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This thesis details the attempted synthesis of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives from the (5R)-5-phenylmorpholin-2-one chiral template, and the synthesis of cycloadducts generated via 1,3-dipolar cycloadditions of the (5S)-5-phenylmorpholin-2-one cyclic template with various heterodipolarophiles. (' The account commences with a' brief introduction into the chemistry of tetrahydroisoquinolines, and their occurrences in nature. Also given are examples of some recent advances in the total synthesis of various tetrahydroisoquinolines, via the PictetSpengler synthesis, and the Bischler-Napieralski reaction. The account continues with a brief introduction to the origins of the project, and the main aims of this part of the thesis. In the second chapter, an introduction into the chemistry of chiral azomethine ylids is given, including some examples of applications of this chemistry, to the synthesis of some naturally occurring target compounds. The account closes with the aims of this part of the thesis. The third chapter details the attempted synthesis of 1,2,3,4-tetrahydroisoquinoline-3carboxylic acid derivatives via Pictet-Spengler reactions of amines derived from the cyclic (5R)-5-phenylmorpholin-2-one chiral template. Also given is an account of the attempted synthesis of similar tetrahydroisoquinolines, via the Bischler-Napieralski reaction of various ~.. amides, also derived from the cyclic template. The chapter closes with a summary of the results, and suggestions for future work. The fourth chapter begins by detailing the synthesis of some chiral azomethine ylids, derived from the (5S)-5-phenylmorpholin-2-one template, and their subsequent 1,3-dipolar cycloadditions. It is shown that cycloadducts accessed via this method require two equivalents of aldehyde, one to generate the ylid, and a further equivalent to act as the dipolarophile. Since this requirement would not be appropriate where the aldehyde is the ; limiting material, the account continues with the studies that were initiated to find a derivate of (5S)-5-phenylmorpholin-2-one that was capable of generating the ylid without the need for an aldehyde, and their subsequent trapping protocols with suitable dipolarophiles. The chapter ends with a summary of the results, and suggestions for future studies. /

This thesis describes the development of a novel methodology to allow the synthesis of skeletally diverse alkaloid-like unnatural compounds. Enantiomerically enriched building blocks are iteratively assembled onto a purification handle using reliable coupling reactions. Subsequently, ring-opening-ring-closing metathesis cascade reactions are used as a complexity generating step to restitch the molecular framework. Chapter 1 introduces the concept of diversity-oriented synthesis, with particular emphasis on strategies used to introduce skeletal diversity. The conceptual idea behind the project is explained, and placed into context using leading examples as the benchmark for success in diversity-oriented synthesis. Chapter 2 describes the synthesis of a range of building blocks, many of which are enantiomerically enriched, on multigram scale. The design of a solid phase 'linker' is described in Chapter 3, as are the solution phase studies used to explore suitable methodologies to couple the building blocks. The use of solid phase chemistry is described in Chapter 4, as well as the use of light fluorous tags as an alternative purification handle. Chapter 5 describes the synthesis and subsequent metathesis of a range of fluorous-tagged metathesis substrates using one building block iteration. The Thesis concludes with the preparation of 45 metathesis precursors using combinations of two building blocks assembled onto a fluoroustagged linker in Chapter 6. Metathesis cascades were carried out, allowing the isolation of 33 complex and skeletally diverse products.

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4-Substituted cyclopentenones are key intermediates in the preparation of an array of highly functionalised cyclopentanes including most importantly in the project, carbocyclic nucleosides which display interesting biological activity. With the discovery that one stereoisomer exhibits generally more biological activity than the opposite stereoisomer and the escalating demand for new drugs to be enantiomerically pure, has led to the principal use ofenzymes in the development of routes to chiral carbocyclic nucleosides. The 1,4-diacetate was prepared via 3,4-diacetoh.)'cyclopentene using a modified method proposed by Deardorff and Mylesl . Following the limited success of this preparation, an alternative approach was adopted. An alternative approach to 1,4diacetoxycyclopentene used the photoaddition of singlet Oh.')'gen to the substrate cyclopentadiene, followed by protection. Elaboration ofthe 1,4-diacetate was attempted to afford various cyclopentenones via asymmetric hydrolysis, followed a photoaddition of methanol to the enone and a Mitsunobu reaction to afford the desired carbocyclic nucleoside. Selective deprotection of the silyl protecting group furnished a carbocyclic nucleoside analogue, which could be used for further elaboration to an array ofinteresting carbocyclic compounds. E),'olution ofthe project led to the synthesis ofseveral chir~l 4-alkyl-8-alkoxy-2-oxa-3aza- bicydo[3.3 .O]oct~3-en-6-Qnes. Further expansion of the tert-butyldimethylsilyl protected bicyclo-Qctenone to the bis-isoxazoline and symmetrical hydroxymethyl cyclopentanone diol were investigated with an array of chemical manipulations.

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