A base-mediated synthesis of N-hydroxy- and N-alkoxyindoles from 2-nitrostyrenes.

Sequential treatment of alkyl 2-(2-nitroaryl)-2-butenoates with potassium tert-butoxide and an electrophile, such as methyl iodide, benzyl bromide and allyl bromide, afforded N-alkoxyindoles. In related reactions, using sodium tert-pentoxide as the base with or without in situ addition of an electrophile afforded N-alkoxy- and N-hydroxyindoles, respectively. Electrophiles such as dimethylsulfate, p-tosyl chloride, and acetic anhydride afforded moderate yields of the respective N-methoxy-, N-tosyloxy, and N-acetoxyindoles, while methyl iodide, benzyl bromide, and 1-bromohexane failed to form alkylated products using sodium tert-pentoxide as the base.

A palladium-catalyzed Barluenga cross-coupling - reductive cyclization sequence to substituted indoles.

A short and flexible synthesis of substituted indoles employing two palladium-catalyzed reactions, a Barluenga cross-coupling of p-tosylhydrazones with 2-nitroarylhalides followed by a palladium-catalyzed, carbon monoxide-mediated reductive cyclization has been developed. A one-pot, two-step methodology was further developed, eliminating isolation and purification of the cross-coupling product. This was accomplished by utilizing the initially added 0.025 equivalents of bis(triphenylphosphine)palladium dichloride, thus serving a dual role in the cross-coupling and the reductive cyclization. It was found that addition of 1,3-bis(diphenylphosphino)propane and carbon monoxide after completion of the Barluenga reaction afforded, in most cases, significantly better overall yields.

DOSE EVALUATION AND PROPOSAL OF LOCAL DIAGNOSTIC REFERENCE LEVELS FOR PAEDIATRIC CARDIAC CATHETERIZATIONS PERFORMED ON A HIGH-SENSITIVITY ANGIOGRAPHIC SYSTEM ALLOWING LOW-DOSE IMAGING.

Radiation doses from paediatric cardiac catheterizations were analysed based on procedure type and patient weight, and local diagnostic reference levels (LDRLs) were proposed. The procedures were performed on a Siemens Artis Q.zen biplane system with high-sensitivity detectors allowing low-dose imaging. Good radiological practice, e.g. adapting dose level and frame rate continuously and minimizing the x-ray field with collimators, was routine during procedures. The median total dose-area-product (DAP) value was 58 µGym2 for diagnostic catheterizations, 48 µGym2 for interventional catheterizations and 33 µGym2 for myocardial biopsies. The median DAP per body weight was 4.0 µGym2 kg-1. The median total fluoroscopy time varied from 6.0 min for myocardial biopsies, to 9.7 and 10.5 min, respectively, for diagnostic and interventional catheterizations. The third quartile of the DAP values in each weight group was proposed as LDRL. LDRLs for fluoroscopy time were determined solely based on procedure type, due to the absence of weight dependence.

Palladium-Catalyzed Double Reductive Cyclization of 2,3-Dinitro-1,4-dialkenylbenzenes. Synthesis of 1H,8H-Pyrrolo[3,2-g]indoles.

A flexible route to both symmetrical and unsymmetrical 1H,8H-pyrrolo[3,2-g]indole has been developed. The key and ultimate step is a double palladium-catalyzed, carbon monoxide mediated reductive cyclization of 1,4-dialkenyl-2,3-dinitrobenzenes. The cyclization precursors were prepared by a double Kosugi-Migita-Stille cross coupling of 1,4-dibromo-2,3-dinitrobenzene with an alkenyltin reagent to give symmetrical products. Unsymetrical cyclization precursors were prepared by two sequential cross couplings using 4-iodo-2,3-dinitrophenyl trifluoromethanesulfonate as the starting material.

Synthesis of the tricyclic indole alkaloids, dilemmaones A and B.

Dilemmaones A-C are naturally occurring tricyclic indole alkaloids possessing a unique hydroxymethylene or methoxymethylene substituent at the C2 position of the indole core and a C6-C7 fused cyclopentanone. Dilemmaone B has been prepared in 5 steps from 5-methylindan-1-one, and dilemmaone A has been prepared in 3 steps from a common precursor, 6-bromo-5-methyl-7-nitroindan-1-one. In both syntheses, key steps include a Kosugi-Migita-Stille cross coupling and a reductive cyclization using hydrogen gas and a transition metal catalyst.

Chemoselectivity in the Kosugi-Migita-Stille coupling of bromophenyl triflates and bromo-nitrophenyl triflates with (ethenyl)tributyltin.

Kosugi-Migita-Stille cross coupling reactions of (ethenyl)tributyltin with all isomeric permutations of bromophenyl triflate and bromo-nitrophenyl triflate were examined in order to determine the chemoselectivity of carbon-bromine versus carbon-triflate bond coupling under different reaction conditions. In general, highly selective carbon-bromine bond cross couplings were observed using for example bis(triphenylphosphine)palladium dichloride (2 mol-%) in 1,4-dioxane at reflux. In contrast, reactions using the same pre-catalyst but in the presence of a three-fold excess of lithium chloride in N,N-dimethylformamide at ambient temperature were in most cases selective for coupling at the carbon-triflate bond. Overall, isolated yields and the selectivity for carbon-bromine bond coupling were significantly higher compared to carbon-triflate bond coupling.

Treatment of valvular aortic stenosis in children: a 20-year experience in a single institution.

OBJECTIVES: This study presents short- and long-term follow-up after treatment for isolated valvular aortic stenosis in children with surgical valvotomy as the preferred 1st intervention. METHODS: All patients aged 0-18 years treated between 1994 and 2013 at our centre were reviewed regarding the mode of first treatment, mortality, reinterventions and the need for aortic valve replacement. RESULTS: A total of 113 patients were identified in local registries. There were 44 neonates, 31 infants and 38 children. The mean follow-up period was 11 years (range 2-22 years). No early deaths and only 2 late deaths were reported. Of the 113 patients, 92 patients had open surgical valvotomy as the 1st intervention. Freedom from reintervention was 80%, 69%, 61%, 57% and 56% at 1, 5, 10, 15 and 20 years, respectively. The main indication for reintervention was valvular stenosis. Freedom from aortic valve replacement was 67%. CONCLUSIONS: Surgical valvotomy of aortic stenosis in this long-term follow-up study resulted in no 30-day mortality and <1% late mortality. Reinterventions were common, with 38% of the patients having further surgery or catheter treatment of the aortic valve before the age of 18 years. Among the 40 patients aged 18 years or older at follow-up, 45% had had the aortic valve replaced. Our data do not allow comparison of catheter and surgical treatment, but, based on these results, we find no reason to change our current policy of surgical treatment as 1st intervention in patients with isolated valvular aortic stenosis.

Carag bioresorbable septal occluder (CBSO): histopathology of experimental implants.

AIMS: The aim of this study was to evaluate local biological responses to the partially bioresorbable nonmetal frame Carag bioresorbable septal occluder system in an experimental setting. METHODS AND RESULTS: A Good Laboratory Practices (GLP) study was performed with implantation of the device into the interatrial septum of 24 German Landrace pigs with follow-up periods of 3, 5, 8 and 15 months (six animals in each group). One non-implant-related death occurred one month after implantation. Histology was obtained by sawing and grinding of the hard-resin embedded specimen after formalin fixation. All occlusion devices were found correctly positioned without any residual shunt at the end of the experiments. Complete endothelialisation could be confirmed histologically in all specimens independent of implantation period. There were only a few lymphocytic infiltrations locally related to the implant materials. Sporadic macrophages and foreign body giant cells were found adjacent to the textile fabric. Resorption of the biodegradable frame material was seen to proceed with implantation time. CONCLUSIONS: This is the first report on histopathology of a septal defect occluder with a bioresorbable filament structure in vivo which is already in clinical use. Good biocompatibility was demonstrated with documentation of timely degradation and substitution of the polymer material by fibromuscular cells and extracellular matrix components.

Syntheses of three naturally occurring polybrominated 3,3'-bi-1H-indoles.

The naturally occurring polybrominated indoles 2,2',5,5'-tetrabromo-3,3'-bi-1H-indole, 2,2',6,6'-tetrabromo-3,3'-bi-1H-indole, and 2,2',5,5',6,6'-hexabromo-3,3'-bi-1H-indole were synthesized using a palladium catalyzed, carbon monoxide mediated, double reductive N-heterocyclization of 2,3-bis(2-nitro-4(or 5)-bromophenyl)-1,4-butadienes as the key step.

Synthesis of N-alkoxy-substituted 2H-benzimidazoles.

Treatment of 2-nitro-N-(2-methyl-1-propen-1-yl)benzenamines with potassium tert-butoxide in tert-butanol followed by the addition of an electrophile affords N-alkoxy-2H-benzimidazoles. Electrophiles including methyl iodide, allylic bromides, propargylic bromides, benzyl bromide, and acetyl chloride gave good to excellent yields of product while 1-iodo- and 2-iodo-butane afforded very low yields.

Double Palladium Catalyzed Reductive Cyclizations. Synthesis of 2,2'-, 2,3'-, and 3,3'-Bi-1H-indoles, Indolo[3,2-b]indoles, and Indolo[2,3-b]indoles.

A palladium catalyzed, carbon monoxide mediated, double reductive cyclization of 1,4-, 1,3-, and 2,3-bis(2-nitroaryl)-1,3-butadienes to afford 2,2'-, 2,3'-, and 3,3'-biindoles, respectively, was developed. In contrast, reductive cyclizations of 1,2-bis(2-nitroaryl)ethenes were nonselective, affording mixtures of monocyclized indoles, indolo[3,2-b]indole, indolo[1,2-c]quinazolin-6(5H)-ones, and 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones. Nonselective product formation was also observed from reductive cyclization of 1,1-bis(2-nitroaryl)ethenes, producing indolo[2,3-b]indoles and indolo[2,3-c]quinolin-6-ones. Carbon monoxide insertion to give the carbonyl containing products was the major or sole reaction path starting from 1,1- or 1,2-bis(2-nitroaryl)ethenes.

Total synthesis of the tetracyclic indole alkaloid ht-13-B.

An expedient synthesis corroborating the proposed structure of the tetracyclic indole alkaloid ht-13-B is presented. Key synthetic steps include acyliminium ion allylation, a Mitsunobu reaction, a palladium-catalyzed Stille-Kelly cross coupling reaction, and a carbon monoxide-mediated palladium-catalyzed reductive N-heterocyclization. The chiral centers are ultimately derived from commercially available trans-4-hydroxy-l-proline.

The temporary placement of endobronchial stents in the management of bronchial compression by transiently enlarged mediastinal structures.

Enlargement of mediastinal structures can cause compression of the trachea and/or bronchi. We describe two case reports in which stenosis of left main bronchus, secondary to compression from an enlarged mediastinal structure, were successfully managed with temporary placement of a metallic self-expanding stent while waiting for the compression to relieve.

Minimally invasive insertion of an equine stented pulmonary valve with a built-in sinus portion in a sheep model.

OBJECTIVES: This study evaluated the feasibility of inserting a new equine stented-valve with a sinus portion in a lamb survival model, through a minimally invasive thoracotomy with right ventricular access without cardiopulmonary bypass. BACKGROUND: Extant surgical or percutaneous methods for inserting biological valves in the right outflow tract have drawbacks and limitations. METHODS: A decellularized equine valved jugular vein, sutured to a self-expanding stent with a sinus portion, was placed through a minimal right thoracotomy using a newly developed flexible hydraulic release device in seven lambs. The approach through the right ventricle into the pulmonary valve position is achieved on a beating heart. RESULTS: The stented valves were correctly positioned in the right outflow tract, were competent up to 6 months as confirmed by angiography and echocardiography, and were well-tolerated by the animals, with endothelialization of the valve demonstrated at 6 months. CONCLUSIONS: The newly developed hydraulic release system allowed for safe and reliable insertion of an equine stented-valve with a sinus portion, through a right transventricular approach on a beating heart, in a sheep survival model.

Complete analysis of the 1H and 13C NMR spectra of diastereomeric mixtures of (R,S- and S,S-)-3,6-dimethoxy-2,5-dihydropyrazine-substituted indoles and their conformational preference in solution.

Complete analysis of the (1)H and (13)C NMR spectra obtained with and without a chemical shift reagent (Eu(fod)(3)), of bis-lactim ether 1 (Schöllkopf auxiliary) and monosubstituted 3- or 2-{(2R,5S or 2S,5S)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl}-1H-indoles is presented using gradient-selected one-dimensional (1D) and two-dimensional NMR techniques, such as 1D TOCSY, 1D NOESY (DPFGSE NOE), gCOSY, NOESY, ROESY gHETCOR, gHSQC and gHMBC. The contour plot of the gCOSY spectrum of 1-10 revealed cross peaks arising from the five-bond coupling between the H2 and H5 resonances of the dihydropyrazine ring for syn- ((5)J(H2, H5) = 4-5.7 Hz) and for anti-isomers ((5)J(H2, H5) = 3.4-3.8 Hz). The magnitude of the coupling constant was utilized to distinguish between the syn- and the anti-isomers (diastereomers). The precise values of (n)J(HH) (n = 3, 4, 5, 6) coupling constants for the indole and 2,5-dihydropyrazine moieties deduced from the calculated NMR spectra were supported by 1D TOCSY and gCOSY experiments and gauge invariant atomic orbital (GIAO) calculations. The magnitude of the coupling constants ((5)J(H2, H5)) indicates that the dihydropyrazine ring exists in a boat conformation. In both isomers, the indole group adopts a 'folded' conformation in which one diastereotopic face is effectively shielded by the aromatic benzene ring of the indole. This is supported by gradient-selected 1D NOESY and 2D NOESY experiments. Theoretical calculations of the conformation were performed to support the through-space shielding effect of the aromatic indole moiety based on the DFT/GIAO calculated (1)H NMR data (chemical shifts and coupling constants) for 2-syn- and 2-anti-diastereomers in CDCl(3).

Myocardial substrates in children with congenital heart disease: relationship to substrate supply, age, growth and desaturation.

AIM: The myocardial uptake of substrates in children has only been investigated on a small scale. The purpose of this study was to define myocardial substrate uptake in relation to the arterial supply of substrates, age, growth and oxygen saturation. METHODS: Thirty patients with congenital heart disease, aged 3 months to 16 years, were studied during cardiac catheterization. Arterial and coronary sinus blood was analyzed for the major fuel metabolites and amino acids. RESULTS: The uptake of all major substrates correlated significantly with the arterial supply: free fatty acids (r = 0.52, p = 0.004), beta-hydroxybutyrate (r = 0.74, p < 0.0001), lactate (r = 0.70, p < 0.0001) and glucose (r = 0.48, p = 0.01). Free fatty acids were the dominant substrate, irrespective of age, growth and saturation. With age, there was an increase in the uptake of lactate (r = 0.61, p = 0.0004) and a decrease in the uptake of beta-hydroxybutyrate (r =-0.41, p = 0.02). In multivariate analyses, these changes were explained by the arterial supply of the substrates, while age per se did not contribute significantly. CONCLUSION: The uptake of myocardial metabolites correlated with the arterial supply. Free fatty acids were the dominant substrate at all ages. The uptake of lactate and beta-hydroxybutyrate, although varying with age, was also determined by the arterial supply.