Conservative versus Interventional Treatment for Spontaneous Pneumothorax.

BACKGROUND: Whether conservative management is an acceptable alternative to interventional management for uncomplicated, moderate-to-large primary spontaneous pneumothorax is unknown. METHODS: In this open-label, multicenter, noninferiority trial, we recruited patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax. Patients were randomly assigned to immediate interventional management of the pneumothorax (intervention group) or a conservative observational approach (conservative-management group) and were followed for 12 months. The primary outcome was lung reexpansion within 8 weeks. RESULTS: A total of 316 patients underwent randomization (154 patients to the intervention group and 162 to the conservative-management group). In the conservative-management group, 25 patients (15.4%) underwent interventions to manage the pneumothorax, for reasons prespecified in the protocol, and 137 (84.6%) did not undergo interventions. In a complete-case analysis in which data were not available for 23 patients in the intervention group and 37 in the conservative-management group, reexpansion within 8 weeks occurred in 129 of 131 patients (98.5%) with interventional management and in 118 of 125 (94.4%) with conservative management (risk difference, -4.1 percentage points; 95% confidence interval [CI], -8.6 to 0.5; P = 0.02 for noninferiority); the lower boundary of the 95% confidence interval was within the prespecified noninferiority margin of -9 percentage points. In a sensitivity analysis in which all missing data after 56 days were imputed as treatment failure (with reexpansion in 129 of 138 patients [93.5%] in the intervention group and in 118 of 143 [82.5%] in the conservative-management group), the risk difference of -11.0 percentage points (95% CI, -18.4 to -3.5) was outside the prespecified noninferiority margin. Conservative management resulted in a lower risk of serious adverse events or pneumothorax recurrence than interventional management. CONCLUSIONS: Although the primary outcome was not statistically robust to conservative assumptions about missing data, the trial provides modest evidence that conservative management of primary spontaneous pneumothorax was noninferior to interventional management, with a lower risk of serious adverse events. (Funded by the Emergency Medicine Foundation and others; PSP Australian New Zealand Clinical Trials Registry number, ACTRN12611000184976.).

A Widely Applicable and Versatile Method for the Ring-Opening 1,3-Carbocarbonation of Donor-Acceptor Cyclopropanes.

A 1,3-carbocarbonation of 2-substituted cyclopropane 1,1-dicarboxylates introduces various saturated or unsaturated carbon residues at the 1- and 3- position of the former three-membered ring. Under copper catalysis, ring-opening attack with a Grignard reagent proceeded smoothly; the intermediate was converted to the final product by reaction with appropriate carbon-based electrophiles under basic conditions. As nucleophiles, Grignard reagents derived from sp3 -, sp2 -, and sp-hybridized carbon residues were successfully employed, whereas various aliphatic bromides and EBX derivatives (for sp moieties) served as electrophiles.

Synthesis of the indeno[1,2-b]indole core of janthitrem B.

The tetracyclic core structure of the majority of indole diterpenoids features a trans-hydrindane moiety that is fused to an indole unit. We report here a novel synthetic route that includes a photo-Nazarov cyclization of a 3-acylindole precursor initially providing the thermodynamically preferred cis-hydrindanone. After reduction and conversion to the cyclopentadiene, dihydroxylation and hydrogenation provided the indoline. The key step generated the trans-system by stereospecific hydride shift on a dioxaphospholane under Grainger's conditions, for the first time applied to an N-heterocycle. When starting from the corresponding indole, we observed the formation of hitherto unknown methanocyclohepta[b]indolones. Deoxygenation of the trans-hydrindanone was achieved after conversion to the 1,3-dithiolane, followed by RANEY® Ni reduction.

Donor-Acceptor Cyclopropanes: Activation Enabled by a Single, Vinylogous Acceptor.

A novel class of highly activated donor-acceptor cyclopropanes bearing only a single, vinylogous acceptor is presented. These strained moieties readily undergo cycloadditions with aldehydes, ketones, thioketones, nitriles, naphth-2-ols and various other substrates to yield the corresponding carbo- and heterocycles. Diastereocontrol can be achieved through the choice of catalyst (Brønsted or Lewis acid). The formation of tetrahydrofurans was shown to be highly enantiospecific when chiral cyclopropanes are employed. A series of mechanistic and kinetic experiments was conducted to elucidate a plausible catalytic cycle and to rationalize the stereochemical outcome.

Role of the Solvent in the Reactivity of Bis-4-imidazoline-2-selone Derivatives toward I2: An Experimental and Theoretical Approach.

The reactivity of 1,1'-bis(3-methyl-4-imidazolin-2-selone)methane (L1) and 1,2-bis(3-methyl-4-imidazolin-2-selone)ethane (L2) toward I2 has been explored in MeCN under different experimental conditions and compared with that in CH2Cl2. The compounds [L1'](I)2 (I), [L1I]n(I)n (II), [L1(µ-Se)](I)2·1/2H2O (III), [L1I](I3)·2I2 (IV), and [L2](I)2·MeCN (V) were obtained and characterized. X-ray diffraction analyses point out an ionic nature for these compounds, which is presumably favored by the polarity of the solvent used. In particular, [L1I]n(I)n (II) represents the first example of an iodonium complex of imidazoline-2-selone derivatives, while [L1(µ-Se)](I)2·1/2H2O (III) represents a unique example of a dicationic [RSeSeSeR] triselane. Density functional theory calculations have allowed us to better understand the nature of the obtained compounds and to justify their formations in polarizing reaction conditions rather than in low polar solvents.

Phosphine-Catalyzed Aryne Oligomerization: Direct Access to α,ω-Bisfunctionalized Oligo(ortho-arylenes).

A phosphine-catalyzed oligomerization of arynes using selenocyanates was developed. The use of JohnPhos as a bulky phosphine is the key to accessing α,ω-bisfunctionalized oligo(ortho-arylenes) with RSe as the substituent at one terminus and CN as the substituent at the other. The in situ formation of R3PSeR' cations, serving as sterically encumbered electrophiles, hinders the immediate reaction that affords the 1,2-bisfunctionalization product and instead opens a competitive pathway leading to oligomerization. Various optimized conditions for the predominant formation of dimers, but also for higher oligomers such as trimers and tetramers, were developed. Depending on the electronic properties of the electrophilic reaction partner, even compounds up to octamers were isolated. Optimization experiments revealed that a properly tuned phosphine as catalyst is of crucial importance. Mechanistic studies demonstrated that the cascade starts with the attack of cyanide; aryne insertion into n-mers leading to (n+1)-mers was ruled out.

Alkyne Aminopalladation/Heck and Suzuki Cascades: An Approach to Tetrasubstituted Enamines.

Alkyne aminopalladation reactions starting from tosylamides are reported. The emerging vinylic Pd species are converted either in an intramolecular Heck reaction with olefinic units or in an intermolecular Suzuki reaction by using boronic acids exhibiting broad functional group tolerance. Tetra(hetero)substituted tosylated enamines are obtained in a simple one-pot process.

Azide-Functionalized Derivatives of the Virulence-Associated Sugar Pseudaminic Acid: Chiral Pool Synthesis and Labeling of Bacteria.

Pseudaminic acid (Pse) is a significant prokaryotic monosaccharide found in important Gram-negative and Gram-positive bacteria. This unique sugar serves as a component of cell-surface-associated glycans or glycoproteins and is associated with their virulence. We report the synthesis of azidoacetamido-functionalized Pse derivatives as part of a search for Pse-derived metabolic labeling reagents. The synthesis was initiated with d-glucose (Glc), which served as a cost-effective chiral pool starting material. Key synthetic steps involve the conversion of C1 of Glc into the terminal methyl group of Pse, and inverting deoxyaminations at C3 and C5 of Glc followed by backbone elongation with a three-carbon unit using the Barbier reaction. Metabolic labeling experiments revealed that, of the four Pse derivatives, ester-protected C5 azidoacetamido-Pse successfully labeled cells of Pse-expressing Gram-positive and Gram-negative strains. No labeling was observed in cells of non-Pse-expressing strains. The ester-protected and C5 azidoacetamido-functionalized Pse is thus a useful reagent for the identification of bacteria expressing this unique virulence-associated nonulosonic acid.

Quantification of Noncovalent Interactions in Azide-Pnictogen, -Chalcogen, and -Halogen Contacts.

The noncovalent interactions between azides and oxygen-containing moieties are investigated through a computational study based on experimental findings. The targeted synthesis of organic compounds with close intramolecular azide-oxygen contacts yielded six new representatives, for which X-ray structures were determined. Two of those compounds were investigated with respect to their potential conformations in the gas phase and a possible significantly shorter azide-oxygen contact. Furthermore, a set of 44 high-quality, gas-phase computational model systems with intermolecular azide-pnictogen (N, P, As, Sb), -chalcogen (O, S, Se, Te), and -halogen (F, Cl, Br, I) contacts are compiled and investigated through semiempirical quantum mechanical methods, density functional approximations, and wave function theory. A local energy decomposition (LED) analysis is applied to study the nature of the noncovalent interaction. The special role of electrostatic and London dispersion interactions is discussed in detail. London dispersion is identified as a dominant factor of the azide-donor interaction with mean London dispersion energy-interaction energy ratios of 1.3. Electrostatic contributions enhance the azide-donor coordination motif. The association energies range from -1.00 to -5.5 kcal mol-1 .

One-Pot Strategy for Symmetrical and Unsymmetrical BOIMPY Fluorophores.

We report the improved direct access to red-emitting BOIMPY fluorophores (λ ≈ 600 nm) via a simple one-pot approach. Our method starts from easily available benzimidazole-2-carboxylic acids and not only greatly improves the overall yields but also saves both costly reagents and time. In addition, the method facilitates the synthesis of novel unsymmetrical BOIMPY motifs. Therefore, these BOIMPY scaffolds derived from the BODIPY core become more accessible for applications as fluorophores at the appealing red edge of the visible spectrum.

Lewis-Acid-Catalyzed (3+2)-Cycloadditions of Donor-Acceptor Cyclopropanes with Thioketenes.

The reactivity of donor-acceptor (D-A) cyclopropanes towards thioketenes was investigated. In a (3+2)-cycloaddition using Sc(OTf)3 as a Lewis acidic catalyst, the corresponding exocyclic thioenol ethers (2-methylidene tetrahydrothiophenes) were formed in moderate to good yields. Unsymmetrical thioketenes provided E/Z mixtures at the double bond, with the Z isomer being preferred.

Extended Benzene-Fused Oligo-BODIPYs: In Three Steps to a Series of Large, Arc-Shaped, Near-Infrared Dyes.

We present a straightforward, three-step synthesis engaging an oligomerization and subsequent one-pot oxidation step to form fully conjugated, benzene-fused oligo-BODIPYs from simple BODIPY precursors. FeCl3 serves as an efficient, bifunctional oxidant for a (multiple) cyclization/desaturation process, applied to ethylene-bridged dimeric, trimeric and oligomeric species to transform linking ethano units into stiff benzene fusions between unsubstituted ß-positions of each BODIPY unit. The structural integrity was verified by X-ray crystallography, and all target compounds were studied in detail by photophysical, electrochemical and computational means. The main S1 excited state gradually converges to a structure-specific excitation limit, displaying a strong shift of the absorption event from about 500 nm (BODIPY monomer) to 955 nm (octamer) with attenuation coefficients up to ca. 500 000 M-1 cm-1 .

GlycoBODIPYs: Sugars Serving as a Natural Stock for Water-soluble Fluorescent Probes of Complex Chiral Morphology.

A range of unprocessed, reducing sugar substrates (mono-, di-, and trisaccharides) is shown to take part in a straightforward four-step synthetic route to water-soluble, uncharged BODIPY derivatives with unimpaired chiral integrity and high fluorescence efficiency. A wide compatibility with several postfunctionalizations is demonstrated, thus suggesting a universal utility of the multifunctional glycoconjugates, which we call GlycoBODIPYs. Knoevenagel condensations are able to promote a red-shift in the spectra, thereby furnishing strongly fluorescent red and far-red glycoconjugates of high hydrophilicity. The synthetic outcome was studied by X-ray crystallography and by comprehensive photophysical investigations in several solvent systems. Furthermore, cell experiments illustrate efficient cell uptake and demonstrate differential cell targeting as a function of the integrated chiral information.

Electrocatalytic Activation of Donor-Acceptor Cyclopropanes and Cyclobutanes: An Alternative C(sp3 )-C(sp3 ) Cleavage Mode.

We describe the first electrochemical activation of D-A cyclopropanes and D-A cyclobutanes leading after C(sp3 )-C(sp3 ) cleavage to the formation of highly reactive radical cations. This concept is utilized to formally insert molecular oxygen after direct or DDQ-assisted anodic oxidation of the strained carbocycles, delivering ß- and γ-hydroxy ketones and 1,2-dioxanes electrocatalytically. Furthermore, insights into the mechanism of the oxidative process, obtained experimentally and by additional quantum-chemical calculations are presented. The synthetic potential of the reaction products is demonstrated by diverse derivatizations.

Regio- and Diastereoselective Copper-Catalyzed Carbomagnesiation for the Synthesis of Penta- and Hexa-Substituted Cyclopropanes.

Despite the highly strained nature of cyclopropanes possessing three vicinal quaternary carbon stereocenters, the regio- and diastereoselective copper-catalyzed carbomagnesiation reaction of cyclopropenes provides an easy and efficient access to these novel persubstituted cyclopropyl cores with a complete regio- and diastereoselectivity.

Cycloadditions of Donor-Acceptor Cyclopropanes and -butanes using S=N-Containing Reagents: Access to Cyclic Sulfinamides, Sulfonamides, and Sulfinamidines.

We present (3+2)- and (4+2)-cycloadditions of donor-acceptor (D-A) cyclopropanes and cyclobutanes with N-sulfinylamines and a sulfur diimide, along with a one-pot, two-step strategy for the formal insertion of HNSO2 into D-A cyclopropanes. These are rare examples of cycloadditions with D-A cyclopropanes and cyclobutanes whereby the 2π component consists of two different heteroatoms, thus leading to five- and six-membered rings containing adjacent heteroatoms.

Regio- and Diastereoselective Dimerization of Diazo Carbonyls: A Cooperative Catalytic Approach to Complex Scaffolds with Four Contiguous Stereocenters.

Starting from readily available o-diazoacyl-substituted arene carboxylates, scaffolds with the 5,9-epoxycyclohepta[b]pyran-2(3H)-one core were obtained by cooperative RhII , Lewis and Brønsted acid catalysis. Four new bonds, three functional groups (lactone, ketal, and alcohol) and four contiguous stereocenters are formed during this regio- and diastereoselective process in a single synthetic step. Intensive optimization and mechanistic studies, including the trapping, isolation, and elucidation of reaction intermediates, led to a plausible mechanistic scenario. The reaction is proposed to involve carbonyl ylides but also transient species of the ketocarbene equilibrium that undergo a cascade of cycloaddition and skeletal rearrangements.

Enantiomerically Pure Constrained Geometry Complexes of the Rare-Earth Metals Featuring a Dianionic N-Donor Functionalised Pentadienyl Ligand: Synthesis and Characterisation.

We report the preparation of enantiomerically pure constrained geometry complexes (cgc) of the rare-earth metals bearing a pentadienyl moiety (pdl) derived from the natural product (1R)-(-)-myrtenal. The potassium salt 1, [Kpdl*], was treated with ClSiMe2 NHtBu, and the resulting pentadiene 2 was deprotonated with the Schlosser-type base KOtPen/nBuLi (tPen=CMe2 (CH2 Me)) to yield the dipotassium salt [K2 (pdl*SiMe2 NtBu)] (3). However, 3 rearranges in THF solution to its isomer 3' by a 1,3-H shift, which elongates the bridge between the pdl and SiMe2 NtBu moieties by one CH2 unit. This is crucial for the successful formation of various monomeric C1 - or dimeric C2 -symmetric rare-earth cgc complexes with additional halide, tetraborohydride, amido and alkyl functionalities. All compounds have been extensively characterised by solid-state X-ray diffraction analysis, solution NMR spectroscopy and elemental analyses.

Protecting-Group-Mediated Diastereoselective Synthesis of C4'-Methylated Uridine Analogs and Their Activity against the Human Respiratory Syncytial Virus.

Adjusting the protecting group strategy, from an alkyl ether to a bidentate ketal at the carbohydrate backbone of uridine, facilitates a switchable diastereoselective α- or ß-C4'/C5'-spirocyclopropanation. Using these spirocyclopropanated nucleosides as key intermediates, we synthesized a variety of C4'-methylated d-ribose and l-lyxose-configured uridine derivatives by a base-mediated ring-opening of the spirocyclopropanol moiety. Investigations of antiviral activity against the human respiratory syncytial virus were carried out for selected derivatives, showing moderate activity.

(Amino)cyclophosphazenes as Multisite Ligands for the Synthesis of Antitumoral and Antibacterial Silver(I) Complexes.

The reactivity of the multisite (amino)cyclotriphosphazene ligands, [N3P3(NHCy)6] and [N3P3(NHCy)3(NMe2)3], has been explored in order to obtain silver(I) metallophosphazene complexes. Two series of cationic silver(I) metallophosphazenes were obtained and characterized: [N3P3(NHCy)6{AgL}n](TfO)n [n = 2, L = PPh3 (2), PPh2Me (4); n = 3, L = PPh3 (3), PPh2Me (5), TPA (TPA = 1,3,5-triaza-7-phosphaadamantane, 6)] and nongem-trans-[N3P3(NHCy)3(NMe2)3{AgL}n](TfO)n [n = 2, L = PPh3 (7), PPh2Me (9); n = 3, L = PPh3 (8), PPh2Me (10)]. 5, 7, and 9 have also been characterized by single-crystal X-ray diffraction, thereby allowing key bonding information to be obtained. Compounds 2-6, 9, and 10 were screened for in vitro cytotoxic activity against two tumor human cell lines, MCF7 (breast adenocarcinoma) and HepG2 (hepatocellular carcinoma), and for antimicrobial activity against five bacterial species including Gram-positive, Gram-negative, and Mycobacteria strains. Both the IC50 and MIC values revealed excellent biological activity for these metal complexes, compared with their precursors and cisplatin and also AgNO3 and silver sulfadiazine, respectively. Both IC50 and MIC values are among the lowest values found for any silver derivatives against the cell lines and bacterial strains used in this work. The structure-activity relationships were clear. The most cytotoxic and antimicrobial derivatives were those with the triphenylphosphane and [N3P3(NHCy)6] ligands. A significant improvement in the activity was also observed upon a rise in the number of silver atoms linked to the phosphazene ring.