Patrizia Galzerano

Diastereodivergent asymmetric sulfa-Michael additions of α-branched enones using a single chiral organic catalyst.

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 catalysts diastereoselection, thereby affording either the syn or anti product with high enantioselectivity.

Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis

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.

Asymmetric organocatalytic cascade reactions with alpha-substituted alpha,beta-unsaturated aldehydes.

In the past decade, asymmetric aminocatalysis has become a fundamental synthetic strategy for the stereoselective construction of chiral molecules. 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. 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. 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 and ketones. In 2005, Ishihara and Nakano additionally extended the potential of chiral primary amines to include the iminium ion activation of a-acyloxy-acroleins toward a stereoselective Diels–Alder process. However, the use of a,b-disubstituted unsaturated aldehydes still represents an elusive and fundamental target for asymmetric aminocatalysis. This is particularly true when considering that an alternative asymmetric metal-catalyzed strategy for the functionalization of this compound class is also lacking. 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 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, 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. 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)-2methylpent-2-enal with high enantioselectivity, indicating that a selective p-facial shielding of the iminium intermediate is effective [Eq. (1)]. The poor diastereocontrol, however, clearly demonstrates that the enamine-based protonation step escapes catalyst control. Nevertheless, the ability of 1 to impart high stereocontrol in the iminium activation of a-branched enals prompted us toward a more intriguing target: the creation of multifunctional compounds, having two contiguous stereocenters, in a one-step process. In addition to the benefit of generating Scheme 1. Targeting a,b-disubstituted unsaturated aldehydes.

Asymmetric Catalytic Aziridination of Cyclic Enones

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.

Controlling Stereoselectivity in the Aminocatalytic Enantioselective Mannich Reaction of Aldehydes with In Situ Generated N-Carbamoyl Imines

A simple and convenient method for the direct, aminocatalytic, and highly enantioselective Mannich reactions of aldehydes with in situ generated N-carbamoyl imines has been developed. Both alpha-imino esters and aromatic imines serve as suitable electrophilic components. Moreover, the judicious selection of commercially available secondary amine catalysts allows selective access to the desired stereoisomer of the N-tert-butoxycarbonyl (Boc) or N-carbobenzyloxy (Cbz) Mannich adducts, with high control over the syn or anti relative configuration and almost perfect enantioselectivity. Besides the possibility to fully control the stereochemistry of the Mannich reaction, the main advantage of this method lies in the operational simplicity; the highly reactive N-carbamate-protected imines are generated in situ from stable and easily handled alpha-amido sulfones.

Organocatalytic Vinylogous Michael Additions

primary amines G . B E N C IVE N N I , P. G A L Z E R A N O , A . M A Z Z A N T I , G . B A RT O L I , P. M E L C H IO R R E * ( U N IV E R S I T À D I B O L O G N A , I T A L Y ; I N S T I T U C I Ó C A T A L A N A D E RE C E R C A I E S T U D I S AVA N Ç A T S , B A RC E L O N A A N D I N S T I T U T E O F C H E M I CA L R E S E A R C H O F C A T A L O N I A , TA R R A G O N A , S P A IN ) Direct Asymmetric Vinylogous Michael Addition of Cyclic Enones to Nitroalkenes via Dienamine Catalysis Proc. Natl. Acad. Sci. U.S.A. 2010, DOI: 10.1073/pnas.1001150107.