This thesis addresses the use of two general methods involving transition-metal catalyzed cyclization for the synthesis of nitrogenous heterocycles. The amino-Heck reaction was applied to the synthesis of spiroimines, pyrroles and simple and amino acid-based imidazoles while ring-closing metathesis was applied to the synthesis of seven- and six-membered lactam analogues of cyclic urea HlV protease inhibitors. The lactams were further derivatized to epoxides, and to cis-diols using Sharpless asymmetric dihydroxylation. Chapter One describes the significance of nitrogenous heterocycles in life and society with examples from peptidomimetics, synthetic and medicinal chemistry. The various approaches used in the design of peptidomimetics are then reviewed. The amino-Heck reaction and ring closing metathesis, used for the synthesis of nitrogenous heterocycles, are introduced briefly with an explanation of the catalytic pathways involved in these two processes. Chapter Two gives a description of the role of palladium in organic and heterocyclic syntheses with applications to carbon-carbon and carbon-nitrogen bond formation. Palladium-catalyzed carbon-nitrogen bond formations are discussed in detail. The Amino-Heck reaction, an important new method for the formation of heterocycles from olefinic oxime derivatives, is then reviewed and discussed in terms of its applications towards the synthesis of various nitrogenous heterocycles. Chapter Three describes the first domino-mode Amino-Heck reaction towards the synthesis of spirobicyclic and tricyclic imines. Cephalotaxine and its ester derivatives, harringtonine and homoharringtonine, have displayed powerful activity against chronic myelogenous leukaemia. 1-Azaspiro [4.4] nonane, which makes the core structure of Cephalotaxine, and its analogues 3.18a-d, were synthesized by a domino Amino-Heck reaction of the dienyl ketone O-pentafluorobenzoyl oximes. The domino Amino-Heck reaction of a trienyl ketone O-pentafluorobenzoyl oxime was also undertaken for the synthesis of a diastereomeric mixture of spirotricyclic imines 3.18g and 19. Chapter Four extends the scope of the Amino-Heck reaction to the synthesis of trisubstituted imidazoles. Various derivatives of imidazoles 4.13a-c were synthesised starting from simple non-peptide aldoximes. The generality of the reaction was further extended to the synthesis of optically-active a-amino acid-based imidazoles 4.22a-c from a-amino aldoximes. The reaction proceeds with little or no racemization as determined by coupling of the (S)-Phe-based imidazole 4.22a with (S)-N-Boc alanine to give a single diastereoisomer 4.24 (95% de, determined by 1H and 13C NMR). The C-terminal amino acid-based imidazoles have found applications as potential cis-amide bond isosteres in pepetidomimetics. The reaction works well for the synthesis of both simple and amino acid-based imidazoles from olefinic derivatives of the respective 0- pentafluorobenzoyl amidoximes. Chapter Five describes a further application of the Amino-Heck reaction from propargylic type derivatives of ketoximes to the synthesis of 2,5-disubstituted pyrroles. Various domino processes, e.g. transmetallation, intermolecular Heck reaction and carbonylation with sequential treatment with alcohols, were attempted for termination of the living palladium(II) complexes that were generated from oxidative addition of palladium into the N-O bond of the oxime followed by triple bond insertion reactions. Termination under Amino-Heck reaction conditions gave the corresponding pyrroles, whereas the amino-Heck-carbonylation-termination with alcohols sequence led to the synthesis of 5-aryl-2-pyrroloesters. Chapter Six presents a detailed overview of ring-closing metathesis. The development and functional group tolerance of ruthenium, molybdenum and other catalysts, and their use in the synthesis of peptidomimetics and non-peptidomimetics-based nitrogenous heterocycles are reviewed. Ring-closing metathesis from diene, ene-yne, ene-yne-ene and diyne precursors are discussed in detail. In addition, other miscellaneous applications of RCM are described. Chapter Seven describes a versatile ring-closing metathesis approach to the synthesis of seven-membered lactam analogues of cyclic urea HN protease inhibitors. The lactams 7.30, 7.40 and 7.48 were synthesized in good to excellent yields and derivatization of the double bond of lactams to epoxides (7.31, 7.41 and 7.49 respectively) and diols [(7.32 and 7.33), 7.42 and 7.50 respectively] was carried out successfully. The synstereoselectively of the N-t-Boc group was determined in the asymmetric dihydroxylation of the lactam 7.30. The enhancement in the syn-directing effect of the N-t-Boc group by C-4 (R)-phenyl group in lactam 7.40 and C-7 (S)-benzyl group in lactam 7.48 was determined by the synthesis of a single diastereoisomer (7.42 and 7.50) from the corresponding lactam. The reinforcement of the syn-stereoselectivity by C-7 (S)-benzyl group of the lactam 7.48 was further confirmed from the synthesis of a single diastereoisomer 7.50 by carrying out the asymmetric dihydroxylation of 7.48 in the absence of ligands.
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