Chapter 1 is the introduction to the thesis. It contains an overview of amino acids and aminyl radicals. The amino acids section includes material on their synthesis through traditional methods and asymmetric syntheses, as well as the use of radical reactions in their formation. The aminyl radical section gives a description of the nature of the radical and then proceeds with general techniques for aminyl radical formation. A more detailed account of our own group's use of sulfenamides and imines in aminyl radical formation is ·covered and the chapter is ended with a look at the work of aminyl radicals in amino acid synthesis and my subsequent intentions in this area. The preparation and cyclisation of sulfenamide precursors derived from [alpha]-amino acids is discussed in chapter 2. Both the cyclisations of aminyl and urethanyl (introduction of benzyloxycarbonyl and tosyl protecting groups onto amine) radicals onto suitably placed alkenyl substituents were investigated. 5-Exo-trig cyclisation reactions successfully afforded the cyclic products in moderate yield with reasonable diastereoselectivity. The effects of the [alpha]-CO2R (where R = Me or tBu), the size of the amino acid side chain and placement of alkenyl substituent (N-substituted or sidechain containing alkene) are discussed. The use of imines as aminyl radical precursors is explored in chapter 3. [Alpha]-amino acids and aldehydes were condensed and the cyclisation products isolated. The formation of aminyl radicals by 5-exo-trig cyclisation and subsequent H-atom abstraction gave moderate to good yields of N-cyclopentyl substituted a-amino acids. Preparation of the aldehydes is discussed. Tandem cyclisations involving aspects of chapters 2 and 3 are looked at in chapter 4. The preparation of the unnatural a-amino acids required for tandem cyclisation and subsequent formation of the sulfenamide or imine is reported. 5-Exo, 6-exo cyclisation of the sulfenamide derivative gave the tandem product in low yield and with moderate diastereoselectivity. This was in contrast to the imine derived reaction which proved unsuccessful. The remaining chapters incorporate the detailing of experimental relevant to the discussion and the presentation of references quoted throughout the thesis.

Ribonucleotide Reductases (RNRs) are crucial enzymes that catalyze reduction of ribonucleotides to deoxyribonucleotides, required for the biosynthesis of DNA. Vital role played by RNR in the biosynthesis of DNA and its control on cell growth made it one of the main targets for anticancer therapy. Several laboratories clarified the aspects of reaction cascades at active site of RNR. Biochemical studies of RNR by Stubbe for the inactivation of RDPR by 2'-chloro-2'-deoxyuridine-5'-diphosphate emphasizes departure of chlorine as an anion, while biomimetic studies by Robins with 6'-O-nitro-2'-chloro-homonucleosides emphasizes the elimination of chlorine substituent from 2'-position as a radical. To clarify the ambiguity in the mechanism of inhibition of RNR by 2'-chloro-2'-deoxyuridine, biomimetic reactions with model 6-O-nitro-1,5-dideoxyhomosugar derivatives were investigated. The study includes several modes: (i) synthesis of 6-O-nitro-1,5-dideoxyhomosugar derivatives with chlorine, bromine or tosyl substituent at the C2 position with ribo and arabino configurations, (ii) biomimetic studies of 6-O-nitro-1,5-dideoxyhomosugar derivatives with Bu3SnH/AIBN to provide chemical evidences to distinguish the nature of elimination of chlorine from 2'-chloro-2'-deoxyuridine upon its incubation with enzyme, and (iii) kinetic studies to differentiate between heterolytic or homolytic C2'-chlorine bond cleavage. In the second half of this dissertation, azido and sulfenamide modified nucleosides and 2-azidolyxofuranoside derivatives have been synthesized with the azido or sulfenamide substitution at a specific site in the sugar or in the base moiety. The electron-induced site specific formation of neutral aminyl radicals (RNH●) and their subsequent reactions have been investigated using ESR spectroscopy. In 2'-AZdC the RNH● site is attached to a 2o C-atom, where as in 4'-AZdC, the RNH● site is attached to a 3o C-atom, respectively. These studies elucidated how stereo and electronic environment affect formation and subsequent reactivity of various types of RNH● generated from azidonucleosides. To avoid the interaction of transient radical with nucleoside heterocyclic bases, 2-azidolyxofuranoside derivatives as a simpler abasic model were synthesized and studied with ESR spectroscopy. Aminyl radical generated from 2-azidolyxofuranoside derivatives subsequently abstracted hydrogen from C5 intramolecularly. These studies were designed to understand the mechanism of damage in various DNA model structures.