Broadening the scope and reactivity of C(1)-ammonium enolates to synthesise alpha-amino acid derivatives

Abstract

The work presented in this thesis focuses on expanding the scope and reactivity of C(1)-ammonium enolates by using electron–deficient aryl ester C(1)-ammonium enolate precursors with N-substituents in the R¹ position (figure 1). So far, most examples presented in the literature show the use of C(1)-ammonium enolate precursor bearing aryl, heteroaryl or alkenyl groups in the R¹ position. In this thesis, the scope of C(1)-ammonium enolate precursors is expanded to encompass benzylic ammonium salts and Schiff base glycine para-nitrophenol esters (figure 1). Both processes developed lead to the synthesis of α-amino acid derivatives, which are building blocks of high interest for the synthetic community.

Chapter 2 presents work towards developing the first catalytic enantioselective [1,2]-rearrangement of benzylic ammonium ylides using isochalcogenourea catalysis (scheme 1). Despite a thorough optimisation of the process, the yield and selectivity could not be improved
to more than 50% yield and 68:32 er. This was mainly due to the instability of the starting material towards the reaction condition. Another substrate was identified (where a –NO₂ group was added in ortho position on the migrating benzylic group Ar²) which proved more stable, unfortunately, further exploration of this reaction falls outside the scope of this thesis.

Chapter 3 presents the development of the first Lewis-base catalysed Michael addition with Schiff base glycine derivatives (scheme 2). The method developed in this thesis uses isochalcogenourea catalysis and introduces Schiff base glycine para-nitrophenol esters as C(1)-ammonium enolate precursors. Michael acceptors with two identical electron-withdrawing sulfone, ester and ketone groups were all successful in the reaction. The scope of the diarylketone Michael acceptors was explored further and a range of enantioenriched α-amino acid derivatives were obtained in good yield and selectivity (up to 89% yield and up to 95:5 er). Other possible expansion to the process were probed, as well as its limitations.

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