Studies towards overcoming current limitations of ru-alkylidene catalysed olefin metathesis

Abstract

Catalytic olefin metathesis has significantly enhanced the power of synthetic chemistry. In particular, Ru-alkylidene catalysed olefin metathesis has played a key role in the discovery of many new and exciting technologies. However, there are still many challenges which remain unaddressed in this field of chemistry. In this thesis, three independent research projects are presented which collectively extend the scope of olefin metathesis. Towards this end, research exploring i) tandem catalysis (Chapter 2), ii) cross-metathesis of sterically hindered olefins (Chapter 3) and iii) olefin metathesis in aqueous media (Chapter 4) are described. In each case, a brief literature survey is used to contextualise the ensuing research, which is presented in manuscript format with its supporting data. Chapter 1 presents a brief overview of Ru-alkylidene catalysed olefin metathesis. This includes an introduction to the general classes of olefin metathesis reactions, namely ring-closing metathesis, cross metathesis and ring-opening metathesis polymerisation, catalysed by Ru-alkylidene complexes. The mechanism of olefin metathesis is also detailed, as are selected examples which highlight the utility of this class of reaction. Chapter 2 describes the development of a tandem olefin metathesis/hydrogenation protocol. Also detailed within this chapter are strategies to prevent concomitant alkene isomerisation during olefin metathesis reactions involving reactive terminal olefins. The methodology developed in this study has been applied to the synthesis of a family of enantiopure lipophilic amino acids. This scalable process delivers lipophilic amino acids with sufficient purity to be directly incorporated into a peptide sequence via solid phase peptide synthesis. Chapter 3 details studies towards the efficient cross-metathesis of previously unreactive substrates. In particular, this chapter describes the use of a cross-metathesis reaction between allylglycine derivatives and methylenecycloalkanes, followed by an acid-catalysed cyclisation, to access a family of enantiopure 1-azaspiropyrrolidines. Ring-expansion of the 1-azaspiropyrrolidine structures conveniently affords 1-azaspiropiperidine motifs. Extension of this strategy was required to access the tricyclic marine alkaloid lepadiformine. This involved cross-metathesis reactions using allylic substituted methylenecycloalkane derivatives, substrates which were previously unreactive in cross-metathesis reactions due to steric hindrance. Towards this end, this chapter details studies towards the development of a steric reversal strategy for the cross-metathesis of sterically hindered olefins. Chapter 4 describes the development of an ammonium-functionalised second generation Hoveyda Grubbs-type complex for olefin metathesis in water. A simple and scalable preparation of a strategically functionalised Ru-alkylidene complex is discussed. This Ru-alkylidene complex exhibits high olefin metathesis activity in water, without the need for additives or surfactants. The ring-closing metathesis and cross-metathesis reaction of various nitrogen- and oxygen-containing substrates is demonstrated. Finally, Chapter 5 contains supporting information for the published manuscripts and experimental data for any unpublished material presented in this thesis.