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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