How Cinchona Alkaloid-Derived Primary Amines Control Asymmetric Electrophilic Fluorination of Cyclic Ketones

Abstract

The origin of selectivity in the α-fluorination of cyclic ketones catalyzed by cinchona alkaloid-derived primary amines is determined with density functional calculations. The chair preference of a seven-membered ring at the fluorine transfer transition state is key in determining the sense and level of enantiofacial selectivity.

Mechanism and Origins of Stereoselectivity in the Cinchona Thiourea- and Squaramide-Catalyzed Asymmetric Michael Addition of Nitroalkanes to Enones

“…The ethyl group on the quinuclidine ring of catalyst 1a was replaced by a methyl group to simplify our calculations (catalyst 1b, Scheme 1). 25,26 Mode B TSs leading to the major and minor products via the scis and s-trans conformations of the enone are shown in Figure 2. The two catalyst conformations considered for these TSs are that seen in TS thio -B cis -(major) and TS thio -B trans -(minor) which differ only by rotation of the quinoline ring by ∼180°(syn-open and anti-open conformations, respectively).…”

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

“…[11][12][13][14] Both theoretical and experimental mechanistic studies of reactions catalyzed by cinchona alkaloid derivatives have been reported. [15][16][17][18][19][20][21][22][23][24][25][26][27] Cucinotta et al studied the conjugate addition of 1,3dicarbonyl compounds to maleimides catalyzed by natural cinchona alkaloids with density functional theory (DFT), but only one possible bifunctional activation mode was considered, the pathway originally proposed by Wynberg. 7 Hintermann et al studied a natural cinchona alkaloid-catalyzed oxa-Michael cyclization using experimental techniques which provided some evidence for concerted O-C and C-H bond formation but other mechanistic possibilities could not be fully excluded.…”

“…This truncation has been reported to have minimal effect on the reaction outcome in related transformations catalyzed by cinchona alkaloid derivatives. 15,16 Previous computational studies have shown that deprotonations of acidic nucleophiles by tertiary amines are facile. 24,25 In our calculations, the quinuclidine nitrogen is protonated.…”

Enantioselective electrophilic fluorination of α-aryl-tetralones using a preparation of N-fluoroammonium salts of cinchonine

“…build a molecular model for justifying this stereoselective behavior with the transition states developed by Lam and Houk (2014) [22], which described a stereoselective model for Cinchona alkaloid-derived primary amines to control the fluorinations of cyclic ketones by the cyclic TS in chair and boat conformations.…”