Catalytic approaches towards heterocyclic aziridine and aryl ethylamine scaffolds

Abstract

Nitrogen-containing heterocyclic scaffolds are prevalent within bioactive molecules and natural products. Of these, aziridine scaffolds represent viable targets, both as bioactive molecules (e.g., as covalent inhibitors) but also as synthetic intermediates within the synthesis of amine-containing molecules. The research described within this thesis details the development of methodologies for the synthesis of heterocyclic aziridine and ethylamine scaffolds.

Despite notable advances, the preparation of complex, α-heterocyclic aziridine variants is particularly challenging, with few examples within the literature. This space is instead dominated by aliphatic and aromatic substituents, presenting a significant gap within the chemical literature. This chapter details the discovery and development of a general method to the diastereoselective synthesis of disubstituted heterocyclic aziridines. Brønsted acid‑catalysis provides access to an intermediate 1,2‑chloroamine, via aza-Michael addition to trisubstituted alkenes. Diastereocontrol of this addition was found to be reliant on trace amounts of acid, and simple S_Ni allowed access to a variety of cis‑aziridines with complete stereochemical fidelity (up to 20:1 d.r.), which are notoriously inaccessible through alternative synthetic methodologies.

Aryl triazole moieties have also demonstrated widespread applicability within materials science, medicinal chemistry and chemical biology. This chapter details the development of a one-pot, modular reaction which can access 1,4-disubstituted 1,2,3-triazolyl aryl ethylamine scaffolds from styrenes. The methodology employs a single copper catalyst, accessing an aryl aziridine in-situ using metal-nitrene aziridination, which is regioselectively ring-opened by sodium azide, with Cu acting as a Lewis acid. Finally, copper catalysed azide-alkyne cycloaddition (CuAAC) delivers the desired products with high yield. The scope of this transformation was explored, and the method was applied to a variety of pharmaceutically relevant motifs.

Date of Award	2 Jul 2026
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Allan Watson (Supervisor)