-0.04, and a surface gravity of log(g)=4.4+-0.1. Combined with an estimate of the stellar density from the transit light curves we deduce a stellar mass of Mstar=0.912+-0.034 Msun and a stellar radius of Rstar=0.944^{+0.060}_{-0.095} Rsun. For three of the transit signals, our results strongly disfavor the possibility that these result from astrophysical false positives. We conclude that the planetary scenario is more likely than that of an astrophysical false positive by a factor of 2e5 (Kepler-20b), 1e5 (Kepler-20c), and 1.1e3 (Kepler-20d), sufficient to validate these objects as planetary companions. For Kepler-20c and Kepler-20d, the blend scenario is independently disfavored by the achromaticity of the transit: From Spitzer data gathered at 4.5um, we infer a ratio of the planetary to stellar radii of 0.075+-0.015 (Kepler-20c) and 0.065+-0.011 (Kepler-20d), consistent with each of the depths measured in the Kepler optical bandpass. We determine the orbital periods and physical radii of the three confirmed planets to be 3.70d and 1.91^{+0.12}_{-0.21} Rearth for Kepler-20b, 10.85 d and 3.07^{+0.20}_{-0.31} Rearth for Kepelr-20c, and 77.61 d and 2.75^{+0.17}_{-0.30} Rearth for Kepler-20d. From multi-epoch radial velocities, we determine the masses of Kepler-20b and Kepler-20c to be 8.7\+-2.2 Mearth and 16.1+-3.5 Mearth, respectively, and we place an upper limit on the mass of Kepler-20d of 20.1 Mearth (2 sigma).Comment: accepted by ApJ, 58 pages, 12 figures revised Jan 2012 to correct table 2 and clarify planet parameter extractio

Crystal Structures of 3-halo-2-organochalcogenylbenzo[b]chalcogenophenes

The structure of the title compounds 3-bromo-2-(phenyl­sulfan­yl)benzo[b]thiophene (C(14)H(9)BrS(2); 1), 3-iodo-2-(phenyl­sulfan­yl)benzo[b]thio­phene (C(14)H(9)IS(2); 2), 3-bromo-2-(phenyl­selan­yl)benzo[b]seleno­phene (C(14)H(9)BrSe(2); 3), and 3-iodo-2-(phenyl­selan­yl)benzo[b]seleno­phene (C(14)H(9)ISe(2); 4) were determined by single-crystal X-ray diffraction; all structures presented monoclinic (P2(1)/c) symmetry. The phenyl group is distant from the halogen atom to minimize the steric hindrance repulsion for all structures. Moreover, the structures of 3 and 4 show an almost linear alignment of halogen–selenium–carbon atoms arising from the intra­molecular orbital inter­action between a lone pair of electrons on the halogen atom and the anti­bonding σ*(Se–C) orbital (n (halogen)→σ*(Se–C)). This inter­action leads to significant differences in the three-dimensional packing of the mol­ecules, which are assembled through π–π and C—H⋯π inter­actions. These data provide a better comprehension of the inter­molecular packing in benzo[b]chalcogenophenes, which is relevant for optoelectronic applications

Three-Dimensional Structure Determination of Surface Sites

Lenaic Leroux is acknowledged for technical assistance at the CRMN. Prof. Paul Tordo and Dr. Olivier Ouari are thanked for providing TEKPo12.International audienceThe spatial arrangement of atoms is directly linked to chemical function. A fundamental challenge in surface chemistry and catalysis relates to the determination of three-dimensional structures with atomic-level precision. Here we determine the three-dimensional structure of an organometallic complex on an amorphous silica surface using solid-state NMR measurements, enabled through a dynamic nuclear polarization surface enhanced NMR spectroscopy approach that induces a 200-fold increase in the NMR sensitivity for the surface species. The result, in combination with EXAFS, is a detailed structure for the surface complex determined with a precision of 0.7 angstrom. We observe a single well-defined conformation that is folded toward the surface in such a way as to include an interaction between the platinum metal center and the surface oxygen atoms

Dynamic nuclear polarization at 40 kHz magic angle spinning

International audienceDNP-enhanced solid-state NMR spectroscopy under magic angle spinning (MAS) is rapidly developing into a powerful analytical tool to investigate the structure of a wide range of solid materials, because it provides unsurpassed sensitivity gains. Most developments and applications of DNP MAS NMR were so far reported at moderate spinning frequencies (up to 14 kHz using 3.2 mm rotors). Here, using a 1.3 mm MAS DNP probe operating at 18.8 T and ∼100 K, we show that signal amplification factors can be increased by up to a factor two when using smaller volume rotors as compared to 3.2 mm rotors, and report enhancements of around 60 over a range of sample spinning rates from 10 to 40 kHz. Spinning at 40 kHz is also shown to increase 29Si coherence lifetimes by a factor three as compared to 10 kHz, substantially increasing sensitivity in CPMG type experiments. The contribution of quenching effects to the overall sensitivity gain at very fast MAS is evaluated, and applications are reported on a functionalised mesostructured organic–inorganic material

DNP Enhanced Solid-State NMR Spectroscopy of Heterogeneous Catalysts

International audienceHeterogeneous catalysts are key to efficient processes in the chemical industry. However, they are difficult to improve because of the lack of access to their active-site structures. Although solid-state NMR is the method of choice to describe at atomic level the structure of catalysts, it is plagued by its intrinsic low sensitivity. This limitation is further exacerbated by the small fraction of active sites on the materials and by their often disordered and multi-site nature. Recently it has been demonstrated that this limit can be overcome by using dynamic nuclear polarization (DNP) which allows enhancement factors of up to 250 in solutions, at a magnetic field of 9.4 T and sample temperatures of ca. 100 K. Key to transposing the high enhancement factors observed for bulk frozen solutions to materials is the use of incipient wetness impregnation. In this approach, the materials are wetted by a minimal amount of radical solution. If the first proof of concepts was reported on model mesoporous silica materials, recent applications by our group and others concern a diverse range of chemical systems such as nanoparticles, mixed oxides, cementitious materials or microcrystalline solids. Here we will present new applications of DNP SENS in heterogeneous catalysis. We will show that DNP SENS allows to directly measure structural information of surface reaction intermediates in alkene metathesis catalysts, namely by obtaining C-C connectivities and bond distances. We will also show how the gain in sensitivity provided by DNP allows us to determine the full three-dimensional atomic-scale structure of a catalytically relevant organometallic complex anchored on a silica surface. This is done through a series of multi-dimensional and multi-nuclear NMR experiments producing several inter-nuclear distance constraints and the implementation of sophisticated NMR structure determination protocols

Probiotic supplements prevented oxonic acid-induced hyperuricemia and renal damage.

Hyperuricemia is highly prevalent and especially common in subjects with metabolic, cardiovascular and renal diseases. In chronic kidney disease, hyperuricemia is extremely common, and uric acid (UA) excretion relies on gut uricolysis by gut microbiota. Current therapy for lowering serum UA includes drugs that may produce undesired secondary effects. Therefore, this pilot study was designed to evaluate the potential of two probiotic supplements to reduce systemic uric acid concentrations. Secondary objectives were to assess whether the hypouricemic effect related to a therapeutic benefit on the hyperuricemia-induced renal damage and hypertension. Analysis of fecal microbiota was also performed. Groups of 6 rats each were followed for 5 weeks and allocated in the following treatment groups: C = Control; HU-ND = Oxonic acid-induced hyperuricemia (HU) +regular diet; HU-P = HU+placebo; HU-F1 = HU+ probiotics formula 1 and HU-F2 = HU+ probiotics formula 2. We confirmed that oxonic acid-induced hyperuricemia produced hypertension and renal functional and structural changes, along with modest changes in the overall composition of fecal microbiota. Both probiotic-containing diets prevented HU, elevated UA urinary excretion and intrarenal UA accumulation induced by oxonic acid. The hypouricemic effect conferred by probiotic supplementation also prevented the renal changes and hypertension caused by hyperuricemia. However, probiotic treatment did not restore the fecal microbiota. In conclusion, we demonstrated for the first time the ability of probiotics containing uricolytic bacteria to lower serum uric acid in hyperuricemic animals with beneficial consequences on blood pressure and renal disease. As probiotics supplements are innocuous for human health, we recommend clinical studies to test if probiotic supplements could benefit hyperuricemic individuals