Lower urinary tract symptoms and sexual functions after endorectal pull-through for Hirschsprung disease : controlled long-term outcomes

Background/purpose: To define the prevalence of lower urinary tract symptoms (LUTS) and outcomes for sexual function after endorectal pull-through (EPT) for Hirschsprung disease (HD) compared to controls. To date, similar controlled studies are lacking. Methods: Patients aged = 4 years (n= 123) operated on forHDat our center between 1987 and 2011were invited to answer questionnaires on LUTS and sexual function (aged = 16 years). Patients with an intellectual disability and patients with a definitive endostomy were excluded. Patients were matched to three controls and also invited to a clinical follow-up for urological investigations including urine flow measurement, renal tract ultrasound, and urinalysis. Results: Altogether, 59 responses concerning LUTS and 24 responses concerning sexual functions were analyzed. No significant differences were demonstrated in the overall prevalence of LUTS between patients (67%) and controls (80%), nor in the prevalence of frequent LUTS (14% vs. 16%; P = NS for both). One patient (2%) had a urethral stricture after laparotomy-assisted EPT. Male patients reported sexual satisfaction and erectile function similar to controls (P N 0.10). Female patients were currently less in stable relationships compared to controls (25% vs. 83%, P= 0.005). Conclusions: Our results support the safety of EPT in patientswith HDwith regard to preservation of the integrity and functioning of the genitourinary tract. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

Cross-Dehydrogenative Couplings between Indoles and β-Keto Esters : Ligand-Assisted Ligand Tautomerization and Dehydrogenation via a Proton-Assisted Electron Transfer to Pd(II)

Cross-dehydrogenative coupling reactions between -ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of -ketoesters and indoles. The mechanism of the reaction between a prototypical -ketoester, ethyl 2-oxocyclopentanonecarboxylate and N-methylindole, has been studied experimentally by monitoring the temporal course of the reaction by 1H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (B97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The compu-tational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the -keto ester ligand from an O,O’-chelate to an C-bound Pd enolate. This ligand tautom-erization event is assisted by the -bound indole ligand. Subsequent scission of the ’-C–H bond takes place via a proton-assisted electron transfer mechanism, where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to pro-duce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA)2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step

Enantioselective Mannich Reaction of β‑Keto Esters with Aromatic and Aliphatic Imines Using a Cooperatively Assisted Bifunctional Catalyst

An efficient urea-enhanced thiourea catalyst enables the enantioselective Mannich reaction between β-keto esters and <i>N</i>-Boc-protected imines under mild conditions and minimal catalyst loading (1–3 mol %). Aliphatic and aromatic substituents are tolerated on both reaction partners, affording the products in good enantiomeric purity. The corresponding β-amino ketones can readily be accessed via decarboxylation without loss of enantiomeric purity

Dynamic Refolding of Ion-Pair Catalysts in Response to Different Anions

Four distinct folding patterns were identified in two foldamer-type urea-thiourea catalysts bearing a basic dimethylamino unit by a combination of X-ray crystallography, solution NMR studies, and computational studies (DFT). These patterns are characterized by different intramolecular hydrogen bonding schemes that arise largely from different thiourea conformers. The free base forms of the catalysts are characterized by folds where the intramolecular hydrogen bonds between the urea and the thiourea units remain intact. In contrast, the catalytically relevant salt forms of the catalyst, where the catalyst forms an ion pair with the substrate or substrate analogues, appear in two entirely different folding patterns. With larger anions that mimic the dialkyl malonate substrates, the catalysts maintain its native fold both in the solid state and in solution, but with smaller halide anions (fluoride, chloride and bromide), the catalysts fold around the halide anion (anion receptor fold) and the intramolecular hydrogen bonds are disrupted. Titration of catalyst hexafluoroacetylacetonate salt with tetra-n-butylammonium chloride results in dynamic refolding of the catalyst from the native fold to the anion receptor fold.peerReviewe

Organocatalysts Fold To Generate an Active Site Pocket for the Mannich Reaction

Catalysts containing urea, thiourea, and tertiary amine groups fold into a three-dimensional organized structure in solution both in the absence as well as in the presence of substrates or substrate analogues, as indicated by solution NMR and computational studies. These foldamer catalysts promote Mannich reactions with both aliphatic and aromatic imines and malonate esters. Hammett plot and secondary kinetic isotope effects provide evidence for the C–C bond forming event as the turnover-limiting step of the Mannich reaction. Computational studies suggest two viable pathways for the C–C bond formation step, differing in the activation modes of the malonate and imine substrates. The results show that the foldamer catalysts may promote C–C bond formation with an aliphatic substrate bearing a cyclohexyl group by enhanced binding of the substrates by dispersion interactions, but these interactions are largely absent with a simpler catalyst. Additional control experiments demonstrate the ability of simple thiourea catalysts to promote competing side reactions with aliphatic substrates, such as reversible covalent binding of the thiourea sulfur to the imine which deactivates the catalyst, and imine to enamine isomerization reactions. In foldamer catalysts, the nucleophilicity of sulfur is reduced, which prevents catalyst deactivation. The results indicate that the improved catalytic performance of foldamer catalysts in Mannich reactions may not be due to cooperative effects of intramolecular hydrogen bonds but simply due to the presence of the folded structure that provides an active site pocket, accommodating the substrate and at the same time impeding undesirable side reactions

Cross-Dehydrogenative Couplings between Indoles and β‑Keto Esters: Ligand-Assisted Ligand Tautomerization and Dehydrogenation via a Proton-Assisted Electron Transfer to Pd(II)

Cross-dehydrogenative coupling reactions between β-ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of β-ketoesters and indoles. The mechanism of the reaction between a prototypical β-ketoester, ethyl 2-oxocyclopentanonecarboxylate, and <i>N</i>-methylindole has been studied experimentally by monitoring the temporal course of the reaction by ¹H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (ωB97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by <i>N</i>-methylindole, which acts as a ligand for Pd­(II). The computational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the β-keto ester ligand from an <i>O</i>,<i>O</i>′-chelate to an α-C-bound Pd enolate. This ligand tautomerization event is assisted by the π-bound indole ligand. Subsequent scission of the β′-C–H bond takes place via a proton-assisted electron transfer mechanism, where Pd­(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to produce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd­(TFA)₂ and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step