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Organocatalytic methodologies for the derivatization of o -QM, p -QM and the analogous aza-QM have been recently developed and involve different catalytic systems such as phosphoric acids, thioureas, squaramides, NHC carbenes or chiral ammonium salts. Besides, phosphines, commonly used as ligands in metal-catalysed reactions, can be also used as organocatalysts. In this case, they are mainly involved as nucleophilic catalysts in reactions such as the Rauhut-Currier (RC) reaction. In this review, an analysis of the recent developments in racemic and enantioselective phosphine-catalysed transformations of o -QM, p -QM and aza- o -QM has been carried out.

The synthesis of aniline derivatives, common building blocks in many pharmaceuticals, agrochemicals, dyes or polymers, has been limited to reactions based on benzene-toluene-xylene derivatives (BTX) due to their ample availability. Despite the large number of existing methodologies, the synthesis of chiral 4-(sec-alkyl)anilines has not been accomplished so far. In this work, a tandem strategy based on the generation of a reactive aza- p -quinone methide (aza- p -QM) intermediate followed by Cu(I)-catalyzed addition of Grignard reagents has been developed.

Chiral indole derivatives are ubiquitous motifs in pharmaceuticals and alkaloids. Herein, the first protocol for catalytic asymmetric conjugate addition of Grignard reagents to various sulfonyl indoles, offering a straightforward approach for the synthesis of chiral 3-sec-alkyl-substituted indoles in high yields and enantiomeric ratios is presented. This methodology makes use of a chiral catalyst based on copper phosphoramidite complexes and in situ formation of vinylogous imine intermediates., (© 2020 Wiley-VCH GmbH.)

1,2,3-Triazoles are unique heterocycles with intriguing physical properties that allow not only the coordination to metals, but also the establishment of supramolecular interactions based on their polarized C-H bonds. In this account, an extensive work of our group on the design and application of 1,2,3-triazole catalysts is covered. Initially, a family of BINOL triazoles (Click-BINOLs) was synthesized and employed in model test reactions in asymmetric metal catalysis such as the Ti-catalyzed addition of alkylzinc reagents to aldehydes. The evolution from the Click-BINOLs to a novel class of triazole-based anion-binding organocatalysts is further discussed. Consequently, these catalysts were successfully applied in alkylation reactions, as well as asymmetric dearomatizations of diverse N-heteroarenes., (© 2017 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Easily accessible and tunable chiral triazoles have been introduced as a novel class of C-H bond-based H-donors for anion-binding organocatalysis. They have proven to be effective catalysts for the dearomatization reaction of different N-heteroarenes. Although this dearomatization approach represents a powerful strategy to build chiral heterocycles, to date only a few catalytic methods to this end exist. In this work, the organocatalyzed enantioselective Reissert-type dearomatization of isoquinoline derivatives employing a number of structurally diverse chiral triazoles as anion-binding catalysts was realized. The here presented method was employed to synthesize a number of chiral 1,2-dihydroisoquinoline substrates with an enantioselectivity up to 86:14 e.r. Moreover, a thorough study of the determining parameters affecting the activity of this type of anion- binding catalysts was carried out., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The asymmetric dearomatization of N-heterocycles is an important synthetic method to gain bioactive and synthetically valuable chiral heterocycles. However, the catalytic enantio- and regioselective dearomatization of the simplest six-membered-ring N-heteroarenes, the pyridines, is still very challenging. The first anion-binding-catalyzed, highly enantioselective nucleophilic dearomatization of pyridines with triazole-based H-bond donor catalysts is presented. Contrary to other more common NH-based H-bond donors, this type of organocatalyst shows a prominent higher C2-regioselectivity and is able to promote high enantioinductions via formation of a close chiral anion-pair complex with a preformed N-acyl pyridinium ionic intermediate. This method offers a straightforward and useful synthetic approach to chiral N-heterocycles from abundant and readily available pyridines., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Tricyclic dibenzoxepines and dibenzazepines are important therapeutic agents for the pharmaceutical industry and academic research. However, their syntheses are generally rather tedious, requiring several steps that involve a Wagner-Meerwein-type rearrangement under harsh conditions. Herein, we present the first copper(I)-catalyzed oxidative CH bond functionalization and ring expansion with TMSCHN2 to yield these important derivatives in a facile and straightforward way., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Helical chirality and selective anion-binding processes are key strategies used in nature to promote highly enantioselective chemical reactions. Although enormous efforts have been made to develop simple helical chiral systems and thus open new possibilities in asymmetric catalysis and synthesis, the efficient use of synthetic oligo- and polymeric helical chiral catalysts is still very challenging and rather unusual. In this work, structural unique chiral oligotriazoles have been developed as C-H bond-based anion-binding catalysts for the asymmetric dearomatization of N-heteroarenes. These rotational flexible catalysts adopt a reinforced chiral helical conformation upon binding to a chloride anion, allowing high levels of chirality transfer via a close chiral anion-pair complex with a preformed ionic substrate. This methodology offers a straightforward and potent entry to the synthesis of chiral (bioactive)heterocycles with added synthetic value from simple and abundant heteroarenes.

A study on the key parameters involved in the anion-binding process and catalytic activity of the new family of CH-bond-based, anion-binding bis-triazole catalysts BisTri was carried out. The effects of substitution at the side arms and the central backbone structure of the catalyst were investigated. Electron-deficient 3,5-bis(trifluoromethyl)phenyl groups at the side arms led to the most strongly bound structures. The evaluation of differently shaped anions showed remarkable binding selectivity of the BisTri derivatives for the chloride anion. Examination of various nucleophiles in a model catalytic alkylation reaction suggested a more complex mechanism than the expected SN 1, in which the nucleophiles also participate partially in activation of the electrophile. DFT calculations were performed to investigate the relationship between the catalyst conformation and the binding affinity. Finally, in silico design and identification of a new, more efficient BisTri catalyst was accomplished., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aims: Cyclooxygenase (COX)-2 inhibition has been reported to suppress the biosynthesis of the gastroprotective lipoxygenase metabolite 15(R)-epi-lipoxin A(4), also termed 'aspirin-triggered lipoxin' (ATL). We tested the hypothesis that the co-administration of aspirin with either the selective COX-2 inhibitor celecoxib or the nonselective COX inhibitor ibuprofen reduces ATL biosynthesis., Methods: We measured the urinary excretion of ATL in 24 patients with both ischaemic heart disease and osteoarthritis, chronically treated with aspirin and co-administered celecoxib 200 mg b.i.d., ibuprofen 600 mg t.i.d., or placebo for 7 days., Results: Baseline ATL was comparable in the three groups. On days 1 and 7, 4 h after co-administration of celecoxib or ibuprofen, ATL levels did not show significant variations (day 1: 0.24 +/- 0.33, 0.26 +/- 0.21 and 0.37 +/- 0.22 ng mg(-1) creatinine, respectively; day 7: 0.21 +/- 0.13, 0.35 +/- 0.15 and 0.23 +/- 0.18 ng mg(-1) creatinine, respectively)., Conclusions: Neither selective nor nonselective COX-2 inhibition appreciably interferes with ATL biosynthesis, suggesting that this mediator is not involved in exacerbating gastrotoxicity by the association of aspirin with COX-2 inhibitors.

Increased blood pressure (BP) may stimulate vascular inflammation, which may itself induce pathological arterial changes. BP variability has been associated with target-organ damage and future cardiovascular complications. We hypothesized that BP variability, as derived from ambulatory BP monitoring, is related to inflammatory markers in newly diagnosed hypertension. Systolic (S) and diastolic (D) BP variabilities were assessed as the SD of 24-h pressure recordings in a cohort of 190 recently (<6 months) diagnosed, untreated hypertensive subjects. Target organ damage, assessed by measuring the carotid artery intima-media thickness, left ventricular mass index, and microalbuminuria, was related to plasma high-sensitivity C-reactive protein (hsCRP) and soluble (s) E-selectin, an endothelium-specific molecule. The patients' age (mean+/-SD) was 53.0+/-8.5 years, and 59% were male. Multivariable analysis identified awake SBP variability (95% confidence interval [CI]: 0.002-0.042, p=0.034) as an independent correlate of hsCRP and awake SBP (95% CI: 0.003-0.014, p=0.003), awake SBP variability (95% CI: 0.003-0.035, p=0.018), and microalbuminuria (95% CI: 0.075-0.280, p=0.001) as independent correlates of sE-selectin. When patients were divided into low and high awake SBP variability groups, age (p=0.001), hsCRP (p=0.0001), and sE-selectin (p=0.005) were significantly different in the two groups. After adjusting for age, these differences remained significant (p=0.022 and p=0.001 for hsCRP and sE-selectin, respectively). In recently diagnosed hypertensive subjects, hsCRP and sE-selectin levels are related to awake SBP variability. High SBP variability is likely associated with vascular inflammation in newly diagnosed hypertension, independent of SBP. (Hypertens Res 2008; 31: 2137-2146).