Chiral Bicyclic Imidazole‐Catalyzed Acylative Dynamic Kinetic Resolution for the Synthesis of Chiral Phthalidyl Esters

Abstract

Utilizing a chiral bicyclic imidazole organocatalyst and adopting a continuous injection process, an alternative route has been developed for the efficient synthesis of chiral phthalidyl ester prodrugs via dynamic kinetic resolution of 3hydroxyphthalides through enantioselective acylation (up to 99 % ee). The computational studies suggest a general base catalytic mechanism differing from the widely accepted nucleophilic catalytic mechanism. The structure analysis of the key transition states shows that the CH-p interactions and not the previously considered cation/p-p interactions between the catalyst and substrate is the dominant factor giving rise to the observed stereocontrol. Figure 1. Representative ester-based prodrugs.

Chemical Synthesis of the Anti‐COVID‐19 Drug Remdesivir

“…In 2010, a novel chiral bicyclic imidazole organocatalyst was developed by our group (Zhang et al., 2010). Over the past decade, this kind of organocatalyst was successfully applied in a number of asymmetric reactions (Liu et al., 2012; Wang et al., 2017; Wang et al., 2020; Wang, Zhang, Liu, Xie, & Zhang, 2014; Wang, Zhang, Xie, & Zhang, 2014; Wang, Zhou, Zhang, Zhang, & Zhang, 2020; Zhang et al., 2019; Zhang, Wang, Xie, Sun, & Zhang, 2014; Zhou et al., 2019; Zhou et al., 2021). In 2012, the first catalytic asymmetric synthesis of P ‐stereogenic phosphoric acid derivatives was developed by our group using the chiral bicyclic imidazole catalyst (Liu et al., 2012).…”

N-Heterocyclic Carbene-Catalyzed Facile Synthesis of Phthalidyl Sulfonohydrazones: Density Functional Theory Mechanistic Insights and Docking Interactions

“…In addition, hemiaminal esters constitute crucial building blocks for several biological systems. In general, these compounds are obtained via a dynamic kinetic resolution process using various substrates . Among the various types of sulfonamides, phthalidyl sulfonamide promoters were found with impressive success.…”

“…In general, these compounds are obtained via a dynamic kinetic resolution process using various substrates. 10 Among the various types of sulfonamides, phthalidyl sulfonamide promoters were found with impressive success. Phthalidyl sulfonamides derivatives are an important class of heterocycles having potent biological and photophysical properties.…”