Insight into Isothiourea‐Catalyzed Enantioselective Addition of Saturated Esters to Iminium Ions

Abstract

The possible mechanisms and origin of the selectivities of isothiourea‐catalyzed addition of saturated esters to iminium ions have been investigated by density functional theory. The favorable reaction pathway includes three stages: formation of an ammonium enolate intermediate, enantioselective addition of the ammonium enolate intermediate to the iminium ion, and dissociation of the catalyst to form the product. The enantioselective addition process is the stereoselectivity‐determining step, while the chemoselectivity‐determining step is included in the formation of the final product. The calculated energy barriers show that the chemoselectivity is thermodynamically controlled, and it depends on the polarities of the products and the nucleophilicities of the N atoms of the enamine reactant moieties of the intermediates. The origin of the stereoselectivity was investigated by non‐covalent interaction analysis of the key transition states. Hydrogen bonding interactions were identified as the determining factor for controlling the stereoselectivity. The obtained insight will be valuable for rational design of novel Lewis base organocatalyst‐promoted enantioselective addition reactions with special chemoselectivities.

Asymmetric oxidative Mannich reactions promoted by photocatalysis and electrochemistry

“…In 2019, this mechanism was supported by Wei and collaborators by using density functional theory. 15…”

“…In 2019, this mechanism was supported by Wei and collaborators by using density functional theory. 15 Rueping and co-workers used N-aryltetrahydroisoquinolines and cyclic ketones to prepare a range of high-value Mannich products with excellent optical purities by employing a combined catalytic system containing a photoredox catalyst and a chiral primary amine organocatalyst (Scheme 11). 16 In the dual catalytic protocol, N-aryltetrahydroisoquinolines were activated by a photoredox catalyst, and ketones were activated by a chiral primary amine catalyst.…”