Cinchona Alkaloid-Catalyzed Asymmetric Conjugate Additions: The Bifunctional Brønsted Acid–Hydrogen Bonding Model

Abstract

Wynberg's report from 1977 that natural cinchona alkaloids catalyze the asymmetric conjugate addition of aromatic thiols to cycloalkenones is a landmark discovery in hydrogen bonding organocatalysis. Wynberg proposed that this reaction proceeded via the formation of a thiolate-alkylammonium tight ion pair and activation of the enone electrophile by a hydrogen bond from the catalyst's hydroxyl group. This reaction model provided the mechanistic basis for understanding Wynberg's reaction and many other asymmetric transformations since. Our quantum mechanical calculations reveal a different model should be used to explain the results: the alkylammonium ion activates the enone by Brønsted acid catalysis, and the catalyst's hydroxyl group orients the thiolate nucleophile. The new model rationalizes the stereoselective outcome of Wynberg's reaction and provides a new, general model for asymmetric cinchona organocatalysis.

Asymmetric Organocatalyzed Aza‐Henry Reaction of Hydrazones: Experimental and Computational Studies

“…The structures observed in the most favorable TS‐I systems indicate that electrophile 1 g interacts with the protonated quinuclidine group of the quinine catalyst before the nucleophilic attack of the nitronate takes place (Figure A). This model has been suggested previously by Houk and co‐workers for other chemical transformations catalyzed by cinchona alkaloids, and a mechanism with similar interaction mode has been proposed by Paton and co‐workers in the Henry reaction of aldehydes catalyzed by chiral phosphazenes . In contrast, all TS‐I steps in which the electrophile is interacting with the OH group of the catalyst show considerably higher energies (Figure B)…”

H-bond donor-directed switching of diastereoselectivity in the Michael addition of α-azido ketones to nitroolefins

“…A broad range of nitroolens 2a-g with different b-aryl substituents all gave the desired syn-5a-g in 73-85% yield and with 7 : 1 to 10 : 1 dr values, with 93-96% ee (entries 1-7, Table 2). b-Alkenyl nitroolens 2h-l furnished adducts syn-5h-l in >12 : 1 dr and 92-94% ee (entries [8][9][10][11][12]. Differently substituted a-azido indanones 1b-e also worked well to give syn-5m-p with high dr and ee values (entries 13-16).…”

“…10 For bifunctional tertiary amine catalysis, theoretical studies have proposed three types of working models that differ in how H-bond donors of the catalysts interact with the nucleophile and electrophile (Scheme 1A). [11][12][13][14][15] The ion pair-hydrogen bonding model (type A) was initially proposed by Wynberg 11a and supported by theoretical studies by Cucinotta and Gervasio. 11b The Brønsted acidhydrogen bonding model (type B) was revealed by Houk et al via quantum mechanical calculations.…”

“…11b The Brønsted acidhydrogen bonding model (type B) was revealed by Houk et al via quantum mechanical calculations. 12 The type A model differs from type B in that the H-bond donor of the catalyst is used to activate the electrophile and to stabilize the nucleophilic intermediate, respectively, with the simultaneously formed alkylammonium ion acting as a Brønsted acid to interact with the rest of the nucleophiles or electrophiles, respectively.…”

Organocatalysis: Fundamentals and Comparisons to Metal and Enzyme Catalysis

“…In 1977, Wynberg and co-workers [209] reported that cinchona alkaloids catalyze the asymmetric conjugate addition of aromatic thiols to cycloalkenones (Scheme 32) [210]. Quantum mechanical calculations proposed transition state of type 63 for these reactions [211]. and the conjugate acids 63 of the corresponding formates.…”