Publications by authors named "Nathan Yee"

106 Publications

Reaction Mechanism Generator v3.0: Advances in Automatic Mechanism Generation.

J Chem Inf Model 2021 May 28. Epub 2021 May 28.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

In chemical kinetics research, kinetic models containing hundreds of species and tens of thousands of elementary reactions are commonly used to understand and predict the behavior of reactive chemical systems. Reaction Mechanism Generator (RMG) is a software suite developed to automatically generate such models by incorporating and extrapolating from a database of known thermochemical and kinetic parameters. Here, we present the recent version 3 release of RMG and highlight improvements since the previously published description of RMG v1.0. Most notably, RMG can now generate heterogeneous catalysis models in addition to the previously available gas- and liquid-phase capabilities. For model analysis, new methods for local and global uncertainty analysis have been implemented to supplement first-order sensitivity analysis. The RMG database of thermochemical and kinetic parameters has been significantly expanded to cover more types of chemistry. The present release includes parallelization for faster model generation and a new molecule isomorphism approach to improve computational performance. RMG has also been updated to use Python 3, ensuring compatibility with the latest cheminformatics and machine learning packages. Overall, RMG v3.0 includes many changes which improve the accuracy of the generated chemical mechanisms and allow for exploration of a wider range of chemical systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jcim.0c01480DOI Listing
May 2021

Sociodemographic Characteristics and Physical Activity in Patients with COPD: A 3-Month Cohort Study.

COPD 2021 May 10:1-13. Epub 2021 May 10.

Department of Medicine, University of Washington, Seattle, WA, USA.

Decreased physical activity (PA) is associated with morbidity and mortality in COPD patients. In this secondary analysis of data from a 12-week longitudinal study, we describe factors associated with PA in COPD. Participants completed the Physical Activity Checklist (PAC) daily for a 7- to 8-day period. PA was measured monthly using the Physical Activity Scale for the Elderly (PASE). At three different time points, daily step count was measured for one week with an Omron HJ-720ITC pedometer. The 35 participants were primarily male (94%) and White (91%), with an average age of 66.5 years and FEV 44.9% predicted. Common activities reported on the PAC were walking (93%), preparing a meal (89%), and traveling by vehicle (96%). PA measured by both PASE score ( = 0.01) and average daily step count ( = 0.04) decreased during follow-up. In repeated measures multivariable modeling, participants living with others had a higher daily step count (ß = 942 steps, = 0.01) and better PASE scores (ß = 46.4, < 0.001). Older age was associated with decreased step count (ß = -77 steps, < 0.001) whereas White race was associated with lower PASE scores (ß = -55.4, < 0.001) compared to non-White race. Other demographic factors, quality of life, and medications were not associated with PA. A better understanding of the role of social networks and social support may help develop interventions to improve PA in COPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15412555.2021.1920902DOI Listing
May 2021

Extracellular sulfite is protective against reactive oxygen species and antibiotic stress in Shewanella oneidensis MR-1.

Environ Microbiol Rep 2021 Jun 18;13(3):394-400. Epub 2021 Apr 18.

Department of Earth and Planetary Sciences, Rutgers University, Piscataway, NJ, USA.

In this study, we investigated the extracellular reactive sulfur species produced by Shewanella oneidensis MR-1 during growth. The results showed that sulfite is the major extracellular sulfur metabolite released to the growth medium under both aerobic and anaerobic growth conditions. Exogenous sulfite at physiological concentrations protected S. oneidensis MR-1 from hydrogen peroxide toxicity and enhanced tolerance to the beta-lactam antibiotics cefazolin, meropenem, doripenem and ertapenem. These findings suggest that the release of extracellular sulfite is a bacterial defence mechanism that plays a role in the mitigation of environmental stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1758-2229.12947DOI Listing
June 2021

Rational Design of New Dihydrobenzooxophosphole-Based Lewis Base Organocatalysts.

Synlett 2020 Apr;31(6):587-591

Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA.

A series of new dihydrobenzooxophosphole-based Lewis Base organocatalysts were designed and synthesized. They are demonstrated effective in trichlorosilane-mediated stereoselective conjugate reductions of C=C bonds. DFT calculations reveal that the strong hydrogen bond between the amide linker and the chloride on silicon in the transition state contributes to the high reactivity of the catalyst .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-1690851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853668PMC
April 2020

Production of methylmercury by methanogens in mercury contaminated estuarine sediments.

FEMS Microbiol Lett 2020 12;367(23)

Department of Environmental Sciences, Rutgers University, New Brunswick, 14 College Farm Road, NJ 08901, USA.

Anaerobic bacteria are known to produce neurotoxic methylmercury [MeHg] when elemental mercury [Hg(0)] is provided as the sole mercury source. In this study, we examined the formation of MeHg in anaerobic incubations of sediment collected from the San Jacinto River estuary (Texas, USA) amended with aqueous Hg(0) to investigate the microbial communities involved in the conversion of Hg(0) to MeHg. The results show that the addition of the methanogen inhibitor 2-bromoethanesulfonate (BES) significantly decreased MeHg production. The mercury methylation gene, hgcA, was detected in these sediments using archaeal specific primers, and 16S rRNA sequencing showed that a member of the Methanosarcinaceae family of methanogens was active. These results suggest that methanogenic archaea play an underappreciated role in the production of MeHg in estuarine sediments contaminated with Hg(0).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/femsle/fnaa196DOI Listing
December 2020

Anoxic photogeochemical oxidation of manganese carbonate yields manganese oxide.

Proc Natl Acad Sci U S A 2020 09 31;117(37):22698-22704. Epub 2020 Aug 31.

Department of Earth and Planetary Sciences, Rutgers University, Piscataway, NJ 08854;

The oxidation states of manganese minerals in the geological record have been interpreted as proxies for the evolution of molecular oxygen in the Archean eon. Here we report that an Archean manganese mineral, rhodochrosite (MnCO), can be photochemically oxidized by light under anoxic, abiotic conditions. Rhodochrosite has a calculated bandgap of about 5.4 eV, corresponding to light energy centering around 230 nm. Light at that wavelength would have been present on Earth's surface in the Archean, prior to the formation of stratospheric ozone. We show experimentally that the photooxidation of rhodochrosite in suspension with light centered at 230 nm produced H gas and manganite (γ-MnOOH) with an apparent quantum yield of 1.37 × 10 moles hydrogen per moles incident photons. Our results suggest that manganese oxides could have formed abiotically on the surface in shallow waters and on continents during the Archean eon in the absence of molecular oxygen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2002175117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502741PMC
September 2020

Frailty in Chronic Obstructive Pulmonary Disease and Risk of Exacerbations and Hospitalizations.

Int J Chron Obstruct Pulmon Dis 2020 11;15:1967-1976. Epub 2020 Aug 11.

Department of Health Services Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.

Background: Frailty is a complex clinical syndrome associated with vulnerability to adverse health outcomes. While frailty is thought to be common in chronic obstructive pulmonary disease (COPD), the relationship between frailty and COPD-related outcomes such as risk of acute exacerbations of COPD (AE-COPD) and hospitalizations is unclear.

Purpose: To examine the association between physical frailty and risk of acute exacerbations, hospitalizations, and mortality in patients with COPD.

Methods: A longitudinal analysis of data from a cohort of 280 participants was performed. Baseline frailty measures included exhaustion, weakness, low activity, slowness, and undernutrition. Outcome measures included AE-COPD, hospitalizations, and mortality over 2 years. Negative binomial regression and Cox proportional hazard modeling were used.

Results: Sixty-two percent of the study population met criteria for pre-frail and 23% were frail. In adjusted analyses, the frailty syndrome was not associated with COPD exacerbations. However, among the individual components of the frailty syndrome, weakness measured by handgrip strength was associated with increased risk of COPD exacerbations (IRR 1.46, 95% CI 1.09-1.97). The frailty phenotype was not associated with all-cause hospitalizations but was associated with increased risk of non-COPD-related hospitalizations.

Conclusion: This longitudinal cohort study shows that a high proportion of patients with COPD are pre-frail or frail. The frailty phenotype was associated with an increased risk of non-COPD hospitalizations but not with all-cause hospitalizations or COPD exacerbations. Among the individual frailty components, low handgrip strength was associated with increased risk of COPD exacerbations over a 2-year period. Measuring handgrip strength may identify COPD patients who could benefit from programs to reduce COPD exacerbations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/COPD.S245505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429100PMC
August 2020

Pressure-dependent kinetics of peroxy radicals formed in isobutanol combustion.

Phys Chem Chem Phys 2020 Sep 26;22(35):19802-19815. Epub 2020 Aug 26.

Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue E17-504, Cambridge, MA 02139, USA.

Bio-derived isobutanol has been approved as a gasoline additive in the US, but our understanding of its combustion chemistry still has significant uncertainties. Detailed quantum calculations could improve model accuracy leading to better estimation of isobutanol's combustion properties and its environmental impacts. This work examines 47 molecules and 38 reactions involved in the first oxygen addition to isobutanol's three alkyl radicals located α, β, and γ to the hydroxide. Quantum calculations are mostly done at CCSD(T)-F12/cc-pVTZ-F12//B3LYP/CBSB7, with 1-D hindered rotor corrections obtained at B3LYP/6-31G(d). The resulting potential energy surfaces are the most comprehensive isobutanol peroxy networks published to date. Canonical transition state theory and a 1-D microcanonical master equation are used to derive high-pressure-limit and pressure-dependent rate coefficients, respectively. At all conditions studied, the recombination of γ-isobutanol radical with O forms HO + isobutanal. The recombination of β-isobutanol radical with O forms a stabilized hydroperoxy alkyl radical below 400 K, water + an alkoxy radical at higher temperatures, and HO + an alkene above 1200 K. The recombination of β-isobutanol radical with O results in a mixture of products between 700-1100 K, forming acetone + formaldehyde + OH at lower temperatures and forming HO + alkenes at higher temperatures. The barrier heights, high-pressure-limit rates, and pressure-dependent kinetics generally agree with the results from previous quantum chemistry calculations. Six reaction rates in this work deviate by over three orders of magnitude from kinetics in detailed models of isobutanol combustion, suggesting the rates calculated here can help improve modeling of isobutanol combustion and its environmental fate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0cp02872jDOI Listing
September 2020

Sulfone-Mediated SAr Reaction as a Powerful Tool for the Synthesis of 4-Quinolinyl Ethers and More-Application to the Synthesis of HCV NS3/4a Protease Inhibitor .

J Org Chem 2020 07 19;85(13):8339-8351. Epub 2020 Jun 19.

Chemical Development US, Boehringer-Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368, United States.

An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor was accomplished.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.0c00554DOI Listing
July 2020

Nickel-Catalyzed Cross-Electrophile Reductive Couplings of Neopentyl Bromides with Aryl Bromides.

J Org Chem 2020 06 9;85(12):8214-8220. Epub 2020 Jun 9.

Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.

5-Cyanoimidazole was identified as an inexpensive ligand for nickel-catalyzed cross-electrophile couplings by screening a diverse set of pharmaceutical compound library. A strategic screening approach led to the discovery of this novel ligand, which was successfully applied in the preparation of various alkylated arene products with good to high yields. Furthermore, the properties of this ligand allowed expanding the scope of reductive couplings to challenging substrates, such as sterically hindered neopentyl halides, which are known to generate motifs that are prevalent in biologically active molecules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.0c00549DOI Listing
June 2020

Synthesis of stable isotope-labelled firocoxib.

J Labelled Comp Radiopharm 2020 06 5;63(8):386-392. Epub 2020 May 5.

Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.

Firocoxib (ML-1,785,713) is a nonsteroidal, potent, and selective COX-2 inhibitor, approved for the control of pain and inflammation associated with osteoarthritis in dogs and horses, as well as to control postoperative pain and inflammation in dogs. We employed a six-step synthesis to prepare firocoxib-[ C ] in an overall yield of 35% from the commercially available bromobenzene-[ C ]. The synthetic route involved the preparation of the key intermediate phenyl- C -methyl sulfide using cesium carbonate and S-methylthiourea sulfate under transition-metal free conditions. A two-step preparation of firocoxib-[ C, H ] via the sulfinic acid derivative of firocoxib and methyl iodide-[ C, H ] using the procedure of Gauthier and Yoshikawa was first undertaken. However, the deuterium atoms of the methyl sulfone undergo extensive exchange in aqueous media even at neutral pH. The isotope-labelled firocoxib is intended as an internal standard for bioanalyses of firocoxib from biological matrices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jlcr.3842DOI Listing
June 2020

Serendipitous Formation of Semiconducting Semi-Nindigo Indigoid by the Degradation of Diindolopyrrole.

J Org Chem 2020 04 19;85(7):5073-5077. Epub 2020 Mar 19.

Department of Chemistry, McGill University, Montreal, Quebec H3A 0B8, Canada.

We report the serendipitous discovery and synthesis of an indigoid "semi-Nindigo" () via oxidation of a diindolopyrrole (). The reaction of with BFEtO affords the borylated derivative (). The electronic spectra of and possess intense long wave absorptions near 600 and 650 nm. Compound is weakly emissive in the near-infrared. Thin-film OFETs fabricated with and both exhibited hole mobility of 10 and 10 cm/(V s), respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.0c00054DOI Listing
April 2020

The evolving redox chemistry and bioavailability of vanadium in deep time.

Geobiology 2020 03 12;18(2):127-138. Epub 2020 Feb 12.

School of Biological and Environmental Sciences, Rutgers University, New Brunswick, NJ, USA.

The incorporation of metal cofactors into protein active sites and/or active regions expanded the network of microbial metabolism during the Archean eon. The bioavailability of crucial metal cofactors is largely influenced by earth surface redox state, which impacted the timing of metabolic evolution. Vanadium (V) is a unique element in geo-bio-coevolution due to its complex redox chemistry and specific biological functions. Thus, the extent of microbial V utilization potentially represents an important link between the geo- and biospheres in deep time. In this study, we used geochemical modeling and network analysis to investigate the availability and chemical speciation of V in the environment, and the emergence and changing chemistry of V-containing minerals throughout earth history. The redox state of V shifted from a more reduced V(III) state in Archean aqueous geochemistry and mineralogy to more oxidized V(IV) and V(V) states in the Proterozoic and Phanerozoic. The weathering of vanadium sulfides, vanadium alkali metal minerals, and vanadium alkaline earth metal minerals were potential sources of V to the environment and microbial utilization. Community detection analysis of the expanding V mineral network indicates tectonic and redox influence on the distribution of V mineral-forming elements. In reducing environments, energetic drivers existed for V to potentially be involved in early nitrogen fixation, while in oxidizing environments vanadate ( ) could have acted as a metabolic electron acceptor and phosphate mimicking enzyme inhibitor. The coevolving chemical speciation and biological functions of V due to earth's changing surface redox conditions demonstrate the crucial links between the geosphere and biosphere in the evolution of metabolic electron transfer pathways and biogeochemical cycles from the Archean to Phanerozoic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/gbi.12375DOI Listing
March 2020

Report of the Joint Workshop on Induced Special Regions.

Life Sci Space Res (Amst) 2019 Nov 15;23:50-59. Epub 2019 Oct 15.

Department of Environmental Sciences, Rutgers University, Piscataway, United States.

The Joint Workshop on Induced Special Regions convened scientists and planetary protection experts to assess the potential of inducing special regions through lander or rover activity. An Induced Special Region is defined as a place where the presence of the spacecraft could induce water activity and temperature to be sufficiently high and persist for long enough to plausibly harbor life. The questions the workshop participants addressed were: (1) What is a safe stand-off distance, or formula to derive a safe distance, to a purported special region? (2) Questions about RTGs (Radioisotope Thermoelectric Generator), other heat sources, and their ability to induce special regions. (3) Is it possible to have an infected area on Mars that does not contaminate the rest of Mars? The workshop participants reached a general consensus addressing the posed questions, in summary: (1) While a spacecraft on the surface of Mars may not be able to explore a special region during the prime mission, the safe stand-off distance would decrease with time because the sterilizing environment, that is the martian surface would progressively clean the exposed surfaces. However, the analysis supporting such an exploration should ensure that the risk to exposing interior portions of the spacecraft (i.e., essentially unsterilized) to the martian surface is minimized. (2) An RTG at the surface of Mars would not create a Special Region but the short-term result depends on kinetics of melting, freezing, deliquescence, and desiccation. While a buried RTG could induce a Special Region, it would not pose a long-term contamination threat to Mars, with the possible exception of a migrating RTG in an icy deposit. (3) Induced Special Regions can allow microbial replication to occur (by definition), but such replication at the surface is unlikely to globally contaminate Mars. An induced subsurface Special Region would be isolated and microbial transport away from subsurface site is highly improbable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lssr.2019.09.002DOI Listing
November 2019

Application of a Preformed Pd-BIDIME Precatalyst to Suzuki-Miyaura Cross-Coupling Reaction in Flow.

J Org Chem 2019 04 15;84(8):4926-4931. Epub 2019 Feb 15.

Chemical Development U.S. , Boehringer Ingelheim Pharmaceuticals, Inc. , 900 Ridgebury Road , Ridgefield , Connecticut 06877 , United States.

The application of a Buchwald's third generation palladacycle containing a dihydrobenzooxaphosphole-based ligand (e.g., BIDIME) was reported in the Suzuki cross-coupling reaction. Using flow technology, high yield and reproducible Suzuki cross-coupling reaction for one of our key intermediates was achieved with Pd loadings as low as 0.5 mol %. This continuous flow approach overcomes catalyst deactivation and scale dependence issues that can be a problem in some traditional batch-mode operations and responds to the challenge of improving process greenness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.8b03040DOI Listing
April 2019

Bio-Orthogonal Chemistry and Reloadable Biomaterial Enable Local Activation of Antibiotic Prodrugs and Enhance Treatments against Infections.

ACS Cent Sci 2018 Dec 12;4(12):1624-1632. Epub 2018 Dec 12.

Shasqi Inc., 665 Third Street, San Francisco, California 94107, United States.

Systemic administration of antibiotics can cause severe side-effects such as liver and kidney toxicity, destruction of healthy gut bacteria, as well as multidrug resistance. Here, we present a bio-orthogonal chemistry-based strategy toward local prodrug concentration and activation. The strategy is based on the inverse electron-demand Diels-Alder chemistry between -cyclooctene and tetrazine and involves a biomaterial that can concentrate and activate multiple doses of systemic antibiotic therapy prodrugs at a local site. We demonstrate that a biomaterial, consisting of alginate hydrogel modified with tetrazine, is efficient at activating multiple doses of prodrugs of vancomycin and daptomycin as well as . These results support a drug delivery process that is independent of endogenous environmental markers. This approach is expected to improve therapeutic efficacy with decreased side-effects of antibiotics against bacterial infections. The platform has a wide scope of possible applications such as wound healing, and cancer and immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acscentsci.8b00344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311693PMC
December 2018

Role of extracellular reactive sulfur metabolites on microbial Se(0) dissolution.

Geobiology 2019 05 27;17(3):320-329. Epub 2018 Dec 27.

School of Biological and Environmental Sciences, Rutgers University, New Brunswick, New Jersey.

The dissolution of elemental selenium [Se(0)] during chemical weathering is an important step in the global selenium cycle. While microorganisms have been shown to play a key role in selenium dissolution in soils, the mechanisms of microbial selenium solubilization are poorly understood. In this study, we isolated a Bacillus species, designated as strain JG17, that exhibited the ability to dissolve Se(0) under oxic conditions and neutral pH. Growth of JG17 in a defined medium resulted in the production and accumulation of extracellular compounds that mediated Se(0) dissolution. Analysis of the spent medium revealed the presence of extracellular sulfite, sulfide, and thiosulfate. Abiotic Se(0) dissolution experiments with concentrations of sulfite, sulfide, and thiosulfate relevant to our system showed similar extents of selenium solubilization as the spent medium. Together, these results indicate that the solubilization of Se(0) by JG17 occurs via the release of extracellular inorganic sulfur compounds followed by chemical dissolution of Se(0) by the reactive sulfur metabolites. Our findings suggest that the production of reactive sulfur metabolites by soil microorganisms and the formation of soluble selenosulfur complexes can promote selenium mobilization during chemical weathering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/gbi.12328DOI Listing
May 2019

Adsorption of Methylmercury onto Geobacter bemidijensis Bem.

Environ Sci Technol 2018 10 25;52(20):11564-11572. Epub 2018 Sep 25.

Department of Environmental Sciences , Rutgers University , New Brunswick , New Jersey 08901 , United States.

The anaerobic bacterium Geobacter bemidijensis Bem has the unique ability to both produce and degrade methylmercury (MeHg). While the adsorption of MeHg onto bacterial surfaces can affect the release of MeHg into aquatic environments as well as the uptake of MeHg for demethylation, the binding of MeHg to the bacterial envelope remains poorly understood. In this study, we quantified the adsorption of MeHg onto G. bemidijensis and applied X-ray absorption spectroscopy (XAS) to elucidate the mechanism of MeHg binding. The results showed MeHg adsorption onto G. bemidijensis cell surfaces was rapid and occurred via complexation to sulfhydryl functional groups. Titration experiments yielded cell surface sulfhydryl concentrations of 3.8 ± 0.2 μmol/g (wet cells). A one-site adsorption model with MeHg binding onto sulfhydryl sites provided excellent fits to adsorption isotherms conducted at different cell densities. The log K binding constant of MeHg onto the sulfhydryl sites was determined to be 10.5 ± 0.4. These findings provide a quantitative framework to describe MeHg binding onto bacterial cell surfaces and elucidate the importance of bacterial cells as possible carriers of adsorbed MeHg in natural aquatic systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.est.8b01987DOI Listing
October 2018

Copper-catalyzed asymmetric hydrogenation of 2-substituted ketones dynamic kinetic resolution.

Chem Sci 2018 May 23;9(19):4505-4510. Epub 2018 Apr 23.

Chemical Development , Boehringer Ingelheim Pharmaceuticals, Inc. , 900 Old Ridgebury Road , Ridgefield , CT 06877 , USA . Email: ; Email:

A new class of tunable heterophosphole dimeric ligands have been designed and synthesized. These ligands have enabled the first examples of Cu-catalyzed hydrogenation of 2-substituted-1-tetralones and related heteroaryl ketones dynamic kinetic resolution, simultaneously creating two contiguous stereogenic centers with up to >99 : 1 dr and 98 : 2 er. The ligand-Cu complexes were isolated and characterized by single crystal X-ray, and DFT calculations revealed a novel heteroligated dimeric copper hydride transition state.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8sc00434jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958347PMC
May 2018

Phenyl radical + propene: a prototypical reaction surface for aromatic-catalyzed 1,2-hydrogen-migration and subsequent resonance-stabilized radical formation.

Phys Chem Chem Phys 2018 May;20(19):13191-13214

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

The C9H11 potential energy surface (PES) was experimentally and theoretically explored because it is a relatively simple, prototypical alkylaromatic radical system. Although the C9H11 PES has already been extensively studied both experimentally (under single-collision and thermal conditions) and theoretically, new insights were made in this work by taking a new experimental approach: flash photolysis combined with time-resolved molecular beam mass spectrometry (MBMS) and visible laser absorbance. The C9H11 PES was experimentally accessed by photolytic generation of the phenyl radical and subsequent reaction with excess propene (C6H5 + C3H6). The overall kinetics of C6H5 + C3H6 was measured using laser absorbance with high time-resolution from 300 to 700 K and was found to be in agreement with earlier measurements over a lower temperature range. Five major product channels of C6H5 + C3H6 were observed with MBMS at 600 and 700 K, four of which were expected: hydrogen (H)-abstraction (measured by the stable benzene, C6H6, product), methyl radical (CH3)-loss (styrene detected), H-loss (phenylpropene isomers detected) and radical adduct stabilization. The fifth, unexpected product observed was the benzyl radical, which was rationalized by the inclusion of a previously unreported pathway on the C9H11 PES: aromatic-catalysed 1,2-H-migration and subsequent resonance stabilized radical (RSR, benzyl radical in this case) formation. The current theoretical understanding of the C9H11 PES was supported (including the aromatic-catalyzed pathway) by quantitative comparisons between modelled and experimental MBMS results. At 700 K, the branching to styrene + CH3 was 2-4 times greater than that of any other product channel, while benzyl radical + C2H4 from the aromatic-catalyzed pathway accounted for ∼10% of the branching. Single-collision conditions were also simulated on the updated PES to explain why previous crossed molecular beam experiments did not see evidence of the aromatic-catalyzed pathway. This experimentally validated knowledge of the C9H11 PES was added to the database of the open-source Reaction Mechanism Generator (RMG), which was then used to generalize the findings on the C9H11 PES to a slightly more complicated alkylaromatic system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8cp01159aDOI Listing
May 2018

Draft genome sequence of sp. WAO an arsenite and sulfide oxidizer isolated from a pyrite rock outcrop in New Jersey.

Stand Genomic Sci 2018 10;13. Epub 2018 Apr 10.

2Department of Environmental Sciences, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey USA.

This genome report describes the draft genome and physiological characteristics of sp. WAO (=DSM 102914), a novel strain of the genus in the family . sp. WAO was isolated from pulverized pyritic shale containing elevated levels of arsenic. This aerobic, gram negative microorganism is capable of facultative chemolithoautotrophic growth under aerobic conditions by oxidizing the electron donors arsenite, elemental sulfur, thiosulfate, polysulfide, and amorphous sulfur. The draft genome is of a single circular chromosome 6,125,776 bp long consisting of 21 scaffolds with a G + C content of 66.84%. A total 5727 genes were predicted of which 5665 or 98.92% are protein-coding genes and 62 RNA genes. We identified the genes and , which encode the large and small subunits of the arsenic oxidase respectively. We also identified the genes for the complete sulfur oxidation pathway which is used to oxidize thiosulfate to sulfate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40793-018-0312-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894208PMC
April 2018

BABIPhos Family of Biaryl Dihydrobenzooxaphosphole Ligands for Asymmetric Hydrogenation.

Org Lett 2018 04 15;20(7):1725-1729. Epub 2018 Mar 15.

Chemical Development US , Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road , Ridgefield , Connecticut 06877 , United States.

Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An efficient route toward various analogues was also established, giving access to phosphines with different electronic and steric properties. The newly obtained ligands demonstrated high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and trisubstituted enamides. This new class of ligands is complementary to previously described bidentate benzooxaphosphole ligands BIBOP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.8b00139DOI Listing
April 2018

Enantioselective Synthesis of α-(Hetero)aryl Piperidines through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights.

Org Lett 2018 03 20;20(5):1333-1337. Epub 2018 Feb 20.

Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc. , 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outersphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.8b00067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835364PMC
March 2018

Development of a Scalable, Chromatography-Free Synthesis of t-Bu-SMS-Phos and Application to the Synthesis of an Important Chiral CF-Alcohol Derivative with High Enantioselectivity Using Rh-Catalyzed Asymmetric Hydrogenation.

J Org Chem 2018 02 23;83(3):1448-1461. Epub 2018 Jan 23.

Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc. , 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.7b03022DOI Listing
February 2018

Modeling study of the anti-knock tendency of substituted phenols as additives: an application of the reaction mechanism generator (RMG).

Phys Chem Chem Phys 2018 Apr;20(16):10637-10649

Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

This work presents kinetic modeling efforts to evaluate the anti-knock tendency of several substituted phenols if used as gasoline additives. They are p-cresol, m-cresol, o-cresol, 2,4-xylenol, 2-ethylphenol, and guaiacol. A detailed kinetic model was constructed to predict the ignition of blends of the phenols in n-butane with the help of reaction mechanism generator (RMG), an open-source software package. The resulting model, which has 1465 species and 27 428 reactions, was validated against literature n-butane ignition data in the low-to-intermediate temperature range. To rank the anti-knock tendency of the additives, engine-like simulations were performed in a closed adiabatic homogenous batch reactor with a volume history derived from the pressure profile of a real research octane number (RON) engine test. The ignition timings of the additive blends were compared to that of primary reference fuels (PRFs) to quantitatively predict the anti-knock ability. The model predictions agree well with experimental determinations of the changes in RON induced by the additives. This study explains the chemical mechanism by which methyl-substituted phenols increase RON, and demonstrates how fundamental chemical kinetics can be used to evaluate practical fuel additive performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c7cp07058fDOI Listing
April 2018

Tellurate enters Escherichia coli K-12 cells via the SulT-type sulfate transporter CysPUWA.

FEMS Microbiol Lett 2017 Dec;364(24)

Soluble forms of tellurium are environmental contaminants that are toxic to microorganisms. While tellurite [Te(IV)] is a well-characterized antimicrobial agent, little is known about the interactions of tellurate [Te(VI)] with bacterial cells. In this study, we investigated the role of sulfate transporters in the uptake of tellurate in Escherichia coli K-12. Mutant strains carrying a deletion of the cysW gene in the CysPUWA sulfate transporter system accumulated less cellular tellurium and exhibited higher resistance to tellurate compared with the wild-type strain. Complementation of the mutation restored tellurate sensitivity and uptake. These results indicate that tellurate enters E. coli cells to cause toxic effects via the CysPUWA sulfate transporter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/femsle/fnx241DOI Listing
December 2017

Enantioselective Nickel-Catalyzed Mizoroki-Heck Cyclizations To Generate Quaternary Stereocenters.

Org Lett 2017 07 12;19(13):3338-3341. Epub 2017 Jun 12.

Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.

The development of enantioselective carbon-carbon bond couplings catalyzed by nonprecious metals is highly desirable in terms of cost efficiency and sustainability. The first nickel-catalyzed enantioselective Mizoroki-Heck coupling is reported. This transformation is accomplished via mild reaction conditions, leveraging on QuinoxP* as a chiral ligand to afford oxindoles containing quaternary stereocenters. Good reactivity and selectivity are observed in the presence of various functional groups. Computational studies suggest that the oxidative addition assembles an atropisomeric intermediate responsible for the facial selectivity of the insertion step.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.7b01054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634709PMC
July 2017

Synthesis of P-Chiral Dihydrobenzooxaphosphole Core for BI Ligands in Asymmetric Transformations.

J Org Chem 2017 05 5;82(10):5456-5460. Epub 2017 May 5.

Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc. , 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.

An efficient and practical synthesis of enantiomerically pure P-chiral dihydrobenzooxaphosphole (BOP) core 1 is developed that is amenable to large scale preparation of the related ligand series. The unique epimerization of the P-chiral center of the undesired (R,R)-diastereomeric phosphine oxide 19 through chlorination followed by crystallization makes this chemical resolution method achieve 65% yield of desired (R,S)-diastereomer 12.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.7b00491DOI Listing
May 2017

Nickel-Catalyzed C-3 Direct Arylation of Pyridinium Ions for the Synthesis of 1-Azafluorenes.

Chem Sci 2016 Aug 19;7(8):5581-5586. Epub 2016 May 19.

Department of Chemical Development US, Boehringer-Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road, Ridgefield, CT, 06877, USA.

The direct arylation of pyridine substrates using non-precious catalysts is underdeveloped but highly desirable due to its efficiency to access important motifs while being extremely cost-effective. The first nickel-catalyzed C-3 direct arylation of pyridine derivatives to provide a new approach to valuable 1-azafluorene pharmacophore frameworks was developed. This transformation is accomplished using air-stable nickel catalyst precursors combined with phenanthroline ligands and tolerates a variety of substituents. Computational studies suggest facile oxidative addition via the pyridinium form, deprotonation, and a subsequent carbo-nickelation cyclization. Nickel homolysis/recombination permits isomerization to the stereochemical array needed for the final elimination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/C6SC01457GDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245920PMC
August 2016