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Background and Purpose: Introducing the calcineurin inhibitors cyclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) decrease survival rates.Experimental Approach: We sought, in a beta-cell culture model, to elucidate the pathogenic mechanisms behind NODAT and the relative contribution of the calcineurin inhibitors. INS-1E cells were incubated at basal and stimulatory glucose concentrations, while exposed to pharmacologically relevant doses of CsA, Tac and vehicle for 6 or 24 h.Results: Tac inhibited basal (P < 0.05), but not glucose-stimulated insulin secretion (GSIS) after 6 h of exposure. After 24 h, both agents inhibited basal and GSIS (P < 0.05). Calcineurin phosphatase activity was decreased by both drugs during all conditions. Apoptosis was only seen with CsA treatment, which also induced a slight suppression of calcineurin and insulin mRNA, as well as increased levels of the sterol receptor element binding protein (SREBP)-1c, a transcription factor thought to suppress genes essential for beta-cell function and induce insulin resistance. Expression levels of nuclear factor of activated T-cells (NFAT)-c1, -c2, -c3 and -c4 were not decreased notably by either drug.Conclusions and Implications: Tac had acute inhibitory effects on basal insulin secretion, but prolonged exposure (24 h) to Tac or CsA revealed similar suppression of insulin secretion. These prolonged effects were mirrored by a total inhibition of calcineurin activity in beta-cells. CsA showed greater inhibition of beta-cell survival and transcriptional markers, essential for beta-cell function. [ABSTRACT FROM AUTHOR]

Abstract Background Neutrophil gelatinase associated lipocalin (NGAL) is a biomarker of kidney injury. We examined plasma levels of NGAL in a cohort of 57 kidney allograft recipients (Tx group, 39 ± 13 years), a uraemic group of 40 patients remaining on the waiting list (47 ± 11 years) and a control group of 14 healthy subjects matched for age, sex and body mass index (BMI). The kidney graft recipients were studied at baseline before transplantation and 3 and 12 months after transplantation and the uraemic group at baseline and after 12 months. Methods NGAL was measured using a validated in-house Time-Resolved Immuno-flourometric assay (TRIFMA). Repeated measurements differed by < 10% and mean values were used for statistical analyses. Spearman rank order correlation analysis and the Kruskal-Wallis non-parametric test were used to evaluate the association of NGAL concentrations with clinical parameters. Results Plasma NGAL levels before transplantation in the Tx and uraemic groups were significantly higher than in the healthy controls (1,251 μg/L, 1,478 μg/L vs. 163 μg/L, p < 0.0001). In the Tx group NGAL concentrations were associated with serum creatinine (R = 0.51, p < 0.0001), duration of end-stage renal failure (R = 0.41, p = 0.002) and leukocyte count (R = 0.29, p < 0.026). At 3 and 12 months plasma NGAL concentrations declined to 223 μg/L and 243 μg/L, respectively and were associated with homocysteine (R = 0.39, p = 0.0051 and R = 0.47, p = 0.0007). Conclusions Plasma NGAL is a novel marker of kidney function, which correlates to duration of end-stage renal failure (ESRD) and serum creatinine in uraemic patients awaiting kidney transplantation. Plasma NGAL is associated with homocysteine in transplanted patients. The prognostic value of these findings requires further studies.

Abstract Background Overdiagnosis in cancer screening is the detection of cancer lesions that would otherwise not have been detected. It is arguably the most important harm. We quantified overdiagnosis in the Danish mammography screening programme, which is uniquely suited for this purpose, as only 20% of the Danish population has been offered organised mammography screening over a long time-period. Methods We collected incidence rates of carcinoma in situ and invasive breast cancer in areas with and without screening over 13 years with screening (1991-2003), and 20 years before its introduction (1971-1990). We explored the incidence increase comparing unadjusted incidence rates and used Poisson regression analysis to compensate for the background incidence trend, variation in age distribution and geographical variation in incidence. Results For the screened age group, 50 to 69 years, we found an overdiagnosis of 35% when we compared unadjusted incidence rates for the screened and non-screened areas, but after compensating for a small decline in incidence in older, previously screened women. Our adjusted Poisson regression analysis indicated a relative risk of 1.40 (95% CI: 1.35-1.45) for the whole screening period, and a potential compensatory drop in older women of 0.90 (95% CI: 0.88-0.96), yielding an overdiagnosis of 33%, which we consider the most reliable estimate. The drop in previously screened women was only present in one of the two screened regions and was small in absolute numbers. Discussion One in four breast cancers diagnosed in the screened age group in the Danish screening programme is overdiagnosed. Our estimate for Denmark is lower than that for comparable countries, likely because of lower uptake, lower recall rates and lower detection rates of carcinoma in situ.

Abstract Background The CONSORT statement specifies the need for a balanced presentation of both benefits and harms of medical interventions in trial reports. However, invitations to screening and newspaper articles often emphasize benefits and downplay or omit harms, and it is known that scientific articles can be influenced by conflicts of interest. We wanted to determine if a similar imbalance occurs in scientific articles on mammography screening and if it is related to author affiliation. Methods We searched PubMed in April 2005 for articles on mammography screening that mentioned a benefit or a harm and that were published in 2004 in English. Data extraction was performed by three independent investigators, two unblinded and one blinded for article contents, and author names and affiliation, as appropriate. The extracted data were compared and discrepancies resolved by two investigators in a combined analysis. We defined three groups of authors: (1) authors in specialties unrelated to mammography screening, (2) authors in screening-affiliated specialties (radiology or breast cancer surgery) who were not working with screening, or authors funded by cancer charities, and (3) authors (at least one) working directly with mammography screening programmes. We used a data extraction sheet with 17 items described as important benefits and harms in the 2002 WHO/IARC-report on breast cancer screening. Results We identified 854 articles, and 143 were eligible for the study. Most were original research. Benefits were mentioned more often than harms (96% vs 62%, P < 0.001). Fifty-five (38%) articles mentioned only benefits, whereas seven (5%) mentioned only harms (P < 0.001). Overdiagnosis was mentioned in 35 articles (24%), but was more often downplayed or rejected in articles that had authors working with screening, (6/15; 40%) compared with authors affiliated by specialty or funding (1/6; 17%), or authors unrelated with screening (1/14; 7%) (P = 0.03). Benefits in terms of reduced breast cancer mortality were mentioned in 109 (76%) articles, and was more often provided as a relative risk reduction than an absolute risk reduction, where quantified (45 articles (31%) versus 6 articles (3%) (P < 0.001)). Conclusion Scientific articles tend to emphasize the major benefits of mammography screening over its major harms. This imbalance is related to the authors' affiliation.

Abstract We have previously described how a series of trials sponsored by Pfizer of its antifungal drug, fluconazole, in cancer patients with neutropenia handicapped the control drug, amphotericin B, by flaws in design and analysis. We describe similar problems in two pivotal trials of Pfizer's new antifungal agent, voriconazole, published in a prestigious journal. In a non-inferiority trial, voriconazole was significantly inferior to liposomal amphothericin B, but the authors concluded that voriconazole was a suitable alternative. The second trial used amphothericin B deoxycholate as comparator, but handicapped the drug by not requiring pre-medication to reduce infusion-related toxicity or substitution with electrolytes and fluid to reduce nephrotoxicity, although the planned duration of treatment was 84 days. Voriconazole was given for 77 days on average, but the comparator for only 10 days, which precludes a meaningful comparison. In a random sample of 50 references to these trials, we found that the unwarranted conclusions were mostly uncritically propagated. It was particularly surprising that relevant criticism raised by the FDA related to the first trial was only quoted once, and that none of the articles noted the obvious flaws in the design of the second trial. We suggest that editors ensure that the abstract reflects fairly on the remainder of the paper, and that journals do not impose any time limit for accepting letters that point out serious weaknesses in a study that have not been noted before.

A mechanistic investigation into the novel combination of the pseudo -halogen effect with enantioselective aminocatalysis unravels the mechanistic intricacies of [6 + 4] and [10 + 6] higher-order cycloadditions and the succeeding new Favorskii-like rearrangements. By introducing the OTf-group into the tropone framework, it can serve both as an activator for the cycloaddition and as a proficient leaving group within the corresponding cycloadduct, thus enabling unprecedented ring-contracting Favorskii-like rearrangements. Integrating the -OTf group creates an electron-deficient 6π-component leveraging the pseudo -halogen effect by enhancing the polarization and introducing new strategic interaction points. This modification complements electron-rich 4π- and 10π-components from amino-activated 2,4-dienals or indene-carbaldehydes. A comprehensive DFT investigation supported by experimental results demonstrates that the [6 + 4] system proceeds through a rate-limiting stepwise exo -cycloaddition leading to a cycloadduct initially in a boat-conformation, subsequently transitioning to the more stable chair-conformation. The change in conformation ensures an S N 1-like expulsion of the -OTf group, generating a stable carbocation bridgehead primed for a novel Favorskii-like seven-to-six ring-contracting rearrangement, resulting in the experimentally observed product. As proof-of-concept for the cycloaddition/Favorskii-like rearrangement, it is demonstrated that this approach can be extended to an unprecedented [10 + 6] cycloaddition. In contrast to the [6 + 4] system, the [10 + 6] system distinguishes itself with a concerted S N 1-like/Favorskii-like six-to-five ring-contracting rearrangement, representing the rate-limiting step. This novel concept results in the experimental isolation of structurally complex products in high peri -, diastereo -, and enantioselectivity with moderate yield. These findings demonstrate the pseudo -halogen effect's multifaceted role in promoting and enabling novel reactivity.

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted-base catalyzed enantioselective (3+2) annulation of donor-acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5-substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic β-cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99 % ee. Surprisingly, aromatic aldehydes afforded the cis-2,5-substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans-cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99 % ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

A novel strategy that combines oxidative aminocatalysis and gold catalysis allows the preparation of chiral α-quaternary isochromanes, a motif that is prevalent in natural products and synthetic bioactive compounds. In the first step, α-branched aldehydes and propargylic alcohols are transformed into α-quaternary ethers with excellent optical purities (>90 % ee) via oxidative umpolung with DDQ and an amino acid-derived primary amine catalyst. Subsequent gold(I)-catalyzed intramolecular hydroarylation affords the isochromane products with retention of the quaternary stereocenter. A second approach explores the use of allylic alcohols as reaction partners for the oxidative coupling to furnish α-quaternary ethers with generally lower enantiopurities. Stereoretentive cyclization to isochromane products is achieved via intramolecular Friedel-Crafts type alkylation with allylic acetates as a reactive handle. A number of synthetic elaborations and a biological study on these α-quaternary isochromanes highlight the potential applicability of the presented method., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

An efficient strategy to obtain a broad array of chiral and achiral heterotropones and their corresponding [4 + 2] cycloadducts is disclosed. This strategy enables access to unique heterotropones and intricate bicyclic structures in high yields and diastereoselectivities through a simple procedure and from easily accessible starting materials.

Novel asymmetric aminocatalytic cycloadditions are described between formyl cycloheptatrienes and 6,6-dimethylfulvene that lead to [4 + 2], [6 + 2], and [4 + 6] cycloadducts. The unprecedented reaction course is dependent on the position of the formyl functionality in the cycloheptatriene core, and each formyl cycloheptatriene isomer displays a distinct reactivity pattern. The formyl cycloheptatriene isomers are activated by a chiral primary diamine catalyst, and the activation mode is dependent on the position of the formyl functionality relative to the cycloheptatriene core. The [4 + 2] and [6 + 2] cycloadducts are formed via rare iminocatalytic inverse electron-demand cycloadditions, while the [4 + 6] cycloadduct is formed by a normal electron-demand cycloaddition. The reactivity displayed by the different formyl cycloheptatrienes was investigated by DFT calculations. These computational studies account for the different reaction paths for the three isomeric formyl cycloheptatrienes. The aminocatalytic [4 + 2], [6 + 2], and [4 + 6] cycloadditions proceed by stepwise processes, and the interplay between conjugation, substrate distortion, and dispersive interactions between the fulvene and aminocatalyst mainly defines the outcome of each cycloaddition.

This study presents a novel photoredox-enabled enantioconvergent catalytic strategy used to construct chiral 2 H -1,3-benzoxazines via an unprecedented oxa-6π electrocyclization utilizing racemic α-substituted glycinates as substrates. The approach leverages a cobalt-based chiral Lewis acid catalyst, which promotes the transformation under thermal or photoredox conditions. While the thermal reaction selectively converts only the ( S )-configured glycinates into enantioenriched 2 H -1,3-benzoxazines (up to 96:4 e.r.), the addition of 0.5 mol % of a commercially available iridium photocatalyst under visible light irradiation transforms the reaction into an enantioconvergent process. Detailed mechanistic and time course studies of optically pure α-deuterated substrates revealed the presence of an enantiospecific kinetic isotope effect, which helped to clarify the role of both the photo- and chiral Lewis acid catalyst in the reaction sequence. In this dual catalytic system, the photocatalyst promotes a dynamic interconversion between the substrate enantiomers─a process not accessible via ground-state chemistry─while the chiral Lewis acid selectively transforms only the ( S )-configured substrates. Further mechanistic evidence for the proposed mechanism is provided by linear free energy relationship analysis, which suggests that the stereodetermining step involves a 6π electrocyclization under both thermal and photoredox conditions.

Compounds featuring atropisomerism are ubiquitous in natural products, therapeutics, advanced materials, and asymmetric synthesis. However, stereoselective preparation of these compounds presents many synthetic challenges. This article introduces streamlined access to a versatile chiral biaryl template through C-H halogenation reactions employing high-valent Pd catalysis in combination with chiral transient directing groups. This methodology is highly scalable, insensitive to moisture and air, and proceeds, in select cases, with Pd-loadings as low as 1 mol%. Chiral mono-brominated, dibrominated, and bromochloro biaryls are prepared in high yield and excellent stereoselectivity. These serve as remarkable building blocks bearing orthogonal synthetic handles for a gamut of reactions. Empirical studies elucidated regioselective C-H activation to be predicated on the oxidation state of Pd and diverging site-halogenation to result from cooperative effects of Pd and oxidant., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The combination of asymmetric organocatalysis with the ( pseudo )-halogen effect enables the formation of chiral norcarane scaffolds in high yields and selectivities (up to 92% yield, >99% ee, and >95:5 d.r.). This was achieved by reacting ( pseudo )-halogenated 3-vinyl chromones with in situ generated chiral dienamines in an inverse electron demand [4 + 2] cycloaddition followed by an intramolecular S N 2 reaction. These scaffolds could easily undergo photoinduced rearrangements or lactonization to form intricate chiral ring structures.

Cycloadditions are an important class of reactions in materials science for the construction of polycyclic aromatic and polycyclic heteroaromatic compounds. Recently, cycloadditions have been expanded beyond the "classical" group of cycloadditions involving six π-electrons, and it is now possible to control cycloadditions for an extended number of π-electrons by applying organocatalysis. This novel field of cycloadditions-termed higher-order cycloadditions-allows new synthetic methodologies to construct polycyclic carbo- and heteroaromatic compounds in two or three dimensions. This concept presents higher-order cycloadditions as a method for accessing two- and three-dimensional azulenes and cyclazines, as well as three dimensional indenes, as polycyclic aromatic and polycyclic heteroaromatic compounds., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Chiral eight-membered carbocycles are important motifs in organic chemistry, natural product chemistry, chemical biology, and medicinal chemistry. The lack of synthetic methods toward their construction is a challenge preventing their rational design and stereoselective synthesis. The catalytic enantioselective [4 + 4] cycloaddition is one of the most straightforward and atom-economical methods to obtain chiral cyclooctadiene derivatives. We report the first organocatalytic asymmetric [4 + 4] cycloaddition of 9 H -fluorene-1-carbaldehydes with electron-deficient dienes affording cyclooctadiene derivatives in good yields and with excellent control of peri-, diastereo-, and enantioselectivities. The reaction concept is based on the aminocatalytic formation of a polarized butadiene component incorporated into a cyclic extended π-system, with restricted conformational freedom, allowing for a stereocontrolled [4 + 4] cycloaddition. FMO analysis unveiled that the HOMO and LUMO of the two reacting partners resemble those of butadiene. The methodology allows for the construction of cyclooctadiene derivatives decorated with various functionalities. The cyclooctadienes were synthetically elaborated, allowing for structural diversity demonstrating their synthetic utility for the formation of, for example, chiral cyclobutene- or cyclooctane scaffolds. DFT computational studies shed light on the reaction mechanism identifying the preference for an initial but reversible [4 + 2] cycloaddition delivering an off-cycle catalyst resting state, from which catalyst elimination is not possible. The off-cycle catalyst-bound intermediate undergoes a retro-[4 + 2] cycloaddition, followed by a [4 + 4] cycloaddition generating a cycloadduct from which catalyst elimination is possible. The reaction pathway accounts for the observed peri-, diastereo-, and enantioselectivity of the organocatalytic [4 + 4] cycloaddition.

The thermal dimerization of cycloheptatriene is predicted to occur by a concerted [6 + 4] cycloaddition via an ambimodal [6 + 4]/[4 + 6] transition state (TS) and a competing stepwise diradical (6 + 2) cycloaddition; both dimers subsequently undergo intramolecular [4 + 2] cycloadditions to afford thermally stable tetracyclic products. The ambimodal TS is the 10π-electron version of the prototype bispericyclic dimerization of cyclopentadiene discovered by Caramella et al. in 2002. Quantum mechanical studies using several common DFT functionals and post-HF methods, ωB97X-D, M06-2X, DLPNO-CCSD(T), NEVPT2, and PWPB95-D3(BJ), and quasiclassical molecular dynamics simulations provide details of bond timing and bifurcation pathways. By comparing the ambimodal [6 + 4]/[4 + 6] TS for cycloheptatriene dimerization with the ambimodal [4 + 2]/[2 + 4] TS of cyclopentadiene dimerization, we found that the high distortion energy in cycloheptatriene dimerization is the key to its relatively high energy barrier. The computational investigations were coupled with experimental studies of the cycloheptatriene dimerization, which resulted in the isolation of the two tetracyclic dimers. At lower temperature, the product from the predicted exo -[6 + 4]/[4 + 6] cycloaddition, followed by a subsequent intramolecular [4 + 2] cycloaddition, predominantly forms, while at higher temperature, the diradical (6 + 2) cycloadduct is the major product.

A novel enantioselective (8+3) cycloaddition between donor-acceptor cyclopropanes and heptafulvenoids catalysed by a chiral bifunctional Brønsted base is described. Importantly, the reaction, which leverages an anionic activation strategy, is divergent from prototypical Lewis-acid activation protocols. A series of cyclopropylketones react with tropones affording the desired (8+3) cycloadducts in high yield and enantiomeric excess. For barbiturate substituted heptafulvenes, the (8+3) cycloaddition with cyclopropylketones proceeds in good yield, excellent diastereoselectivity and high enantiomeric excess. The experimental work is supported by DFT calculations, which indicate that the bifunctional organocatalyst activates both the donor-acceptor cyclopropane and tropone; the reaction proceeds in a step-wise manner with the ring-closure being the stereodetermining step., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The concept of umpolung, or polarity reversal, introduced by Seebach and Corey nearly half a century ago, ushered a new paradigm into synthetic chemistry. Novel connections were able to be forged among functional groups that were typically inaccessible. Conceptually, an umpolung reaction is identified only upon retrosynthetic analysis. Stoichiometric examples have served as a platform to develop and refine elegant methodologies into catalytic processes. The advent of these unconventional arrangements of canonical synthons into new points of diversity has expanded the repertoire of the synthetic toolbox. Within this context, asymmetric organocatalyzed methodologies remain rare, and there are even fewer aminocatalyzed variants.Recent years have witnessed a renaissance in α-functionalizations of aldehydes, specifically in the context of oxidative umpolung strategies. Unlike previous open-shell approaches, application of a quinone-based oxidant in conjunction with an aminocatalyst leads to a discrete, substitutionally labile quinone adduct. These have proven to be valuable building blocks toward polar reactivity─auguring the advent of new avenues to construct tetrasubstituted tertiary stereocenters through the application of conventional nucleophiles to form C-C, C-N, C-O, and C-S bonds through an organocatalyzed cross-nucleophile coupling (organo-CNC) reaction. The resulting nonepimerizable stereocenter demonstrates high optical fidelity and provides a significant advancement in many applications that suffer from racemization, such as in vivo studies.This strategy harnesses a trifunctional aminocatalyst to promote an unusual S N 2 reaction at a highly congested center. The selection of the quinone oxidant and nucleophile converges to a continuum of reactivity ranging from enantioselective oxidation to stereoselective substitution. A remarkable aspect of these developments is the identification of an asymmetric S N 2 dynamic kinetic resolution (S N 2-DKR) manifold. These organo-CNC reactions are highly modular and demonstrate complete stereocontrol from the catalyst with minimal influence from incoming chiral nucleophiles. Leveraging this facet, these technologies have been extended to peptidic bioconjugations bearing bio-orthogonoal linker molecules.This Account aims to highlight the progress, from an internal perspective, toward directing the initial result into established methodologies. Within this construct, the underlying principles of each reaction will be disseminated with specific content on inherent challenges and opportunity. Combined, these will serve as an instructive tool to stimulate applications in cross-disciplinary interfaces.

This article discloses the direct α-amination of α-branched aldehydes applying nitrogen-based nucleophiles. Under organocatalyzed, oxidative conditions α-branched aldehydes are umpoled to their electrophilic synthons and, subsequently, displaced by a variety of nucleophilic amines to form tetrasubstituted tertiary centers. A similar strategy has been previously employed to form congested C-C, C-O, and C-S bonds; however, unsatisfactory results were received when extending the methodology to include C-N bonds. Initially, intramolecular α-amination reactions were undertaken to foster dihydroquinoxaline-type products. A solvent exchange to the polar, aprotic solvent, MeNO 2 , proved critical to facilitate intermolecular α-C-N bond formation with a wide range of amine coupling partners ( N -heterocycles, N,N -diaryl amines, and anilines). Application of the solvent exchange to the enantioselective S N 2-DKR manifold provided distinct regimes leading to refinement in yield and enantioselectivity.

Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C(sp 2 )-C(sp 3 ) stereogenic axis have been observed in natural compounds; however, their enantioselective synthesis remains almost completely unexplored. Herein we disclose a new class of chiral C(sp 2 )-C(sp 3 ) atropisomers obtained with high levels of stereoselectivity (up to 99% ee) by means of an organocatalytic asymmetric methodology. Multiple molecular motifs could be embedded in this class of C(sp 2 )-C(sp 3 ) atropisomers, showing a broad and general protocol. Experimental data provide strong evidence of the conformational stability of the C(sp 2 )-C(sp 3 ) stereogenic axis (up to t 1/2 25  ° C >1000 y) in the obtained compounds and show kinetic control over this rare stereogenic element. This, coupled with density functional theory calculations, suggests that the observed stereoselectivity arises from a Curtin-Hammett scenario establishing an equilibrium of intermediates. Furthermore, the experimental investigation led to evidence of the operating principle of central-to-axial chirality conversions.

The Diels-Alder reactions of tropolone and its conjugate base with N-methylmaleimide have been explored computationally and experimentally. Previous studies of the [4+2] cycloaddition under basic conditions show that both endo- and exo-products are obtained in similar, but variable amounts. Density functional theory (ωB97X-D) explorations of potential energy surfaces, and molecular dynamics trajectories show that the reaction involves an ambimodal transition state for the reaction of the ammonium tropolonate with N-methylmaleimide, and that similar amounts of endo- and exo-products are obtained. The thermal reaction, studied experimentally in detail here for the first time, is predicted to form the endo-adduct through an ambimodal transition state. The exo-adduct can be formed from the same transition state, but requires a hydrogen shift, that hinders this reaction dynamically. Longer reaction times give a small excess of the exo-product, which is thermodynamically more stable., (© 2021 Wiley-VCH GmbH.)

An efficient and exceptionally stereoselective synthesis of chiral cycl[3.2.2]azines has been realized by means of the rational design and utilization of novel (E)-3-benzylidene-3H-pyrrolizines in iminium-ion-catalyzed [8+2] cycloaddition reactions. The presented protocol allows for the incorporation of diverse enals, including cinnamaldehydes, enolizable aldehydes, and substrates of extended conjugation. The obtained products contain both an electron-rich alkenyl pyrrole moiety and an electron-deficient carbaldehyde substituent, and both moieties can undergo selective transformations with retention of the stereochemical information established in the [8+2] cycloaddition., (© 2021 Wiley-VCH GmbH.)

Saturated carbonyl compounds are, via their enolate analogues, inherently nucleophilic at the α-position. In the presence of a benzoquinone oxidant, the polarity of the α-position of racemic α-branched aldehydes is inverted, allowing for an enantioselective etherification using readily available oxygen-based nucleophiles and an amino acid-derived primary amine catalyst. A survey of benzoquinone oxidants identified p-fluoranil and DDQ as suitable reaction partners. p-Fluoranil enables the preparation of α-aryloxylated aldehydes using phenol nucleophiles in up to 91 % ee, following either a one-step or a two-step, one-pot protocol. DDQ allows for a more general etherification protocol in combination with a broader range of alcohol nucleophiles with enantioselectivities up to 95 % ee. Control experiments and isolation of a key quinol intermediate supports a mechanism proceeding via an S N 2 dynamic-kinetic resolution. These studies provide the basis for an aminocatalytic umpolung concept that allows for the asymmetric construction of tertiary ethers in the α-position of aldehydes., (© 2021 Wiley-VCH GmbH.)

An enantioselective methodology to construct trans-Diels-Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo-halogen effect to direct an endo-selective, secondary-amine catalyzed Diels-Alder reaction allowing for the subsequent formation of trans-Diels-Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α-brominated or α-pseudo-halogenated enone to form a fleeting cis-Diels-Alder intermediate. The endo-transition state-enhanced by the (pseudo-)halogen effect-sets the stereochemistry that allows for a subsequent S N 2-like reaction at a tertiary center to obtain the trans-Diels-Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies., (© 2021 Wiley-VCH GmbH.)

Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93-98% ee). The obtained products are important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as octahydrobenzo[ h ]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16 representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique profile and a clear morphological change.

The S N 2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an S N 2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an S N 2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective S N 2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an S N 2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric S N 2 dynamic kinetic resolution to be used for a variety of future reactions.

The first enantioselective [12 + 2] cycloaddition has been developed for the construction of a chiral cycl[3.2.2]azine core, a tricyclic moiety with a central ring-junction nitrogen atom, by an operationally simple one-step organocatalytic process. The reaction concept builds upon aminocatalytically generated 12π-components derived from 5 H -benzo[ a ]pyrrolizine-3-carbaldehydes reacting with different electron-deficient 2π-components and affording the complex scaffold of benzo[ a ]cycl[3.2.2]azine (indolizino[3,4,5- ab ]isoindole) with excellent enantio- and diastereoselectivity in good yields. The developed reaction is robust toward diverse substituent patterns and has been extended to different classes of electron-deficient 2π-components by minor variations in reaction setup. The obtained [12 + 2] cycloadducts are electron-deficient in nature, and their reaction with nucleophiles have been demonstrated. The enantioselective [12 + 2] cycloaddition with α,β-unsaturated aldehydes as the electron-deficient 2π-components relies upon an unconventional, simple aminocatalyst. In order to understand the high stereoselectivity of the [12 + 2] cycloaddition for this simple catalyst, combined experimental and computational investigations were performed. The investigations point to activation of both the 5 H -benzo[ a ]pyrrolizine-3-carbaldehyde and the α,β-unsaturated aldehyde by the aminocatalyst and that the reaction proceeds by a stepwise cycloaddition, where especially the ring-closure is crucial for the stereochemical outcome. For other electron-deficient 2π-components, such as α,β-unsaturated ketoesters and nitroolefins, a more sterically demanding aminocatalyst has been applied and the corresponding [12 + 2] cycloadducts are obtained with excellent stereoselectivity. The [12 + 2] cycloaddition with vinyl sulfones afforded fully unsaturated systems, which display photoluminescence properties and for which quantum yields have been evaluated.

This prospective cohort study evaluates associations between structural and ultrastructural parameters in baseline biopsies from human kidney transplants and long-term graft survival after more than 14 years' follow-up. Baseline kidney graft biopsies were obtained prospectively from 54 consecutive patients receiving a kidney transplant at a single institution. Quantitative measurements were performed on the baseline biopsies by computer-assisted light microscopy and electron microscopy. Stereology-based techniques estimated the fraction of interstitial tissue, the volume of glomeruli, mesangial fraction, and basement membrane thickness of glomerular capillaries. The fraction of occluded glomeruli and scores according to the Banff classification were achieved. Kidney graft survival was analyzed by Kaplan-Meier estimates and Cox regression. Association to long-term kidney function was also analyzed. The long-term surviving kidney transplants were characterized at implantation by less arteriolar hyaline thickening (P < 0.001) and less interstitial fibrosis (P = 0.001), as well as a lower fraction of occluded glomeruli (P = 0.004) and lower glomerular volume (P = 0.03). At the latest follow-up, eGFR was decreased by 12 ml/min/1.73 m 2 per unit increase in the score for arteriolar hyalinosis at implantation (P = 0.02), and eGFR was decreased by 19 ml/min/1.73 m 2 per 10 6 μm 3 increase in glomerular volume at baseline (P = 0.03). The unbiased Cavalieri estimate of glomerular volume and the ultrastructural parameters are the first to be evaluated in a cohort study with prospective follow-up for more than 14 years. The study shows that baseline biopsies from human kidney grafts contain extraordinary long-term prognostic information, and it highlights the importance of these intrinsic graft factors.

The cinchona-alkaloid-catalyzed cycloaddition reactions of 2-cyclohexenone with tropone and various heptafulvenes give [8+2] or [4+2] cycloadducts, depending on the substituents present on the heptafulvene. We report the results of new experiments with heptafulvenes, containing diester and barbiturate substituents, which in combination with computational studies were performed to elucidate the factors controlling [8+2] vs [4+2] cycloaddition pathways, including chemo-, regio-, and stereoselectivities of these higher-order cycloadditions. The protonated cinchona alkaloid primary amine catalyst reacts with 2-cyclohexenone to form a linear dienamine intermediate that subsequently undergoes a stepwise [8+2] or [4+2] cycloaddition. Both tropone and the different heptafulvenes initially form [8+2] cycloadducts. The final product is ultimately decided by the reversibility of the [8+2] cycloaddition and the relative thermal stability of the [4+2] products. The stereoisomeric transition states are distinguished by the steric interactions between the protonated catalyst and tropone/heptafulvenes. The [8+2] cycloaddition of barbiturate-heptafulvene afforded products with an unprecedented trans -fusion of the five- and six-membered rings, while the [8+2] cycloadducts obtained from cyanoester-heptafulvene and diester-heptafulvene were formed with a cis -relationship. The mechanism, thermodynamics, and origins of stereoselectivity were explained through DFT calculations using the ωB97X-D density functional.

The use of pseudo enantiomers is a well-known method of achieving products of complementary stereochemistry. Only rarely can different enantiomers of a product be accessed without modulation of the catalyst. Recently, a system was reported wherein two different enantiomers of spirocycles were obtained by a cascade reaction of unsaturated pyrrolin-4-ones with mercaptoacetaldehyde catalyzed by a single optimized cinchona alkaloid squaramide-derived organocatalyst. It was originally proposed that the E/Z geometry of the unsaturated pyrrolin-4-one dictated the stereochemistry of the spirocycle product, but this was not investigated further. In the present work, we have investigated the nature of a pseudo-enantiomeric organocatalyst conformation applying density functional theory calculations for investigating the transition states for the reaction. Furthermore, the influence of the double-bond geometry of the pyrrolin-4-one has been studied beyond what is possible to test experimentally. The results provide a greater understanding for this class of reactions that may be applicable in future methodology development., (© 2020 Wiley-VCH GmbH.)

A highly stereoselective 1,3-dipolar [6+4] cycloaddition towards bridged azabicyclo[4.3.1]decane scaffolds has been developed, reacting aldehydes, 2-aminomalonates and tropone under mild conditions in the presence of a chiral phosphoric acid catalyst. The scope is demonstrated for a series of aldehydes and 2-aminomalonates, and the reaction proceeds in high yields, >95:5 d.r. and up to 99 % ee. A series of transformations, as well as a mechanistic proposal, are presented., (© 2020 Wiley-VCH GmbH.)

Background: A growing body of evidence suggest that the children's physical activity (PA) level in early childhood education and care (ECEC) settings are insufficient. Since most children attend ECEC settings for many hours on most days of the week, and these institutions reach children across the socioeconomic spectrum, the ECEC settings may serve as an ideal avenue for increasing physical activity level, reduce sedentary time and enhance the overall health of young children. This paper investigates the effectiveness of the "Active Kindergarten - Active Children" study to increase children's PA level and reduce sedentary time within the ECEC setting., Methods: Accelerometers were used to asses PA and sedentary time. A total of 116 three to four-year olds took part in a randomised controlled trial in 11 ECEC settings. Participants were cluster-randomised, by ECEC setting, to either a 12 week staff-led and expert-supported intervention or a waiting list control group., Results: The intervention group increased time spent in moderate- and vigorous intensity PA by 10 min/day (95% CI = 3, 18; P = 0.01), took 1909 more steps per day (95% CI = 1130, 2688; P < 0.01) and reduced sedentary time with 14 min/day (95% CI = - 27, - 1; P = 0.04) compared to the control group. The intervention group had a 2.4 higher odds (95% CI = 1.05, 5.7; P = 0.04) of meeting the PA recommendations compared to the control group at follow-up., Conclusions: Our results show that a flexible staff-led and expert-supported multicomponent PA intervention can increase total PA level, moderate- and vigorous intensity PA and reduce time spent sedentary in three to four-year old children during their stay in ECEC settings., Trial Registration: The trial was retrospectively registered on September 19, 2020 and available online at ClinicalTrials.gov: No. NCT04555746 .

The first stereoselective, near-equimolar, and metal-free oxidative bioconjugation of amino acids and oligopeptides to aldehydes is presented. Based on a newly developed organocatalytic oxidative concept, the C-terminal and side-chain carboxylic acid functionalities of amino acids and oligopeptides are shown to couple in a stereoselective manner to α-branched aldehydes catalyzed by a chiral primary amine and a quinone as oxidizing agent. The oxidative coupling generally proceeds in high yield. For aspartic acid, selective coupling of the side-chain, or the C-terminal carboxylic acid, is demonstrated depending on the protection strategy. The stereoselective, oxidative bioconjugation concept is extended to a series of oligopeptides where coupling to carboxylic acid functionalities is presented. Bioorthogonal linker molecules for further functionalization are obtained by merging the oxidative coupling strategy with the click concept. It is demonstrated that the configuration of the new stereocenter is determined exclusively by the organocatalyst., (© 2020 Wiley-VCH GmbH.)

Organocatalytic enantioselective 1,3-dipolar [6+4] cycloadditions of pyrylium ion intermediates with fulvenes promoted by a chiral primary amine catalyst have been developed to proceed in moderate to good yields and high enantioselectivities. The resultant chiral bicyclo[6.3.0]undecane scaffold containing a transannular bridging ether is densely functionalised providing a rigid scaffold for further manipulations. Computational studies give important insights into the role of the primary amine catalyst. Analysis of the reaction shows that the catalytic reaction proceeds in a step-wise manner and rationalises the stereochemical outcome of the reaction. Several stereoselective complexity-generating transformations, facilitated by the diverse functional groups and transannular bridge, are presented, highlighting the versatility of the core towards a number of the cyclooctanoid natural products., (© 2020 Wiley-VCH GmbH.)

We report an experimental discovery and computational investigation of the first photochemical stereoselective [1,3]-sigmatropic silyl shift of an allylsilane. An organocatalytic enantioselective cascade annulation generates a trimethylsilyl- o -isotoluene reactant in >99:1 e.r., and this trimethylsilyl- o -isotoluene contains an allylic silane moiety that undergoes a stereoselective photochemical [1,3]-silyl shift to form a benzylsilane with 96:4 e.r. The mechanism of this unprecedented [1,3]-silyl shift has been elucidated by a series of experimental studies and CASSCF, DFT, and TD-DFT calculations on model systems and the experimental system. The highly stereoselective photoreaction is proposed to occur via a singlet silyl/allyl conical intersection. This is a new demonstration of the role of conical intersections in selective photochemistry.

The concept of pericyclic reactions and the explanation of their specificity through orbital symmetries introduced a new way of understanding reactions and looking for new ones. One of the 1965 Woodward-Hoffmann communications described "the (as yet unobserved) symmetry-allowed 6 + 4 combination", the prediction of a new field of "higher-order" cycloadditions, involving more than six electrons. Later these authors predicted exo -stereoselectivity for the [6 + 4]-cycloaddition. Chemists rushed to test this prediction (for the most part successfully). For more than half a century, chemists have hunted for additional higher-order cycloadditions. The application of catalysis within organic chemistry allows the accomplishment of previously unattainable reactions, including higher-order cycloadditions. The many examples of [8 + 2], [6 + 4], and cycloadditions of even higher electron-counts discovered since the Woodward-Hoffmann rules were introduced illustrate the difficulty in predicting which of these transformations will occur when two highly unsaturated molecules react. Periselectivity has been a challenge, and the development of enantioselective variants has been elusive. While progress was made, the rise of organocatalysis in asymmetric synthesis has led to a surge of interest in stereoselective versions of higher-order cycloadditions. Through organocatalytic activation of conjugated cyclic polyenes and heteroaromatic compounds, asymmetric [8 + 2]-, [6 + 4]-, and [10 + 4]-cycloadditions have been realized by our groups. In this century, [6 + 4]-cycloadditions have been found also to occur in enzyme-catalyzed reactions for the biosynthesis of spinosyn A, heronamide, and streptoseomycin natural products. A whole new class of enzymes, the pericyclases that catalyze pericyclic reactions, has been discovered. A remarkable aspect of these recent developments is the cross-disciplinary research involved: from organic synthesis to computational studies integrated with experimental studies of reaction mechanisms, intermediates, and dynamics, to understanding mechanisms of enzyme catalysis and engineering of enzymes. This Account describes how our groups have been involved in the expansion of the higher-order cycloaddition frontiers. We describe both the history and recent progress in higher-order cycloadditions, and how these advances have been made by our collaborative experimental and computational studies. Progress in asymmetric organocatalysis, incorporating enantioselective higher-order cycloadditions in organic synthesis, and the stereoselective synthesis of important scaffolds will be highlighted. Experimental progress and computational modeling with density functional theory (DFT) has identified ambimodal cycloaddition pathways and led to the realization that multiple products of pericyclic reactions are linked by common transition states. Molecular dynamic simulations have provided fundamental understanding of factors controlling periselectivity and have led to discoveries of a group of enzymes, the pericyclases, which catalyze pericyclic reactions such as [6 + 4]-cycloadditions.

Nucleophile-nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α-functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions. These quinol-intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α-thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α-branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Methylglyoxal (MG) is a toxic glycolytic by-product associated with increased levels of inflammation and oxidative stress and has been linked to ageing-related diseases, such as diabetes and Alzheimer's disease. As MG is a highly reactive dicarbonyl compound, forming both reversible and irreversible adducts with a range of endogenous nucleophiles, measuring endogenous levels of MG are quite troublesome. Furthermore, as MG is a small metabolite it is not very immunogenic, excluding conventional ELISA for detection purposes, thus only more instrumentally demanding LC-MS/MS-based methods have demonstrated convincing quantitative data. In the present work we develop a novel bifunctional MG capture probe as well as a high specificity monoclonal antibody to finally setup a robust reaction-based ELISA (ReactELISA) method for detecting the highly reactive and low-level (nM) metabolite MG in human biological specimens. The assay is tested and validated against the current golden standard LC-MS/MS method in human blood plasma and cell-culture media. Furthermore, we demonstrate the assays ability to measure small perturbations of MG levels in growth media caused by a small molecule drug buthionine sulfoximine (BSO) of current clinical relevance. Finally, the assay is converted into a homogenous (no-wash) AlphaLISA version (ReactAlphaLISA), which offers the potential for operationally simple screening of further small molecules capable of perturbing cellular MG. Such compounds could be of relevance as probes to gain insight into MG metabolism as well as drug-leads to alleviate ageing-related diseases., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Diarylprolinol silyl ethers are among the most utilized stereoselective organocatalysts for the construction of complex molecules. With their debut in 2005, these catalysts have been applied in numerous method developments primarily leveraging enamine and iminium-ion catalysis. These strategies have extended into the preparation of complex molecules in both academic and industrial settings. This Review intends to give an overview of the application of the diarylprolinol silyl ether catalysts in total synthesis. Furthermore, integration of these catalysts in patent literature is also disclosed highlighting the versatility of the catalytic system.

The development of the first chemo-, regio-, and stereoselective hetero-[6+4] and -[6+2] cycloadditions of heteroaromatic compounds via amino aza- and diazafulvenes is presented. Pyrroles, imidazoles, and pyrazoles substituted with a formyl group react with an aminocatalyst to generate an electron-rich hetero-6π-component that reacts in a chemo-, regio-, and stereoselective manner with electron-deficient dienes and olefins. For the hetero-[6+4] cycloaddition of the pyrrole system with dienes, a wide variation of both reaction partners is possible, providing attractive pyrrolo-azepine products in high yields and excellent enantioselectivities (99% ee). The hetero-[6+4] cycloaddition reaction concept is extended to include imidazoles and pyrazoles, giving imidazolo- and pyrazolo-azepines. The same activation concept is successfully employed to include hetero-[6+2] cycloadditions of the pyrrole system with nitroolefins, giving important pyrrolizidine-alkaloid scaffolds. Experimental NMR and mechanistic studies allowed for the identification of two different types of intermediates in the reaction. The first intermediate is the result of a rapid formation of an iminium ion, which generates a hetero-6π aminofulvene intermediate as a mixture of two isomers. Density functional theory calculations were used to determine the mechanism and sources of asymmetric induction in the hetero-[6+4] and -[6+2] cycloadditions. After formation of the reactive hetero-6π-components, a stepwise addition occurs with the diene or olefin, leading to a zwitterionic intermediate that undergoes cyclization to afford the cycloadduct, followed by eliminative catalyst release. The stereoselectivity is controlled by the second step, and computations elaborate on the various substrate and catalyst effects that alter the experimentally observed enantioselectivities. The computational studies provided a basis for improving the enantioselectivity of the hetero-[6+2] cycloaddition.

The first organocatalysed, metal-free cross-nucleophile coupling of indoles with α-branched aldehydes forming acyclic stereoselective quaternary carbon centres is presented. Applying an amino acid-derived catalyst with suitable organic oxidants affords the desired enantioenriched indole functionalised products with moderate to excellent yield and enantioselectivity. Two metal-free oxidative protocols employing either DDQ or a sequential approach that uses two organocatalysts to facilitate the use of O 2 as the terminal oxidant are disclosed. These methods are compatible with various indoles ranging from electron-rich to -deficient substituents at the C-2, -5, -6, and -7-positions reacting with a series of different α-branched aldehydes.

Methylglyoxal (MG) is quantitatively the most important precursor to advanced glycation end-products (AGEs), and evidence is accumulating that it is also a causally linked to diabetes and aging related diseases. Living systems primarily reside on the glyoxalase system to detoxify MG into benign d-lactate. The flux to either glycation or detoxification, accordingly, is a key parameter for how well a system handles the ubiquitous glyoxal burden. Furthermore, insight into proteins and in particular their individual modification sites are central to understanding the involvement of MG and AGE in diabetes and aging related diseases. Here, we present a simple method to simultaneously monitor the flux of MG both to d-lactate and to protein AGE formation in a biological sample by employing an alkyne-labeled methylglyoxal probe. We apply the method to blood and plasma to demonstrate the impact of blood cell glyoxalase activity on plasma protein AGE formation. We move on to isolate proteins modified by the MG probe and accordingly can present the first general inventory of more than 100 proteins and 300 binding sites of the methylglyoxal probe on plasma as well as erythrocytic proteins. Some of the data could be validated against a number of in vivo and in vitro targets for advanced glycation previously known from the literature; the majority of proteins and specific sites however were previously unknown and may guide future research into MG and AGE to elucidate how these are functionally linked to diabetic disease and aging.