Generation and Reactivity of C(1)‐Ammonium Enolates by Using Isothiourea Catalysis

Abstract

C(1)‐Ammonium enolates are powerful, catalytically generated synthetic intermediates applied in the enantioselective α‐functionalisation of carboxylic acid derivatives. This minireview describes the recent developments in the generation and application of C(1)‐ammonium enolates from various precursors (carboxylic acids, anhydrides, acyl imidazoles, aryl esters, α‐diazoketones, alkyl halides) using isothiourea Lewis base organocatalysts. Their synthetic utility in intra‐ and intermolecular enantioselective C−C and C−X bond forming processes on reaction with various electrophiles will be showcased utilising two distinct catalyst turnover approaches.

Catalytic enantioselective synthesis of 1,4-dihydropyridines via the addition of C(1)-ammonium enolates to pyridinium salts

“…C(1)-Ammonium enolates, 1 derived from chiral tertiary amine Lewis base catalysts, 2 have emerged as synthetically powerful catalytically-generated intermediates for enantioselective C–C bond formation. Traditionally, reaction of C(1)-ammonium enolates with electrophiles such as Michael acceptors and carbonyl derivatives (ketones, imines) in formal [4+2] 3 and [2+2] 4 cycloadditions has enabled a wide variety of enantioenriched heterocycles to be accessed ( Scheme 1A ).…”

Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Conjugate Addition to para-Quinone Methides

“…C(1)-Ammonium enolate intermediates [52][53][54][55], generated by the reaction of a tertiary amine Lewis base catalyst with a ketene, anhydride or acyl imidazole [56], have found widespread application for the synthesis of heterocyclic scaffolds in high yield and with excellent enantiocontrol. Traditionally these approaches have been limited by the requirement for the electrophilic reaction partner to contain a latent nucleophilic site to facilitate catalyst turnover.…”

“…This conceptual obstacle has resulted in catalysis via C(1)-ammonium enolates being mostly applied for formal cycloaddition reactions. More recently, aryl esters have emerged as alternative C(1)-ammonium enolate precursors [55,57,58]. Significantly, following acylation of the tertiary amine catalyst by the aryl ester, a nucleophilic aryloxide is liberated, which may be exploited again in the catalytic cycle to facilitate ammonium enolate formation and catalyst turnover (Scheme 1a) [55,59].…”

“…More recently, aryl esters have emerged as alternative C(1)-ammonium enolate precursors [55,57,58]. Significantly, following acylation of the tertiary amine catalyst by the aryl ester, a nucleophilic aryloxide is liberated, which may be exploited again in the catalytic cycle to facilitate ammonium enolate formation and catalyst turnover (Scheme 1a) [55,59]. This strategy offers a potentially Molecules 2021, 26, 6333 2 of 13 general solution to allow the expansion of electrophile scope within catalytic processes using C(1)-ammonium enolate intermediates.…”

Chiral Isothiourea-Catalyzed Kinetic Resolution of 4-Hydroxy[2.2]paracyclophane

“…Considering the interest in compound 2, we thus thought about developing an alternative organocatalytic kinetic resolution protocol to control the esterification of rac-2. Chiral isothioureas (ITUs) emerged as easily available and powerful catalysts for numerous applications [29][30][31][32] and have been very successfully used for the kinetic resolution of different racemic alcohols [33][34][35][36][37]. Inspired by this unique catalysis potential, we therefore became interested in testing those chiral catalysts for the, to the best of our knowledge, so far not investigated acylative kinetic resolution of 4hydroxy[2.2]paracyclophane 2 (Scheme 1).…”