Preparation of (S)-tert-ButylPyOx and Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids

A. (S)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)picolinamide (2). A 1 L one-necked round-bottomed flask equipped with a 3.0 cm x 1.4 cm, egg-shaped, Teflon-coated magnetic stirring bar is sealed with a septum and connected via needle adapter to a two-tap Schlenk adapter attached to an oil bubbler and a nitrogen/vacuum manifold (Note 1). The flask is dried with a heat gun under vacuum and cooled under a stream of nitrogen. The flask is charged with 2-picolinic acid (1) (6.15 g, 50.0 mmol, 1.00 equiv) (Note 2), evacuated and back-filled with nitrogen three times, then charged with dichloromethane (300 mL, 0.17 M) (Note 3) and N-methylmorpholine (7.59 g, 8.25 mL, 75.0 mmol, 1.50 equiv). The flask is cooled in an ice/water bath and iso-butylchloroformate (6.86 mL, 7.17 g, 52.5 mmol, 1.05 equiv) is added dropwise over 30 min by syringe pump. The reaction mixture is stirred for an additional 30 min while remaining submerged in the ice/water bath. A separate 100 mL one-necked round-bottomed flask is sealed with a septum and connected via needle adapter to the two-tap Schlenk adapter and manifold, dried with a heat gun under vacuum, and allowed to cool under a stream of nitrogen. This flask is charged with (S)-tert-leucinol (6.45 g, 55.0 mmol, 1.10 equiv), dichloromethane (40 mL), and N-methylmorpholine (6.07 mL, 5.56 g, 55.0 mmol, 1.10 equiv). The resulting clear solution is taken up in a syringe and transferred dropwise using a syringe pump over the course of 1 h to the stirring reaction mixture in the ice/water bath. The cooling bath is removed, and the pale gold colored reaction mixture is stirred for an additional 6 h at 23 °C. Upon consumption of starting material (Note 4), the mixture is quenched at ambient temperature with a single addition of an aqueous solution of saturated NH_4Cl (50 mL), diluted with additional H_2O (25 mL), and transferred into a 1 L separatory funnel. The phases are separated, and the aqueous phase is extracted with CH_2Cl_2 (3 x 100 mL). The combined organic phases are washed with an aqueous solution of saturated NaHCO_3 (1 x 50 mL) and brine (1 x 50 mL). The combined organic phases are dried over Na_2SO_4 (10 g, 15 min while agitating), filtered through a M pore glass frit, and concentrated by rotary evaporation (28 °C, 15 mmHg). Excess N-methylmorpholine is further removed by placing the crude residue under high vacuum (< 12 mmHg, 12 h) to provide a pale red solid (Note 5). The crude residue is dissolved in 10 mL of acetone and purified via silica gel flash chromatography (Note 6). The combined product-containing fractions are concentrated by rotary evaporation (40 °C, 15 mmHg) to yield a solid, which is dried under high vacuum (< 12 mmHg, 12 h) to afford (S)-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide (2) as a white amorphous solid (9.88-9.95 g, 44.4-44.8 mmol, 89-90% yield) (Note 7)

Minimal Trinification

We study the trinified model, SU(3)_C x SU(3)_L x SU(3)_R x Z_3, with the minimal Higgs sector required for symmetry breaking. There are five Higgs doublets, and gauge-coupling unification results if all five are at the weak scale, without supersymmetry. The radiative see-saw mechanism yields sub-eV neutrino masses, without the need for intermediate scales, additional Higgs fields, or higher-dimensional operators. The proton lifetime is above the experimental limits, with the decay modes p -> \bar\nu K^+ and p -> \mu^+ K^0 potentially observable. We also consider supersymmetric versions of the model, with one or two Higgs doublets at the weak scale. The radiative see-saw mechanism fails with weak-scale supersymmetry due to the nonrenormalization of the superpotential, but operates in the split-SUSY scenario.Comment: 23 pages, uses axodra

Probing Yukawa Unification with K and B Mixing

We consider corrections to the unification of down-quark and charged-lepton Yukawa couplings in supersymmetric GUTs, which links the large nu_tau-nu_mu mixing angle to b -> s transitions. These corrections generically occur in simple grand-unified models with small Higgs representations and affect s -> d and b -> d transitions via the mixing of the corresponding right-handed superpartners. On the basis of a specific SUSY-SO(10) model, we analyze the constraints from K-Kbar and B-Bbar mixing on the additional \tilde{d}_R-\tilde{s}_R rotation angle theta. We find that epsilon_K already sets a stringent bound on theta, theta^{max}=O(1 degree), indicating a very specific flavor structure of the correction operators. The impact of the large neutrino mixings on the unitarity triangle analysis is also briefly discussed, as well as their ability to account for the sizeable CP-violating phase observed recently in B_s -> psi phi decays.Comment: 19 pages. Discussion in Sec. 5.2 slightly extended; minor numerical modifications in Secs. 5.1 to 5.4, conclusions unchanged. Version to appear in JHE

Mechanistic Understanding of the Heterogeneous, Rhodium-Cyclic (Alkyl)(Amino)Carbene-Catalyzed (Fluoro-)Arene Hydrogenation

Recently, chemoselective methods for the hydrogenation of fluorinated, silylated, and borylated arenes have been developed providing direct access to previously unattainable, valuable products. Herein, a comprehensive study on the employed rhodium-cyclic (alkyl)(amino)carbene (CAAC) catalyst precursor is disclosed. Mechanistic experiments, kinetic studies, and surface-spectroscopic methods revealed supported rhodium(0) nanoparticles (NP) as the active catalytic species. Further studies suggest that CAAC-derived modifiers play a key role in determining the chemoselectivity of the hydrogenation of fluorinated arenes, thus offering an avenue for further tuning of the catalytic properties. Copyright © 2020 American Chemical Society

Flavor Physics in an SO(10) Grand Unified Model

In supersymmetric grand-unified models, the lepton mixing matrix can possibly affect flavor-changing transitions in the quark sector. We present a detailed analysis of a model proposed by Chang, Masiero and Murayama, in which the near-maximal atmospheric neutrino mixing angle governs large new b -> s transitions. Relating the supersymmetric low-energy parameters to seven new parameters of this SO(10) GUT model, we perform a correlated study of several flavor-changing neutral current (FCNC) processes. We find the current bound on B(tau -> mu gamma) more constraining than B(B -> X_s gamma). The LEP limit on the lightest Higgs boson mass implies an important lower bound on tan beta, which in turn limits the size of the new FCNC transitions. Remarkably, the combined analysis does not rule out large effects in B_s-B_s-bar mixing and we can easily accomodate the large CP phase in the B_s-B_s-bar system which has recently been inferred from a global analysis of CDF and DO data. The model predicts a particle spectrum which is different from the popular Constrained Minimal Supersymmetric Standard Model (CMSSM). B(tau -> mu gamma) enforces heavy masses, typically above 1 TeV, for the sfermions of the degenerate first two generations. However, the ratio of the third-generation and first-generation sfermion masses is smaller than in the CMSSM and a (dominantly right-handed) stop with mass below 500 GeV is possible.Comment: 44 pages, 5 figures. Footnote and references added, minor changes, Fig. 2 corrected; journal versio

Underground Neutrino Detectors for Particle and Astroparticle Science: the Giant Liquid Argon Charge Imaging ExpeRiment (GLACIER)

The current focus of the CERN program is the Large Hadron Collider (LHC), however, CERN is engaged in long baseline neutrino physics with the CNGS project and supports T2K as recognized CERN RE13, and for good reasons: a number of observed phenomena in high-energy physics and cosmology lack their resolution within the Standard Model of particle physics; these puzzles include the origin of neutrino masses, CP-violation in the leptonic sector, and baryon asymmetry of the Universe. They will only partially be addressed at LHC. A positive measurement of $\sin^22\theta_{13}>0.01$ would certainly give a tremendous boost to neutrino physics by opening the possibility to study CP violation in the lepton sector and the determination of the neutrino mass hierarchy with upgraded conventional super-beams. These experiments (so called ``Phase II'') require, in addition to an upgraded beam power, next generation very massive neutrino detectors with excellent energy resolution and high detection efficiency in a wide neutrino energy range, to cover 1st and 2nd oscillation maxima, and excellent particle identification and $\pi^0$ background suppression. Two generations of large water Cherenkov detectors at Kamioka (Kamiokande and Super-Kamiokande) have been extremely successful. And there are good reasons to consider a third generation water Cherenkov detector with an order of magnitude larger mass than Super-Kamiokande for both non-accelerator (proton decay, supernovae, ...) and accelerator-based physics. On the other hand, a very massive underground liquid Argon detector of about 100 kton could represent a credible alternative for the precision measurements of ``Phase II'' and aim at significantly new results in neutrino astroparticle and non-accelerator-based particle physics (e.g. proton decay).Comment: 31 pages, 14 figure

Lepton flavour violation in the MSSM

We derive new constraints on the quantities delta_{XY}^{ij}, X,Y=L,R, which parametrise the flavour-off-diagonal terms of the charged slepton mass matrix in the MSSM. Considering mass and anomalous magnetic moment of the electron we obtain the bound |delta^{13}_{LL} delta^{13}_{RR}|<0.1 for tan beta=50, which involves the poorly constrained element delta^{13}_{RR}. We improve the predictions for the decays tau -> mu gamma, tau -> e gamma and mu -> e gamma by including two-loop corrections which are enhanced if tan beta is large. The finite renormalisation of the PMNS matrix from soft SUSY-breaking terms is derived and applied to the charged-Higgs-lepton vertex. We find that the experimental bound on BR(tau -> e gamma) severely limits the size of the MSSM loop correction to the PMNS element U_{e3}, which is important for the proper interpretation of a future U_{e3} measurement. Subsequently we confront our new values for delta^{ij}_{LL} with a GUT analysis. Further, we include the effects of dimension-5 Yukawa terms, which are needed to fix the Yukawa unification of the first two generations. If universal supersymmetry breaking occurs above the GUT scale, we find the flavour structure of the dimension-5 Yukawa couplings tightly constrained by mu -> e gamma.Comment: 37 pages, 15 figures; typo in Equation (35) and (49) correcte

Metabolism and hydrophilicity of the polarised 'Janus face' all-cis tetrafluorocyclohexyl ring, a candidate motif for drug discovery

This work was supported by the Initial Training Network, FLUOR21, funded by the FP7 Marie Curie Actions of the European Commission (FP7-PEOPLE-2013-ITN-607787). JM is supported by a University Research Fellowship from the Royal Society. The research leading to these results has received funding from the European Research Council under the EU 7th Framework Programme (FP7/2007-2013)/ERC No 336289.The metabolism and polarity of the all-cis tetra-fluorocyclohexane motif is explored in the context of its potential as a motif for inclusion in drug discovery programmes. Biotransformations of phenyl all-cis tetra-, tri- and di- fluoro cyclohexanes with the human metabolism model organism Cunninghamella elegans illustrates various hydroxylated products, but limited to benzylic hydroxylation for the phenyl all-cis tetrafluorocyclohexyl ring system. Evaluation of the lipophilicities (Log P) indicate a significant and progressive increase in polarity with increasing fluorination on the cyclohexane ring system. Molecular dynamics simulations indicate that water associates much more closely with the hydrogen face of these Janus face cyclohexyl rings than the fluorine face owing to enhanced hydrogen bonding interactions with the polarised hydrogens and water.Publisher PDFPeer reviewe

Nucleon Decay Searches with large Liquid Argon TPC Detectors at Shallow Depths: atmospheric neutrinos and cosmogenic backgrounds

Grand Unification of the strong, weak and electromagnetic interactions into a single unified gauge group is an extremely appealing idea which has been vigorously pursued theoretically and experimentally for many years. The detection of proton or bound-neutron decays would represent its most direct experimental evidence. In this context, we studied the physics potentialities of very large underground Liquid Argon Time Projection Chambers (LAr TPC). We carried out a detailed simulation of signal efficiency and background sources, including atmospheric neutrinos and cosmogenic backgrounds. We point out that a liquid Argon TPC, offering good granularity and energy resolution, low particle detection threshold, and excellent background discrimination, should yield very good signal over background ratios in many possible decay modes, allowing to reach partial lifetime sensitivities in the range of 1034−1035 years with exposures up to 1000 kton×year, often in quasi-background-free conditions optimal for discoveries at the few events level, corresponding to atmospheric neutrino background rejections of the order of 105. Multi-prong decay modes like e.g. p→μ−π+K+ or p→e+π+π− and channels involving kaons like e.g. p→K+ν¯, p→e+K0 and p→μ+K0 are particularly suitable, since liquid Argon imaging (...)This work was in part supported by ETH and the Swiss National Foundation. AB, AJM and SN have been supported by CICYT Grants FPA-2002-01835 and FPA-2005-07605-C02-01. SN acknowledges support from the Ramon y Cajal Programme. We thank P. Sala for help with FLUKA while she was an ETH employee