During the last decades chemists have witnessed the development of thousands of new catalytic reactions driven by need and interest from both industrial and academic settings. Asymmetric catalysis has been one of the focus areas as a result of the increased need for optically active compounds in life science. Many catalytic asymmetric processes are based on metal complexes and rely on activation modes such as Lewis acid catalysis, atom-transfer catalysis, as well as s-and p-bond insertions. Recently, organocatalysis [1] has emerged as a powerful source of enantioselective transformations and has led to the development of a-,[2] b-, [3] g-, [4] and SOMOactivations, [5] as well as cascade, domino, and tandem reactions. [6] Aromatic compounds are ubiquitous as medicines and functionalized materials, and are often formed by electrophilic substitution reactions. [7] Friedel-Crafts alkylations, in particular of highly nucleophilic aromatic compounds such as phenols and anilines, are difficult owing to the regioselectivity and the competitive nucleophilic heteroatoms, which lead to undesired alkylation products. The application of copper catalysis to direct the substitution meta to an amido group through dearomatizing oxy-cupration [8] provides a recent example of where selectivity has been circumvented. Additionally, it has been shown by Gaunt and co-workers that para-substituted phenols can be converted into highly functionalized chiral molecules through oxidative dearomatization and intramolecular enamine catalysis.[9] Breaking aromaticity changes the reactivity from nucleophilic to electrophilic, [10] and thus makes it susceptible to addition of systems such as enamines.Electrochemical reactions often follow environmentally friendly protocols because electrons, as reagents, are inherently pollution free. The ability of electrochemistry to reverse the polarity of a functional group-by selective removal or addition of electrons-makes it thus possible to induce reactions of otherwise nonreactive molecules.[11] Successful combinations of electrochemistry and metal catalysis or mediated electron-transfer processes have been reported in numerous cases, [11] although the risk of having electrode fouling is always present. For example, palladium metal deposition on the cathode has been observed from the reduction of palladium(II), which is generated at the anode, in an undivided cell. [12] Organocatalysts are stable organic molecules and many stereoselective organocatalytic reactions are performed under conditions not possible for metalcatalyzed reactions. We thus anticipated that it might be possible to combine organocatalysis with anodic molecular transformations. [11b, 13] Herein, the combination of electrochemistry and asymmetric organocatalysis is presented. This new concept is demonstrated by a direct intermolecular a-arylation [14] of aldehydes using electron-rich aromatic compounds providing meta-alkylated anilines-a transformation not possible by Friedel-Crafts reactions of anilines (Scheme 1). We show the poten...

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A major focus of organocatalysis [1] has been the development of domino, cascade, and one-pot reactions.[2] These classes of reactions enable the construction of molecules with great structural complexity with a minimum of manual operations, thereby saving time, effort, and production cost. Moreover, given the current focus on the development of more environmental-friendly procedures, these reactions, with their fewer purification steps, are useful alternatives to the classical stepwise approaches.Recently, the aza-Diels-Alder reaction between an N-aryl imine and an olefin moiety (the Povarov reaction) [3] has attracted considerable attention, [4,5] as this reaction provides a simple route to a variety of nitrogen-containing polycyclic structures. In general, N heterocycles are of broad interest due to their vast abundance in natural and pharmaceutical compounds, and for instance tetrahydroquinolines have shown biological activity in numerous examples.[6] However, though they possess a tetrahydroquinoline core structure, suggesting potentially interesting biological properties, the class of octahydroacridines remains virtually unexplored due to their limited availability. This type of compounds may be accessed through an intramolecular Povarov reaction, in which an e,z-unsaturated aldehyde upon condensation with an aryl amine, subsequently undergoes a formal cycloaddition and re-aromatization, affording the final product. However, access to optically active octahydroacridines has so far exclusively been based on a chiral pool approach and, furthermore, limited diastereomeric control is often observed. [7] To the best of our knowledge, no catalytic asymmetric approaches to these interesting N-heterocyclic structures have been described to date.We imagined a route (Scheme 1), in which the addition of malononitrile derivatives to an a,b-unsaturated aldehyde employing aminocatalysis would furnish a suitable intermediate, which could be trapped in a following condensation/ cyclization cascade by an aniline derivative. Optimally, the stereocenter of the initial addition step would direct the subsequent cycloaddition, hereby controlling the formation of the optically active octahydroacridines with high diastereoselectivity.Herein, we describe a protocol for the preparation of a series of octahydroacridines having four stereocenters with excellent enantio-and diastereomeric control. A rationale for the stereochemical outcome of the reaction is proposed, and further derivatizations of the products are demonstrated, such as the selective hydrolysis of one of the nitrile functionalities, leading to octahydroacridines with five stereocenters.In order to reach an efficient one-pot protocol, the initial organocatalytic addition step was first investigated. At the outset, slightly modified conditions to those previously reported [2e] were applied. Accordingly, with malononitrile 2 a, 2 equiv of hex-2-enal (1 a), and 10 mol % of (S)-2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilyloxymethyl]pyrrolidine (3) as the catalyst in C...

An easy and simple one-pot approach for the formation of optically active substituted 1,4-dihydropyridines by using asymmetric organocatalysis is presented. The one-pot reaction of alpha,beta-unsaturated aldehydes with beta-diketones or beta-ketoesters and primary amines gives optically active 2,3-substituted 1,4-dihydropyridines in moderate yields and with enantioselectivities up to 95 % ee. It is also demonstrated that the optically active 1,4-dihydropyridines can be used in situ for the direct enantioselective reduction of, for example, alpha-ketoesters with high enantioselectivity.