Developing and broadening the reactivity of C(1)-ammonium enolates 

Abstract

Enantioselective catalysis has been explored extensively and has allowed access to of chiral products with high levels of enantiocontrol. Within this area, isothioureas have been confirmed as highly effective Lewis-base catalysts for a wide range of enantioselective processes. Among these isothiourea-catalysed asymmetric transformations, C(1)- ammonium enolates are representative of a catalytically generated reactive intermediates. These species are traditionally generated by treatment of the Lewis base either with carboxylic acid derivatives or acyl imidazoles to generate a precursor acyl ammonium species that undergoes deprotonation to generate the enolate. A current limitation of these approaches when using isothioureas is that an α-aryl, α-alkenyl, or an α-heteroaryl substituent is necessary to facilitate this transformation. Unsubstituted or α-alkyl substituted C(1)-ammonium enolate precursors typically demonstrate a complete lack of reactivity, with these constraints commonly ascribed to the acidity of the acyl ammonium precursor disfavouring formation of the C(1)-ammonium enolate.

To overcome this challenge, this thesis describes the development of α-silyl substituted carboxylic acids as precursors to α-alkyl and α-unsubstituted C(1)-ammonium enolates, through an alternative desilylation pathway (instead of deprotonation) to form the desired C(1)-ammonium enolate. This protocol was applied in enantioselective [2+2] cycloadditions with ketones and enones to deliver chiral β-lactones. This strategy provides a straightforward way to obtain a wide range of enantio-enriched β-lactones in good overall yields. The use of commercially available or easily prepared starting materials with low catalyst loading (5 mol%) under a mild condition makes this method practical and economical.

Enantiomerically pure β-lactones are of great interest due to their presence in numerous of natural products and biologically active molecules. The enantioselective synthesis of β- lactones is valuable for both industrial and academic due to their versatile properties.

A range of perfluoroalkyl ketones and phosphorus substituted ketones with various substituents are tolerated in this transformation, while the use of α-silyl substituted carboxylic acids precursors allows the effective incorporation of C(3)-alkyl substituents and C(3)- unsubstituted using isothiourea catalyst for the first time. Moreover, the regioselectivity was also excellent when we employ trifluoromethyl enones as the electrophile, preferentially generating the [2+2] cycloaddition product rather than Michael-addition formal [4+2] product.

Mechanistic studies have been carried out, that indicates this process proceeds through an initial kinetic resolution of an in situ prepared α-silyl substituted anhydride, Pseudo overall zero order kinetics observed.

To sum up, this thesis demonstrated an effective, practical strategy to broadening the reactivity of C(1)-ammonium enolates, approaching novel high value enantioenriched molecules in a straightforward manner.

Date of Award	14 Jun 2023
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Andrew Smith (Supervisor)