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The synthesis of some novel 3′-spirocyclic-oxindole compounds, based on the spiro[indole-3,5′-isoxazolidin]-2(1H)-one, the 2′H-spiro[indole-3,6′-[1,3]oxazinane]-2,2′(1H)-dione and the 2′H-spiro[indoline-3,3′-pyrrolo[1,2-c][1,3′]oxazine]-1′,2(1H)-dione heterocyclic structures, is described. These compounds were prepared from methyl α-(2-nitrophenyl)acrylate via [1,3]-dipolar cycloaddition reactions with two acyclic nitrones and one cyclic nitrone followed by reduction of the cycloadducts and then treatment with triphosgene. Two of these compounds showed significant cytostatic activity on three cancer cell lines with GI50 values of 2.6–4.1 μM on the human breast cancer cell line, MCF-7.

The synthesis of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid, including novel 3-(2- and 3-pyridyl)-substituted analogues and the novel cyclopropa[c]quinoline-7b-carboxylic acid and their ester and amide derivatives is described. These syntheses involve diastereoselective cyclopropanation reactions of methyl 2-(2-nitrophenyl)acrylate and (3E)-(pyridin-2-ylmethylene)- and (3E)-(pyridin-3-ylmethylene)-1,3-dihydro-2H-indol-2-one with ethyl (dimethyl sulfuranylidene) acetate (EDSA). The synthesis of methyl cyclopropa[c]quinoline-7b-carboxylate involves a regioselective reductive cyclization of a nitro-diester precursor. The relative stereochemistry of key compounds has been determined by single-crystal X-ray structural analysis.

The spirocyclic ring structure is a feature of a number of naturally-occurring and synthetic products that possess interesting biologically activities. This thesis describes our efforts towards synthesising various spirocyclic heterocycles as potential cancer therapeutics targeting the cell-cycle. Three different spirocyclic scaffolds, A-C, were accessed through a variety of cycloaddition reactions and several of these were investigated for their cytostaticity and protein-inhibition properties. To gain further insights into the development of novel CDK2 inhibitors, part of this research was conducted at the Anti-Cancer Drug Design Initiative (ADDI) laboratory, University of Newcastle upon the Tyne, UK. This thesis is divided into three primary synthetic chemistry chapters, based upon discussion surrounding the main chemistries used to derive the various spirocyclic oxindole scaffolds of the types A-C. Chapter 2 describes the use of the phosphine-catalysed [3+2]-cycloaddition reaction to synthesise racemic and enantio-enriched versions of spirocycles of type A. Chapter 3 describes the use of the cyclopropanation reaction to synthesise spirocycles of type B. Lastly, Chapter 4 describes the employment of the [1,3]-dipolar cycloaddition reaction of nitrones to the synthesis of spirocycles of type C. A discussion on the CDK2 research, performed in the UK, towards a new synthetic strategy employing directed ortho metalation chemistry is then provided in Chapter 5. The cellular cytostaticity screening against the cancer cell lines, H460, MCF-7 and SF-268, and protein inhibition studies against the cell-cycle proteins CDK2, CDK5, gSK-3 and MDM2, for a range of the spirocycles synthesised in Chapters 2-4, is then given and discussed in Chapter 6. Final conclusions and future work are drawn together in Chapter 7. All synthetic methods and physical and spectroscopic data are provided for all compounds in Chapter 8. Lastly, an appendix including all X-ray crystal structures and

The phosphine-catalysed [3+2]-cycloaddition of the 2-methylene γ-lactams 4 and 5 and the acrylate 6 with the ylides derived from the ethyl ester, the amide or the chiral camphor sultam derivative of 2-butynoic acid (7a-c) give directly, or indirectly after reductive cyclization, spiro-heterocyclic products. The acid 32 underwent Curtius rearrangement and then acid hydrolysis to give two novel spiro-cyclic ketones, 41 and 42.