A Theoretical Mechanistic Study of the Asymmetric Desymmetrization of a Cyclicmeso-Anhydride by a Bifunctional Quinine Sulfonamide Organocatalyst

Abstract

Cinchona alkaloids and their derivatives are widely used as organocatalysts in asymmetric synthesis. In particular, sulfonamide derivatives of cinchona alkaloids are highly enantioselective desymmetrization catalysts in the ring opening of a variety of cyclic anhydrides. To better understand the mechanism of catalysis, as well as to identify the basis for enantioselectivity by this catalyst, we have performed DFT calculations of this reaction with a cyclic meso anhydride. Herein, we report calculations for two reaction pathways, one concerted and one stepwise, for the production of each enantiomer of the desymmetrized product using the complete sulfonamide catalyst I. Our results are consistent with both the enantioselectivity of this transformation and the catalytic role of the quinuclidine moiety. We find that the stepwise pathway is the relevant pathway in the production of the major enantiomer. Our calculations highlight the role of differential distortion of the anhydride-methanol complex in the transition state as the factor leading to stereoselectivity.

Ionic Liquid Gels: Supramolecular Reaction Media for the Alcoholysis of Anhydrides

“…Indeed, the catalytic desymmetrization of cyclic meso-anhydrides has been widely studied for the purpose of elucidating its mechanism − and as a benchmark of new enantioselective catalysts . After the pioneering work of the groups of Oda and Aitken with native Cinchona alkaloids, , and the subsequent optimization by Bolm and co-workers, , also chiral Lewis acids, monomeric and dimeric alkaloid derivatives, ,, bifunctional compounds, − and chiral Brønsted acids proved to be competent catalysts for this class of reactions.…”

Catalytic, asymmetric azidations at carbonyls: achiral and meso-anhydride desymmetrisation affords enantioenriched γ-lactams

“…As is the case in the analogous sulfonamides, 34 the Cinchona alkaloid-derived sulfamide catalysts exist as a pair of rotamers in a ca. 2 : 1 ratio at 25 °C on the 1 H NMR spectro-Fig.…”

“…As is the case in the analogous sulfonamides, 34 the Cinchona alkaloid-derived sulfamide catalysts exist as a pair of rotamers in a ca. 2 : 1 ratio at 25 °C on the 1 H NMR spectroscopic timescale, which interconvert by rotation about the C9–C4′ bond axis.…”

New insights into the Lewis acidity of guanidinium species: Lewis acid interaction provides reactivity

“…The density functional theory (DFT) calculation has been recognized as a reliable method to shed light on this mechanism and the quality of activation modes in organocatalyst reactions [40]. However, the computational investigation has been conducted only in a handful of cases where the guanidinium species contribute to reaction through the Lewis acid activating mode (Scheme 2) [16,[41][42][43][44][45][46][47][48][49].…”

“…The calculation revealed the Lewis acid-base complexation between guanidinium and thiolate during the asymmetric thio-Michael reaction. Later, the same group of researchers extended their study to a broader range of substrates [41][42][43][44][45][46][47][48]. In 2015, the Wong group demonstrated that the unconventional bifunctional Brønsted-Lewis acid activation mode performs a catalytic function in the isomerization reaction of alk-3-ynoate (Scheme 2b) [49].…”