In spite of the many catalytic methodologies available for the asymmetric functionalization of carbonyl compounds at their α and β positions, little progress has been achieved in the enantioselective carbon–carbon bond formation γ to a carbonyl group. Here, we show that primary amine catalysis provides an efficient way to address this synthetic issue, promoting vinylogous nucleophilicity upon selective activation of unmodified cyclic α,β-unsaturated ketones. Specifically, we document the development of the unprecedented direct and vinylogous Michael addition of β-substituted cyclohexenone derivatives to nitroalkenes proceeding under dienamine catalysis. Besides enforcing high levels of diastereo- and enantioselectivity, chiral primary amine catalysts derived from natural cinchona alkaloids ensure complete γ-site selectivity: The resulting, highly functionalized vinylogous Michael adducts, having two stereocenters at the γ and δ positions, are synthesized with very high fidelity. Finally, we describe the extension of the dienamine catalysis-induced vinylogous nucleophilicity to the asymmetric γ-amination of cyclohexene carbaldehyde.

A significant limitation of modern asymmetric catalysis is that, when applied to processes that generate chiral molecules with multiple stereogenic centers in a single step, researchers cannot selectively access the full matrix of all possible stereoisomeric products. Mirror image products can be discretely provided by the enantiomeric pair of a chiral catalyst. But modulating the enforced sense of diastereoselectivity using a single catalyst is a largely unmet challenge. We document here the possibility of switching the catalytic functions of a chiral organic small molecule (a quinuclidine derivative with a pendant primary amine) by applying an external chemical stimulus, in order to induce diastereodivergent pathways. The strategy can fully control the stereochemistry of the asymmetric conjugate addition of alkyl thiols to α-substituted α,β-unsaturated ketones, a class of carbonyls that has never before succumbed to a catalytic approach. The judicious choice of acidic additives and reaction media switches the sense of the catalyst's diastereoselection, thereby affording either the syn or anti product with high enantioselectivity.

The development of novel and efficient catalytic methodologies for the stereoselective preparation of chiral aziridines is an important synthetic target.[1] Aziridines constitute a key structural feature of several classes of natural products and are extremely versatile building blocks that can undergo synthetically useful transformations.[2] The catalytic asymmetric aziridinations of olefins provide direct and useful access to such a valuable scaffold, and great efforts and progress have been made in this field.[3] However, to our knowledge, a general and highly stereoselective aziridination of simple a,b-unsaturated enones is still lacking. [4,5] Herein, we report an organocatalytic solution to this synthetic problem that is founded upon the use of a readily available chiral primary amine catalyst salt as well as on a rationally designed N-centered nucleophile.Previously reported asymmetric aziridinations of enones have severe restrictions in scope, as only chalcones are suitable substrates: metal-based systems [4] can provide highly enantioenriched compounds protected as N-tosyl derivatives, a protecting group that can prove to be difficult to remove, whereas two ingenious organocatalytic entries to nonprotected aziridines, showing moderate enantioselectivity (up to 67 % ee), were recently reported through the use of chiral tertiary amines. [5] Recently, the spectacular advances achieved in the field of chiral secondary amine catalysis [6] have set the conditions for the development of a highly chemo-and stereoselective aziridination of a,b-unsaturated aldehydes. [7] Central to the success of this approach was the ability of the organocatalyst to integrate orthogonal activation modes (iminium ion and enamine catalysis) into a more elaborate reaction sequence, [8] thus promoting first the nucleophilic addition of a N-centered nucleophile followed by an intramolecular cyclization (Scheme 1). We sought to extend this organocatalytic strategy to a,b-unsaturated ketones, an idea that was mainly triggered by the recent applications of chiral primary amine salts as efficient activators of enones through iminium catalysis.[9] The reduced steric constraints of primary amines offers the unique possibility of catalyzing processes between sterically demanding partners, overcoming the inherent difficulties of chiral secondary amine catalysis.In particular, we recently introduced the catalyst primary amine salt 1, [10] which is made by combining the easily available 9-amino(9-deoxy)epi-hydroquinine 2 with d-N-Boc phenylglycine (3; Boc = tert-butyloxycarbonyl). Salt 1 exhibits high reactivity and selectivity in the enantioselective conjugate additions of carbon-,[10a] oxygen-, [10b] and sulfurcentered [10c] nucleophiles to a,b-unsaturated ketones.To consolidate salt 1 as a general and selective iminium catalyst for enones, we questioned whether this catalytic system might be successfully extended to the highly enantioselective amine conjugate addition, a primary strategy for C À N bond construction. [11] Prompted by the s...

Double-cross: Proline catalyzes the double Mannich reaction of acetaldehyde with N-Boc imines in excellent yields (up to 99 %; Boc = tert-butoxycarbonyl) and close to perfect diastereo- and enantioselectivities. Depending on the choice of catalysts, both the chiral, pseudo-C(2)-symmetric diastereomer and the corresponding meso compound can be prepared. Cross double Mannich reactions of acetaldehyde with two different imines are also demonstrated.

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In the past decade, asymmetric aminocatalysis has become a fundamental synthetic strategy for the stereoselective construction of chiral molecules.[1] The extraordinary pace of innovation and progress in aminocatalysis has been dictated mainly by the discovery of distinct catalytic activation modes which have enabled previously inaccessible transformations. [2] To the same extent, the design of novel structural classes of organic catalysts has also ignited the field, enabling the activation of challenging types of carbonyl substrates. Whereas chiral secondary amines have proven invaluable for the asymmetric functionalization of aldehydes, primary amine catalysis has offered the unique possibility of participating in processes between sterically demanding partners. [3] Therefore it overcomes the inherent difficulties of chiral secondary amines in generating congested covalent intermediates. Chiral primary amine based catalysts have been successfully used for the enamine activation of challenging substrates, such as a,a-disubstituted aldehydes [4] and ketones.[5] In 2005, Ishihara and Nakano [6a] additionally extended the potential of chiral primary amines to include the iminium ion activation of a-acyloxy-acroleins toward a stereoselective Diels-Alder process.[6] However, the use of a,b-disubstituted unsaturated aldehydes still represents an elusive and fundamental target for asymmetric aminocatalysis. [7] This is particularly true when considering that an alternative asymmetric metal-catalyzed strategy for the functionalization of this compound class is also lacking.[8]Herein we show that the chiral primary amine catalyst 1 provides an efficient solution to this longstanding and sought after issue, activating a,b-disubstituted enals toward a welldefined iminium/enamine tandem sequence (Scheme 1). Specifically, we developed organocascade reactions [9] which combine two intermolecular and stereoselective steps involving a Michael addition/amination pathway. The described olefin aryl-amination and thio-amination processes afford straightforward access to valuable precursors of a-amino acids which have two adjacent stereogenic centers, one of which is quaternary, with very high optical purity.Recently we and others, independently, [4b, 5] established chiral primary amine 1-directly derived from natural cinchona alkaloids-as an effective catalyst for ketone activation. We additionally demonstrated the versatility of 1, which can combine orthogonal catalysis modes (iminium and enamine activations) into one mechanism, thus promoting an intramolecular tandem reaction with a,b-unsaturated ketones.[10] On this basis, we hypothesized whether the unique ability of catalyst 1 to engage in iminium ion formation with encumbered enones while enforcing high geometric control and facial discrimination, might be extended to the challenging class of a,b-disubstituted enals. Preliminary investigations revealed that the TFA salt of 1 was able to promote the Friedel-Crafts alkylation of 2-methyl-1H-indole with (E)-2-methylpent-2-enal...

The first catalytic method for the asymmetric aziridination of cyclic enones is described. The presented organocatalytic strategy is based on the use of an easily available organocatalyst that is able to convert a wide range of cyclic enones into the desired aziridines with very high enantiomeric purity and good chemical yield. Such a method may very well open up new opportunities to stereoselectively prepare complex chiral molecules that possess an indane moiety, a framework that is found in a large number of bioactive and pharmaceutically important molecules.

Dedicated to the Centenary of the Italian Chemical SocietyThe development of novel and highly enantioselective transformations is one of the most exciting goals for organic chemists involved in the competitive and stimulating field of asymmetric organocatalysis. [1] In this area, the remarkable advances in the application of chiral secondary amine catalysts (asymmetric aminocatalysis) [2a,b] are linked with the accessibility of divergent carbonyl activation modes, through either nucleophilic enamine [2c] or dienamine [2e] intermediates, electrophilic iminium ions [2d] or even radical [2f] intermediates. In particular, the incredibly high efficiency and generality demonstrated by some "privileged" organocatalysts such as proline [3a] (I) or the synthetic MacMillan imid-A C H T U N G T R E N N U N G azA C H T U N G T R E N N U N G olidinones [2d] (II) and the silyl-protected diarylprolinols catalysts [3b] (III) (Scheme 1) have consolidated asymmetric aminocatalysis as a reliable and powerful synthetic tool for the chemo-and enantioselective functionalization of carbonyl compounds.[2] These general and readily available catalysts represent an important starting point for the investigations of new asymmetric processes because they often avoid the need for multiple screening processes of catalysts to determine the optimal reaction conditions. However, because aminocatalysis may face problems of increasing complexity and diversity, the privileged catalysts might not always be the best candidates to solve some specific and challenging tasks (Scheme 1). In this context, the stereocontrolled conjugate addition of prochiral trisubstituted carbon nucleophiles to a,b-unsaturated aldehydes through iminium activation still represents a daunting synthetic challenge [4] because the privileged catalysts generally allow the formation of products with high enantioselectivity but with poor diastereocontrol. [5] Herein, we describe the development of a new bifunctional chiral primary amine thiourea catalyst and its application in the first asymmetric conjugate addition of oxindoles to enals. A bifunctional catalyst was chosen because it was thought that only concomitant and synergistic activation of both the reacting partners may enforce high diastereocontrol during CÀC bond formation. The high levels of both enantio-and diastereoselectivity achieved demonstrate the ability of the catalyst to provide a solution to the challenging problem of generating valuable chiral scaffolds with contiguous quaternary and tertiary stereocenters.[6] Moreover, we demonstrated for the first time that chiral primary amine thiourea catalysts, which during the last two years have been successfully applied in many enamine-based asymmetric transformations expanding the synthetic potential of aminocatalysis, [7] can also be effective for iminium ion activation of a,b-unsaturated aldehydes.For exploratory studies, we selected the reaction between 3-methyl oxindole (1 a) and cinnamaldehyde (2 a), a combination of simple and readily available starting ...