Cyclopropyl Iminium Activation: Reactivity Umpolung in Enantioselective Organocatalytic Reaction Design

Abstract

The intrinsic donor-acceptor reactivity pattern of conjugated, unsaturated carbonyl compounds predictably alternates along the carbon chain (Scheme 1). Consequently, electrophiles are predisposed to react at the a (d 2 ) and g (d 4 ) donor positions, whereas nucleophiles add to the b (a 3 ) and d (a 5 ) acceptor positions. Direct inversion of this inherent selectivity is known as reactivity umpolung, [1] and often provides a platform for the development of novel transformations. While various activation modes that allow for a (a 2 /d 2 ), b (a 3 ), g (d 4 ), and e (d 6 ) functionalization have been reported through secondary amine organocatalysis, [2] umpolung strategies remain elusive outwith the confines of SOMO activation [2b] and processes mediated by N-heterocyclic carbenes (NHCs). [3,4] Because pyrrolidine-and imidazolidinone-based organocatalysts require carbonyl substrates to generate the transient intermediates that are central for catalysis, the substrate scope is limited to aldehydes and ketones with varying degrees of unsaturation. With a view to extending the substrate scope of secondary-amine-catalyzed processes, and providing an entry point into the design of homologous variants of addition reactions to a,b-unsaturated iminium ions, we began exploring the reactivity of cyclopropane carbaldehydes.Cyclopropane behaviour has striking parallels with that of olefins.[5] In addition to their ability to interact with adjacent p systems, cyclopropanes function as effective donors when activated by adjacent low-lying empty orbitals: this can be rationalized by considering the Walsh orbitals. [6,7] Striking manifestations of the electron-donating aptitude of cyclopropanes include: 1) the unusual thermodynamic stability of the cyclopropylcarbinyl cation, [8] and 2) the bond-length asymmetry of cyclopropanecarbonitirile (Dd (distalÀvicinal) = 0.033 ) as a consequence of hyperconjugation. [9,10] Of particular pertinence to this study is the latter observation. It was envisaged that the well described conjugation between a cyclopropane moiety and polar multiple bonds might form the basis of an activation strategy involving cyclopropyl iminium salts. Indeed, Wang and co-workers have described that the nucleophilic addition of benzenethiols to cyclopropanecarbaldehydes can be catalyzed by proline.[11] The similarities in bonding between this species and that of conventional a,b-unsaturated iminium ions, together with the expected interaction of the cyclopropyl moiety with the conjugated iminium functionality, motivated us to investigate the reactivity of cyclopropane carbaldehydes [12] upon unification with secondary amines (Scheme 2). Formally, nucleophilic addition to the transient cyclopropyl iminium species would constitute a formal umpolung of the g-position of a dienamine;[2c] d 4 !a 4 (Scheme 1). Moreover, by intercepting the transient enamine with an electrophile, this strategy would give an unprecedented method for the organocatalytic formation of 1,3-difunctionalized products in a single operation (Sche...

Infrared Multiphoton Dissociation Spectroscopic Analysis of Noncovalent Interactions in Organocatalysis

“…Consequently, this steering group can encode for conformer I or II , depending on the configuration of the stereogenic center. By locking the phenyl group in the π–π conformation (i.e., 6 ; II ) or the CH–π conformation (i.e., 5 ; I ), it is possible to generate diastereomeric “conformer equivalents”19b of the two rotamers, which are believed to be important for enantioinduction. As expected, the global minimum of 5 was calculated to be the one allowing for CH–π interaction (i.e., I , Φ NCCC = +45.4°; Φ NCCF = –79.0°).…”

Organocatalytic enantioselective desymmetrisation

“…220 By employing MacMillan's first-generation catalyst C-147, nucleophilic addition at the g-position could be achieved, with subsequent capture of an electrophile at the a-position. 220 By employing MacMillan's first-generation catalyst C-147, nucleophilic addition at the g-position could be achieved, with subsequent capture of an electrophile at the a-position.…”

Dekonstruktion kovalenter Organokatalyse

“…[93] Wirw endeten den Ansatz der Reaktionsdekonstruktion auch auf die Entwicklung der ersten katalytischen, enantioselektiven Dichlorierung von meso-Cyclopropancarbaldehyden an (38 und 39;A bbildung 6). [94] Im Zentrum der Arbeitshypothese stand der Vorschlag,d ass ein vermeintliches Cyclopropyl-Iminiumion-Intermediat (34,35) . .…”