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A direct and mild strategy for the synthesis of benzo[a]azulenes based on an organocatalytic [10+4] cycloaddition reaction is described. The strategy enables a diversity-oriented approach for the synthesis of various poly-functionalised azulenes from easily accessible starting materials.

The mechanisms and origins of chemo- and stereoselectivities of the organocatalytic [6+4] cycloaddition between 2-cyclopentenone and tropone have been investigated by a combined computational and experimental study. In the presence of a cinchona alkaloid primary amine catalyst and an acid additive, 2-cyclopentenone forms a cross-dienamine intermediate that subsequently undergoes a stepwise [6+4] cycloaddition reaction via a zwitterionic intermediate. The rate-determining transition state features a strong hydrogen-bonding interaction between the tropone oxygen atom and the protonated quinuclidine directing the reaction course leading to a highly periselective [6+4] cycloaddition. The importance of the strong hydrogen-bonding interaction is also demonstrated by the influence of the concentration of the acid additive on the yields and enantioselectivities of the reaction. The corresponding [4+2] cycloaddition reaction has a much higher energy barrier. The enantioselectivity of the [6+4] cycloaddition originates from different repulsive hydrogen-hydrogen interactions that distinguish the diastereomeric transition states.

A new reactivity in organocatalysis is proposed to account for the coupling of carboxylic acids to α-branched aldehydes by combining primary amine catalysis and an oxidant. The developed methodology is an enantioselective α-coupling of aromatic and aliphatic carboxylic acids to α-branched aldehydes and proceeds in high yields (up to 97%) and for most examples good enantioselectivities (up to 92% ee). On the basis of experimental and mechanistic observations, the role of the primary amine catalyst is discussed.

An organocatalyzed asymmetric [4+2]-cycloaddition between tropolones and electron-deficient dienophiles is presented. Complex and biologically interesting dihydrohomobarrelenone scaffolds are formed through a Diels-Alder reaction utilizing bifunctional Brønsted-base catalysis, affording the corresponding bridged bicyclic cycloadducts in up to quantitative yields with good enantio- (up to 92 % ee) and diastereoselectivity (up to >20:1 d.r.). The synthetic value of the obtained products is explored by downstream transformations, including photoisomerizations, and their biological relevancy by in vivo testing in MCF-7 cancer cells., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel strategy for the direct enantioselective oxidative homocoupling of α-branched aldehydes is presented. The methodology employs open-shell intermediates for the construction of chiral 1,4-dialdehydes by forming a carbon-carbon bond connecting two quaternary stereogenic centers in good yields and excellent stereoselectivities for electron-rich aromatic aldehydes. The 1,4-dialdehydes were transformed into synthetically valuable chiral pyrrolidines. Experimental mechanistic investigations based on competition experiments combined with computational studies indicate that the reaction proceeds through a radical cation intermediate and that reactivity and stereoselectivity follow different trends., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first peri- and stereoselective [10+4] cycloaddition between catalytically generated amino isobenzofulvenes and electron-deficient dienes is described. The highly stereoselective catalytic [10+4] cycloaddition exhibits a broad scope with high yields, reflecting a robust higher-order cycloaddition. Experimental and computational investigations support a kinetic distribution of intermediate rotamers dictating the enantioselectivity, which relies heavily on additive effects., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel reaction that provides chiral allenes by amino catalytic activation of either aldehydes or α,β-unsaturated aldehydes for reaction with alkynyl-substituted enones is presented. The reaction forms a variety of trisubstituted allenes in high yields and with excellent stereoselectivities. The utility of the reaction concept is demonstrated by the synthesis of chiral furan derivatives in high yields and stereoselectivities., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel mechanism for the epoxidation of enals with hydrogen peroxide catalyzed by diarylprolinol silyl ether supported by experimental 13 C kinetic isotope effects (KIEs) and density functional theory calculations is presented. Normal 13 C KIEs, measured on both the carbonyl- and β-carbon atoms of the enal, suggest participation of both carbon atoms in the rate-determining step. Calculations show that the widely accepted iminium-ion mechanism does not account for this experimental observation. A syn-S N 2' substitution mechanism, which avoids formation of a discrete iminium-ion intermediate, emerges as the most likely mechanism based on agreement between experimental and predicted KIEs.

A novel concept for catalytic asymmetric coupling reactions is presented. Merging organocatalysis with single-electron oxidation by using a catalytic amount of a copper(II) salt and air as the terminal oxidant, we have developed a highly stereoselective carbon-carbon oxidative coupling reaction of α,β-unsaturated aldehydes. The concept relies on the generation of a dienamine intermediate, which is oxidized to an open-shell activated species that undergoes highly selective γ-homo- and γ-heterocoupling reactions. In the majority of examples presented, only a single stereoisomer was formed., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The [8+2] cycloaddition of indene-2-carbaldehydes and nitro olefins is described to provide benzonorbornene scaffolds in a highly peri-, diastereo-, and enantioselective fashion in the presence of a C 2 -symmetric aminocatalyst. This reaction, which proceeds through a transient semi-aromatic amino isobenzofulvene, represents the first example of catalytic formation and transformation of these species. Quantum chemical calculations suggest a kinetically controlled stepwise mechanism where the stereochemistry is determined in the first bond-forming event. Beyond the useful [8+2] cycloadducts, [10+4] cycloadducts have been identified in silico as potential off-pathway intermediates., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An enantioselective organocatalytic strategy, combining Brønsted base and N-heterocyclic carbene catalysis in a unique manner, is demonstrated for a concise construction of the privileged cyclopenta[ b ]benzofuran scaffold, present in many bioactive compounds having both academic and commercial interests. The reaction concept relies on an intramolecular one-pot double cyclization involving a cycle-specific enantioselective Michael addition followed by a benzoin condensation of ortho -substituted cinnamaldehydes. Cyclopenta[ b ]benzofurans were achieved in moderate to good yields, with excellent stereoselectivities. A proof of principle for a diastereodivergent variation is demonstrated through the synthesis of cyclopenta[ b ]benzofurans containing two contiguous aromatic substituents in a substitution pattern present in commercial and natural compounds. Furthermore, several transformations have been performed, demonstrating the synthetic utility of the products. Finally, insights into the activation mode and stereoindution models are presented for this new synthetic strategy.

The first stereoselective organocatalyzed [3+2] cycloaddition reaction of donor-acceptor cyclopropanes is presented. It is demonstrated that by applying an optically active bifunctional Brønsted base catalyst, racemic di-cyano cyclopropylketones can be activated to undergo a stereoselective 1,3-dipolar reaction with mono- and polysubstituted nitroolefins. The reaction affords functionalized cyclopentanes with three consecutive stereocenters in high yield and stereoselectivity. Based on the stereochemical outcome, a mechanism in which the organocatalyst activates both the donor-acceptor cyclopropane and nitroolefin is proposed. Finally, chemoselective transformations of the cycloaddition products are demonstrated., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The α-oxoaldehyde methylglyoxal is a ubiquitous and highly reactive metabolite known to be involved in aging- and diabetes-related diseases. If not detoxified by the endogenous glyoxalase system, it exerts its detrimental effects primarily by reacting with biopolymers such as DNA and proteins. We now demonstrate that during ketosis, another metabolic route is operative via direct non-enzymatic aldol reaction between methylglyoxal and the ketone body acetoacetate, leading to 3-hydroxyhexane-2,5-dione. This novel metabolite is present at a concentration of 10%-20% of the methylglyoxal level in the blood of insulin-starved patients. By employing a metabolite-alkyne-tagging strategy it is clarified that 3-hydroxyhexane-2,5-dione is further metabolized to non-glycating species in human blood. The discovery represents a new direction within non-enzymatic metabolism and within the use of alkyne-tagging for metabolism studies and it revitalizes acetoacetate as a competent endogenous carbon nucleophile., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

High on cycloaddi(c)tions: The impact of the Woodward-Hoffmann [4n+2] rule for thermally allowed cycloaddition reactions and the challenges associated with moving from six to ten electrons are discussed in this Essay., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new indium(III)-catalyzed reaction for the synthesis of a series of indolizine scaffolds has been developed. This methodology was highly efficient, allowing a low catalyst loading of 2 mol % (down to 0.5 mol %) and rendering the products in high yields through a 5-exo-dig aza-Conia-ene reaction. Furthermore, the possibility of incorporating an electrophile into the generated pyrrolidone ring in a one-pot synergistic fashion was demonstrated. Finally, based on experimental observations, a mechanism proposal was outlined., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Although many studies have reported on physical activity (PA) levels using accelerometers, a thorough description of the PA pattern in preschool children during their stay in the preschool, is lacking in the current literature. Furthermore, there remains a lack of understanding of the PA level and pattern in children in the lower end of the PA continuum. The first aim of this study was therefore to describe the PA pattern during a week-long stay in a preschool in all children born in 2011 (either three or four-year-olds) attending public preschools in a municipality in Norway. The second aim was to describe the PA level and pattern of the children who are the least physically active. This cross-sectional study included baseline data from 95% of children ( N  = 111) participating in a randomized controlled physical activity intervention (Active Kindergarten - Active Children study). The participants wore an Actigraph accelerometer, in week 39 in 2015, from when they arrived at the preschool on Monday morning and throughout their stay of five consecutive days. The amount of moderate- to vigorous-intensity PA (MVPA) per day ranged from 16 min to 116 min, and sedentary time ranged from 2.7 h to 6.5 h per day in the least and most sedentary child, respectively. The least physically active 25% of children were less active throughout the entire day, and only a few of them managed to achieve the recommended level of MVPA on any weekday. The physical activity levels and patterns among the least active children described in this study may help to inform interventions targeting this group.

We here present a conceptually novel reaction-based ELISA principle (ReactELISA) for quantitation of the carbon nucleophilic lipid metabolite acetoacetate. Key to the assay is the utilization of a highly chemoselective Friedländer reaction that captures and simultaneously stabilizes the nucleophilic metabolite directly in the biological matrix. By developing a bifunctional biotinylated capture probe, the Friedländer-acetoacetate adduct can be trapped and purified directly in streptavidin coated wells. Finally, we outline the selection and refinement of a highly selective recombinant antibody for specific adduct quantitation. The setup is very robust and, as we demonstrate via miniaturization for microplate format, amenable for screening of compounds or interventions that alter lipid metabolism in liver cell cultures. The assay-principle should be extendable to quantitation of other nucleophilic or electrophilic and perhaps even more reactive metabolites provided suitable capture probes and antibodies.

Cycloadditions that involve more than six π electrons are termed higher-order cycloadditions and are an excellent tool for solving complex synthetic challenges, as they provide direct access to polycyclic scaffolds that contain medium-sized rings. They have interesting synthetic potential for the discovery of new bioactive molecules and in natural product synthesis. It is peculiar that stereocontrolled [8+2] and [6+4] cycloadditions have been largely neglected for the past 50 years. Here we demonstrate a cross-dienamine activation of 2-cyclopentenone and the unprecedented endocyclic linear-dienamine activation of 2-cyclohexenones and 2-cycloheptenones. These dienamine intermediates undergo aminocatalytic stereoselective [8+2], [6+4] and formal [4+2] cycloadditions with various heptafulvenes. The periselectivities of the cycloadditions are controlled based on the ring size of the 2-cycloalkenones and the substitution patterns of the heptafulvenes. The chiral products obtained undergo various chemical and photochemical single-step transformations that give access to other classes of all-carbon polycyclic scaffolds.

A formal asymmetric α-alkenylation of aldehydes is reported based on the organocatalytic reaction of aldehydes with nitroacrylates. The reaction proceeds in a one-pot manner forming the products with up to 77% yield and up to >99% ee. This strategy is also successfully applied for the synthesis of α-exo-methylene-γ-butyrolactones and skipped diene scaffolds in a highly enantioselective manner.

Cycloaddition reactions are among the most important tools for the construction of cyclic compounds in organic synthesis, since these reactions are vital to access natural products and biologically active compounds. Organocatalysis plays an increasingly pivotal role in these reactions, often allowing several stereocenters to be selectively created and integrated in the target molecule. Among the large number of efficient types of organocatalysts available, the diarylprolinol silyl ethers have been established as one of the most frequently used in aminocatalysis allowing for novel activation modes and reaction concepts. In this review, we will focus on the different activation modes made available by the diarylprolinol silyl ether system with the aim of highlighting their applicability in asymmetric cycloadditions for the assembly of complex molecular architectures.

A novel alkyl functionalization of unactivated alkyl quinolines has been developed combining InCl 3 activation with organocatalytic activation of α,β-unsaturated aldehydes in a synergistic fashion. The reaction proceeds in a highly stereoselective manner as a sequence involving two consecutive synergistic catalytic cycles (Lewis acid- and iminium ion-catalyzed) and requires neither pre-activated alkyl quinoline substrates with electron-withdrawing substituents nor highly activated electrophiles. The reaction provides selectively double- or mono-addition products in good yields and high to excellent stereoselectivities. Furthermore, based on spectroscopic and labelling experiments, the mechanisms for the reactions are discussed., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first asymmetric [3+2] cycloaddition of vinyl aziridines with α,β-unsaturated aldehydes, based on synergistic catalysis, is disclosed. This methodology allows the formation of attractive pyrrolidine structures in good yields (up to 84 %), moderate diastereoselectivity, and high enantioselectivity values (up to >99 % ee). Additionally, a tricyclic pyrrolidine core structure found in biologically active molecules was synthesized in a one-pot fashion by using the presented reaction concept. Finally, a mechanistic proposal is outlined., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An asymmetric catalytic aza-Diels-Alder/ring-closing cascade reaction between acylhydrazones and in situ formed trienamines is presented. The reaction proceeds through a formal aza-Diels-Alder cycloaddition, followed by a ring-closing reaction forming the hemiaminal ring leading to chiral bicyclic azaheterocycles in moderate to good yield (up to 71 %), good enantio- (up to 92 % ee) and diastereoselectivity (up to >20:1 d.r.). Furthermore, transformations are presented to show the potential application of the formed product., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel reaction based on synergistic catalysis, combining palladium- and organocatalysis has been developed. The palladium catalyst activates vinyl benzoxazinanones via a decarboxylation to undergo a [4+2] cycloaddition with iminium-ion activated α,β-unsaturated aldehydes. The reaction is demonstrated to proceed for a number of combinations of vinyl benzoxazinanones reacting with α,β-unsaturated aldehydes, providing highly substituted vinyl tetrahydroquinolines in good to high yields, and excellent enantio- and diastereoselectivities (>98 % ee and >20:1 d.r.). The palladium catalyst used in the synergistic catalysis can be re-used in a one-pot sequential coupling reaction with an aromatic boronic acid forming the coupling product in 95 % yield, >20:1 d.r. and 99 % ee., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel enantioselective organocatalytic strategy is presented for the synthesis of tetrahydrofurobenzofuran and methanobenzodioxepine natural product core structures. The strategy is based on a pair of divergent reaction pathways in which hydroxyarenes react with γ-keto-α,β-unsaturated aldehydes, catalyzed by a chiral secondary amine. One reaction pathway, which leads to chiral 5,5-fused acetals with two stereocenters-the tetrahydrofurobenzofuran scaffolds-proceeds in moderate yields and up to 96 % ee. The other reaction pathway provides 5,6-bridged methanobenzodioxepine scaffolds with three stereocenters in moderate to good yields and up to 95 % ee. The reaction is remarkable as it can proceed with catalyst loadings as low as 0.25 mol %, providing one of the highest known turnover numbers in iminium ion catalysis. Furthermore, the hemiacetal tetrahydrofurobenzofuran can undergo functionalizations including reduction, oxidation, and allylation. Finally, the effects involved in the substrate control for the divergent pathways, based on both experimental and computational studies, have been investigated. A model involving steric, electronic and stereoelectronic interactions is discussed to rationalize the observed selectivities., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The enantio- and diastereoselective formation of indenes spirofused to highly substituted cyclopropanes is described. The application of a new cinchona alkaloid derived ammonium salt in a phase transfer catalysis setup facilitates high selectivity and excellent yields at low catalyst loadings (0.1-1.0 mol%).

The asymmetric formation of spiroindenes containing up to four contiguous stereocenters from the reaction of benzofulvenes with 2,4-dienals through trienamine catalysis is described. The benzofulvene core was found to be an excellent starting point for the synthesis of interesting spiroindenes through a formal cycloaddition pathway. The reaction was mediated by a diphenylprolinol silyl ether catalyst, and a diverse array of spiroindenes were obtained in high yields with excellent stereoselectivity. An attractive feature of the developed system is the possibility to diversify the product scaffold significantly by further manipulation of the chiral spiroindenes. Thus, three intramolecular ring-closing reactions following the organocatalytic step resulted in highly complex polycyclic systems., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Organocatalytic formed dienamines are shown to be involved in dynamic resolution of 2-cyclohexylidene acetaldehydes. By reaction of racemic 2-cyclohexylidene acetaldehydes with benzoquinones in the presence of a diarylprolinol-silyl ether catalyst, tricyclic products are formed in good to high yield and excellent enantioselectivity, while the diastereoselectivity depends on the substituent in the 2-cyclohexylidene acetaldehydes. Studies based on experimental observations and DFT-calculations point to a dynamic thermodynamic resolution-directed pathway. Some transformations of the optically active products are also presented.

Oxadendralenes are integrated in a novel manner into a one-pot cascade utilizing synergistic catalysis for the construction of valuable and complex bicyclic heterocyclic scaffolds. The construction is based on the organocatalytic activation of the oxadendralenes generating a vinylogous iminium-ion intermediate which is set-up for a 1,6-addition with an enamine formed from an aldehyde and the same organocatalyst. This reaction generates a cyclic oxadendralenic intermediate, which acts as an electron-deficient heterodiene reacting in a Lewis-acid catalyzed hetero-Diels-Alder reaction with vinyl ethers to form tetrahydroisochromenes with five continuous stereocenters in high yields, >20 : 1 dr and 99% ee. This synergistic organo- and Lewis-acid catalysed system also displays high tolerance for variation in oxadendralenes and aldehydes, which provides tetrahydroisochromenes with high diversity in the substituent pattern and the same excellent stereoselectivities. Mechanistic studies have been performed to account for the activation modes and stereochemical outcome of the reaction. The reaction concept has been extended to also include a sequential organocatalytic reaction of oxadendralenes with aldehydes, in which the enamine formed from the aldehyde and the organocatalyst act both in the first catalytic cycle forming the cyclic oxadendralenic intermediate and in a second catalytic cycle leading to tetrahydroisochromenes in good yields and excellent stereoselectivities. Mechanistic studies reveal that the stereochemistry of the organocatalyst has an influence on the diastereoselectivity of the reaction sequence. Some transformations of the tetrahydroisochromenes are also presented. The chiral tetrahydroisochromenes formed might be applied in the diversified synthesis of important drugs.

The regio- and stereoselective control of cycloaddition reactions to polyconjugated systems has been demonstrated by applying asymmetric organocatalysis. Reaction of 2,4-dienals with nitrones allows for a highly regio- and stereoselective 1,3-dipolar cycloaddition in the presence of an aminocatalyst. The first cycloaddition on the remote olefin can be followed either by a cascade reaction or by other selective reactions of the remaining olefin. The chiral products are obtained in good to high yields and excellent diastereo- and enantioselectivities. The remote selective concept has been extended to 2,4,6-trienals by means of a novel enantioselective triple cascade 1,3-dipolar cycloaddition reaction. The formation of chiral poly 1,3-amino alcohols is also demonstrated.

Asymmetric organocatalysis has witnessed a remarkable development since its "re-birth" in the beginning of the millenium. In this rapidly growing field, computational investigations have proven to be an important contribution for the elucidation of mechanisms and rationalizations of the stereochemical outcomes of many of the reaction concepts developed. The improved understanding of mechanistic details has facilitated the further advancement of the field. The diarylprolinol-silyl ethers have since their introduction been one of the most applied catalysts in asymmetric aminocatalysis due to their robustness and generality. Although aminocatalytic methods at first glance appear to follow relatively simple mechanistic principles, more comprehensive computational studies have shown that this notion in some cases is deceiving and that more complex pathways might be operating. In this Account, the application of density functional theory (DFT) and other computational methods on systems catalyzed by the diarylprolinol-silyl ethers is described. It will be illustrated how computational investigations have shed light on the structure and reactivity of important intermediates in aminocatalysis, such as enamines and iminium ions formed from aldehydes and α,β-unsaturated aldehydes, respectively. Enamine and iminium ion catalysis can be classified as HOMO-raising and LUMO-lowering activation modes. In these systems, the exclusive reactivity through one of the possible intermediates is often a requisite for achieving high stereoselectivity; therefore, the appreciation of subtle energy differences has been vital for the efficient development of new stereoselective reactions. The diarylprolinol-silyl ethers have also allowed for novel activation modes for unsaturated aldehydes, which have opened up avenues for the development of new remote functionalization reactions of poly-unsaturated carbonyl compounds via di-, tri-, and tetraenamine intermediates and vinylogous iminium ions. Computational studies have played a pivotal role in the elucidation of the regioselectivities observed for such systems because these pose a challenge due to the presence of multiple reactive sites in these intermediates. Charge distribution and π-orbital coefficient calculations have been applied to explain the observed regioselectivity of the given reactions. The calculation of more elaborate energetic pathways has allowed for in silico identification of high-energy intermediates, such as zwitterions, and transition-state structures, which have also provided information on the driving force controlling the reaction course and outcome.

The stereoselective [3 + 2] cycloaddition between vinylcyclopropanes and α,β-unsaturated aldehydes promoted by combined palladium and organocatalysis is disclosed. The unique synergistic catalytic system allows for the stereoselective formation of highly substituted cyclopentanes with up to four stereocenters in high yields and selectivities. Vinylcyclopropanes with two different geminal substituents facilitate the formation of cyclopentanes containing a quaternary stereocenter. Furthermore, the developed reaction performs well on gram scale, and a number of transformations are demonstrated.

Conjugated cyclic trienes have the potential for different types of cycloaddition reactions. In the present work, we will, in a novel asymmetric cycloaddition reaction, demonstrate that the organocatalytic reaction of 2-acyl cycloheptatrienes with azomethine ylides proceeds as a [3+2] cycloaddition, which is in contrast to the Lewis acid-catalyzed reaction, in which a [3+6] cycloaddition takes place. In the presence of a chiral organosuperbase, 2-acyl cycloheptatrienes react in a highly enantioselective manner in the [3+2] cycloaddition with azomethine ylides, providing the 1,3-dipolar cycloaddition product in high yields and up to 99 % ee. It is also shown that the diene formed by the reaction can undergo stereoselective dihydroxylation, bromination, and cycloaddition reactions. Finally, based on experimental observations, some mechanistic considerations are discussed., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first catalytic enantioselective cycloaddition reaction to α,β,β-trisubstituted nitroolefins is reported. For this purpose, nitroolefin oxetanes were employed in the reaction with 2,4-dienals promoted by trienamine catalysis. This methodology provides a facile and efficient strategy for the synthesis of highly functionalized chiral spirocyclohexene-oxetanes with two adjacent tetrasubstituted carbon atoms in high yields and excellent selectivities. This strategy also enabled access to chiral spirocyclohexene-cyclobutanes and -azetidines. Additionally, the obtained scaffolds can undergo diverse transformations leading to complex structures with up to four stereocenters, and we demonstrate that the nitro group, under nucleophilic conditions, can be applied for ring-opening of the oxetane., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first enantioselective formal [4+2] cycloadditions of 3-nitroindoles are presented. By using 3-nitroindoles in combination with an organocatalyst, chiral dihydrocarbazole scaffolds are formed in moderate to good yields (up to 87%) and enantioselectivities (up to 97% ee). The reaction was extended to include enantioselective [4+2] cycloadditions of 3-nitrobenzothiophene. The reaction proceeds through a [4+2] cycloaddition/elimination cascade under mild reaction conditions. Furthermore, a diastereoselective reduction of an enantioenriched cycloadduct is presented. The mechanism of the reaction is discussed based on experimental and computational studies., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The catalytic modes of action of three squaramide-derived bifunctional organocatalysts have been investigated using DFT methods. The [5+2] cycloaddition between oxidopyrylium ylides and enals was used as the model reaction. Two primary modes were possible for the different catalysts studied. The preference for one mode over the other was due to the possibility of additional favorable π-π interactions between the hydrogen-bond activated pyrylium ylide and an electron-deficient aromatic ring bonded to the squaramide NH group. The model can be extended to other reactions catalyzed by the same catalysts, such as formal [2+2] cycloadditions between nitroalkenes and α,β-unsaturated aldehydes. The computational results were in excellent concurrence with the available experimental reports on the observed total enantioselectivity and differences in diastereoselectivity depending on the substrate and the reaction., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Asymmetric organocatalysis has experienced an incredible development since the beginning of this century. The expansion of the field has led to a large number of efficient types of catalysts. One group, the diarylprolinol silyl ethers, was introduced in 2005 and has been established as one of the most frequently used in aminocatalysis. In this Minireview, we will take a look in the rear-view mirror, ten years after the introduction of the diarylprolinol silyl ethers. We will focus on the perspectives of the different activation modes made available by this catalytic system. Starting with a short introduction to aminocatalysis, we will outline the properties that have made the diarylprolinol silyl ethers a common choice of catalyst. Furthermore, we will describe the major tendencies in the activation and reaction concepts developed with regard to reactivity patterns and combinations with other activation concepts., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A general organocatalytic cross-dienamine activation strategy to produce chiral multifunctionalized norcamphor compounds having a large diversity in substitution pattern is presented. The strategy is based on a Diels-Alder reaction of an amino-activated cyclopentenone reacting with most common classes of electron-deficient olefins, such as nitro-, ester-, amide-, and cyano-substituted olefins, chalcones, conjugated malononitriles, CF3-substituted enones, and fumarates. The corresponding norcamphor derivatives are formed in good yield, excellent enantioselectivities, and with complete diastereoselectivity. Furthermore, it is demonstrated that quaternary stereocenters and spiro norcamphor compounds can be formed with high stereoselectivity. The present development provides a simple, direct, and efficient approach for the preparation of important norcamphor scaffolds., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The highly enantioselective dienamine-mediated formation of 5-bromo-6-(trifluoromethyl)-3,4-dihydro-2H-pyrans from α,β-unsaturated aldehydes and α-bromo-(trifluoromethyl)-enones employing a C2-symmetric aminocatalyst is described. The products are demonstrated to be applicable in coupling reactions directly onto the ring, thereby granting access to a broad scope of highly substituted 6-(trifluoromethyl)-dihydropyran compounds.

The first asymmetric regio- and diastereodivergent γ-allylation of cyclic α,β-unsaturated aldehydes based on combined organocatalysis and transition-metal catalysis is disclosed. By combining an aminocatalyst with an iridium catalyst, both diastereomers of branched allylated products can be achieved in moderate to good yields and excellent regio- and stereoselectivities. Furthermore, by replacing the iridium catalyst with a palladium catalyst, the linear allylated products are formed in good yields and excellent regio- and enantioselectivities. The developed method thus provides selective access to all six isomers of the γ-allylated product in a divergent fashion by choosing the appropriate combination of organocatalyst, transition-metal catalyst, and ligand., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel asymmetric organocatalytic 1,6-addition/1,4-addition sequence to 2,4-dienals is described. Based on a 1,6-Friedel-Crafts/1,4-oxa-Michael cascade, the organocatalyst directs the reaction of hydroxyarenes with a vinylogous iminium-ion intermediate to give only one out of four possible regioisomers, thus providing optically active chromans in high yields and 94-99 % ee. Furthermore, several transformations are presented, including the formation of an optically active macrocyclic lactam. Finally, the mechanism for the novel reaction is discussed based on computational studies., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Patients with end-stage renal disease (ESRD) have a high risk of cardiovascular disease. Small dense low-density lipoprotein (sdLDL) particles are particularly atherogenic. Marine n-3 polyunsaturated fatty acids (PUFA) may have a beneficial effect on numbers of sdLDL particles, and the aim of this study was to investigate the effect of n-3 PUFA on plasma levels of sdLDL in patients with ESRD., Methods: ESRD patients with cardiovascular disease (n = 161) on chronic hemodialysis were randomized to treatment with 1.7 g of n-3 PUFA (n = 81) or 2 g of placebo (olive oil; n = 80) for 3 months. The study was double-blinded. Densities of LDL and percentages of sdLDL (sdLDL%) of total LDL were measured before and after intervention. On the basis of sdLDL%, patients were classified as having lipid pattern A, I (intermediate), or B defined by a successive increase in sdLDL concentration and decrease in lipid particle size., Results: n-3 PUFAs significantly reduced triglycerides. However, LDL cholesterol remained unchanged. In the n-3 group, the LDL density did not change significantly during follow-up. Similarly, the LDL density remained unchanged in the placebo group. In the n-3 group, the sdLDL% was 34% at baseline and unchanged at follow-up. At baseline 71% had LDL pattern A, 9% had pattern I, and 20% had pattern B, and none of these patterns were significantly changed by n-3 PUFA supplementation., Conclusion: Dietary supplementation with 1.7 g of n-3 PUFA had no effect on LDL density or sdLDL levels in patients with ESRD., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Aim: In subjects without kidney disease, adiponectin appears to have anti-inflammatory, anti-diabetic, and anti-atherogenic effects. n-3 polyunsaturated fatty acids (PUFA) from seafood have several beneficial effects in patients with endstage renal disease (ESRD) and the aim of the present study was to assess the effect of n-3 PUFA supplementation on plasma adiponectin levels in ESRD patients., Methods: In a double blinded intervention trial, 162 ESRD patients (mean age 67 years  ± 13, 56 women and 106 men) undergoing chronic hemodialysis were randomized to 1.7 g n-3 PUFA daily or placebo for 3 months. Adiponectin, plasma lipids and lipoproteins were measured at baseline and after the intervention period., Results: At baseline, adiponectin was positively correlated to HDL-cholesterol (r = 0.55, p < 0.001) and inversely correlated to plasma triglycerides, body mass index (BMI) and high sensitive C-reactive protein (Hs-CRP) (r = -0.32, p < 0.01, r = -0.43, p < 0.01, and r = -0.21, p < 0.01, respectively). Furthermore, adiponectin was inversely correlated to the plasma levels of the two major n-3 PUFA docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (r = -0.19, p < 0.001, and r = -0.30, p < 0.001, respectively). Baseline plasma adiponectin levels were high in both groups but after 3 months of supplementation no significant change was observed in the groups. Thus, n-3 PUFA supplementation did not change adiponectin levels., Conclusion: We found an elevated plasma adiponectin level, which was inversely associated with plasma levels of DHA and EPA at baseline. Supplementation with n-3 PUFAs for 3 months did not change adiponectin levels. The negative result in this study may be related to a relatively low dose and future studies with higher dose and longer duration are needed to explore this mechanism.

A novel organocatalytic activation mode of cyclopropanes is presented. The reaction concept is based on a design in which a reactive donor-acceptor cyclopropane intermediate is generated by in situ condensation of cyclopropylacetaldehydes with an aminocatalyst. The mechanism of this enamine-based activation of cyclopropylacetaldehydes is investigated by the application of a combined computational and experimental approach. The activation can be traced to a favorable orbital interaction between the π-orbital of the enamine and the σ*C-C orbital of the cyclopropyl ring. Furthermore, the synthetic potential of the developed system has been evaluated. By the application of a chiral secondary amine catalyst, the organocatalytically activated cyclopropanes show an unexpected and highly stereoselective formation of cyclobutanes, functionalizing at the usually inert sites of the donor-acceptor cyclopropane. By the application of 3-olefinic oxindoles and benzofuranone, biologically relevant spirocyclobutaneoxindoles and spirocyclobutanebenzofuranone can be obtained in good yields, high diastereomeric ratios, and excellent enantiomeric excesses. The mechanism of the reaction is discussed and two mechanistic proposals are presented.

The stereochemical outcome of most aminocatalytic transformations is determined by the steric-shielding or hydrogen-directing approach. However, in recent years several reactions have appeared in which the stereochemical outcome is beyond these two approaches. This Concept article will highlight such reactions and postulate that the stereochemical outcome can be accounted for by electrostatic interactions between the catalyst-bound substrate and the reagent in the transition state., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Highly enantioselective organocatalytic [4+2]-cycloaddition of in situ generated trienamines with 4-nitro-5-styrylisoxazoles as α,β-unsaturated ester surrogates is presented. The synthetic utility of this strategy is demonstrated by transforming the formed cycloadducts into optically active carboxylates.

Attractive carbocyclic structures are accessed via a highly regio- and enantioselective aminocatalytic γ-addition of cyclic enals to vinyl phosphonates followed by a one-pot intramolecular Horner-Wadsworth-Emmons reaction. It is also demonstrated that nitro olefins can act as electrophiles in a similar reaction concept, providing carbocycles in equally high stereoselectivity.

The organocatalytic asymmetric α-alkylation of aldehydes by 1,6-conjugated addition of enamines to p-quinone methides is described. Employing a newly developed class of chiral secondary amine catalysts, α-diarylmethine-substituted aldehydes with two contiguous stereocenters have been synthesized in a simple manner with good diastereocontrol and excellent enantioselectivity.

The direct conjugation of a labeled proteome to a cleavable azide resin utilizing the copper-catalyzed azide alkyne cycloaddition is demonstrated. The procedure omits the classical streptavidin- and biotin-based affinity enrichment step and represents an operationally simpler, cheaper and less contaminated alternative for protein purification.

The organocatalytic activation of Morita-Baylis-Hillman alcohols via H-bonding-iminium-ion formation is demonstrated for the first time. This activation strategy enables the Morita-Baylis-Hillman alcohols to undergo a formal SN2' reaction. In combination with the well-established enamine reactivity, this creates a new reactivity pattern. The application of this new activation mode for the synthesis of bicyclic α-alkylidene-ketones is demonstrated. The developed reaction sequence proceeds efficiently affording nature-inspired target products with four contiguous stereogenic centers in a highly stereoselective manner., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)