Aziridine–Metathesis based Approaches to Alkaloid Synthesis

Abstract

The aim of the project is to synthesise (–)-morphine utilising aziridine and metathesis chemistry. The thesis is divided into three chapters. Chapter 1 provides brief reviews on the subjects of total synthesis of morphine; ringrearrangement metathesis (RRM) and regioselective ring-opening of aziridines. Chapter 2 focuses on the research findings in the past three years. Two routes, A and B, were investigated in attempts to synthesise morphine (Scheme 1). In route A, sulfonyl cyclopentene II was prepared from ring-closing metathesis of a diene precursor, which was synthesised from lithiated cinnamylsulfone and butadiene monoxide. Subsequently, RRM reactions of several α-SO2Ph allyl derivatives of II were investigated and some interesting results were obtained. The synthesis of 2,3-trans vinylaziridine III was achieved in seven steps beginning with a Grignard reaction of (4- methoxyphenyl)magnesium bromide with butadiene monoxide. Subsequently, some highly regioselective ring-opening reactions of III with sulfur-stabilised anionic nucleophiles were achieved. However, in an attempt to synthesise compound I from II and III, no reaction was observed. This led to the investigation of route B, in which five methods for the synthesis of compound IV were investigated. The practical approach deployed a novel Al-mediated substitution of the 4-tosyl group of the tosyl tetrahydropyridine counterpart of IV, prepared from V and III, with a phenylthio group.

Chapter 3 provides the experimental details and characterisation data.