The study of organometallic chemistry in the context of catalysis can be approached from a stoichiometric perspective, in which PGM complexes are examined in the context of understanding fundamental reactions to provide insight into established catalytic transformations. Alternatively, a catalytic perspective can be adopted, in which an unknown or underdeveloped transformation is identified and PGM catalysis is employed to assist in the further development of this area. In this regard, two general goals of this thesis are: 1) to explore alternative ligation strategies based on P,S-functionalized indene ligands, with a particular focus of studying divergent stoichiometric reactivity between related cationic and zwitterionic PGM complexes; and 2) to identify general PGM catalysts for the cyclohydroamination of alkylaminoalkenes and the hydroamination of internal alkynes with secondary alkylamines. The preparation and divergent reactivity of a previously unreported class of coordinatively unsaturated cationic and zwitterionic Cp*Ir(P,S) complexes that feature structurally analogous P,S-indene and mono-deprotonated P,S-indenide ancillary ligands, respectively, are discussed. The cationic complex was observed to activate organosilanes via the first well-documented H-Si addition across an M-SR linkage. In contrast, the unusual stoichiometric reactivity of the putative zwitterion with CH3CN or Ph2SiH2 can be viewed as resulting from the dual action of the Lewis acidic Cp*Ir fragment and the Lewis basic 10?-electron indenide unit within this formally charge-separated zwitterion. Building on these initial studies, the synthesis of structurally related (benzyl)Pt(P,S) borato- and carbanion-based zwitterions and cationic complexes featuring the P,S-indene and indenide ligand framework are also presented. In the context of hydroamination studies, [Ir(COD)Cl]2 was identified as an effective pre-catalyst for the efficient synthesis of pyrrolidine and piperidine heterocycles via the cyclohydroamination of tethered aminoalkenes. Following optimization studies of this catalyst system, a broad substrate scope that included the cyclization of primary and secondary alkyl- or arylamines was established. A kinetic and mechanistic evaluation of this reaction suggested the operative pathway as involving olefin activation in a manner that had not previously been documented for Ir-catalyzed alkene hydroamination. In the pursuit of a general catalyst for the alkyne hydroamination reaction, an effective gold pre-catalyst featuring a P,N-ligand was identified and was used in the addition of a variety of functionalized dialkylamines to internal alkynes. In particular, the first examples of the regioselective addition of dialkylamines to unsymmetrically substituted alkynes are discussed. A preliminary mechanistic survey, consisting of kinetic and stoichiometric experiments, has provided empirical evidence to support a mechanism comprised of turnover-limiting alkyne insertion into a Au?N bond followed by proto-deauration.

Biologically many disease states lead to changes in expressed proteins. Therefore, "system changes" that occur must be considered in any treatment for the disease. This new approach to drug design and discovery would be particularly applicable to the diseases that involve adaptive changes in the central nervous system, such as neuropathic pain. There is growing evidence that drugs behave differently in pathological states than in normal states, thus preventing their effectiveness in pathological disease states. Therefore, a new paradigm for drug design is needed. In recent years, the melanocortin-4 receptor (MC4R) found in the spinal cord and CNS has received growing attention as a therapeutic target. MC4R based agonist ligands produce anti-opioid effects, and researchers have shown that an antagonist of the MC4R can produce pronounced anti-allodynic effect. Opioid receptors have been the central and most efficacious targets sought after for relieving neuropathic pain. In our new approach, single peptide molecules are designed to interact with opioid receptors as an agonist, and as an antagonist at the MC4 receptor. For the treatment of pain, a series of linear and cyclic peptides based on the overlapping pharmacophores of endogenous melanocyte stimulating hormone and opioid ligands are designed through computational aided molecular modeling and synthesized. Throughout the studies the opioid pharmacophore is maintained towards the N-terminal while melanocortin pharmacophore is maintained towards the C-terminal. Cyclization of peptides has been the central synthetic feature in designing the bifunctional ligands. The use of microwave has been shown to be very efficient in cyclizing the peptides. Solvent, reagent, power and temperature conditions are established for the microwave application in aiding the macromolecules for cyclizing their side chain termini.

La fonctionnalisation directe de liaisons C-H offre une alternative plus économe en atomes et étapes que les traditionnelles méthodes de synthèse basées sur la transformation de molécules pré fonctionnalisées. Ainsi, les réactions d'amination intermoléculaire de liaisons C(sp3)-H avec des nitrènoïdes sont généralement effectuées avec des rendements et des régiosélectivités modérés et utilisent pour cela des catalyseurs coûteux. Dans ce contexte, nous avons créé de nouveaux systèmes bifonctionnels pour la formation de liaisons C-N aliphatiques catalysée par le cuivre et l'argent. Ces systèmes se sont cependant avérés inefficaces dans les conditions réactionnelles utilisées.Les travaux effectués dans le cadre de cette thèse se sont également concentrés sur la fonctionnalisation nucléophile d'anilides par oxydation à l'iode hypervalent. Grâce à cette méthodologie les triflation et triflimidation directes d'acétanilides ont été accomplies dans des conditions oxydantes douces, en présence de triflate et de triflimidate d'argent, respectivement. Ces transformations procèdent avec de bons rendements et présentent une régiosélectivité parfaite pour la position para. / The direct functionalization of C-H bonds offers an attractive, atom- and step-economical alternative to traditional methods based on functional group transformations. Intermolecular C(sp3)-H amination reactions involving nitrene intermediates usually proceed with moderate yields and regioselectivities. In this context, new bifunctional compounds were developed and applied to copper and silver-catalyzed C-N bond-forming reactions. These systems, however, have been found to be ineffective under the reaction conditions.Our research has also focused on the iodine(III)-mediated nucleophilic functionalization of anilides. The direct triflation and triflimidation of acetanilides were accomplished with the use of affordable and easy-to-handle silver(I) triflate or triflimidate respectively, under mild oxidative conditions, exhibiting perfect regioselectivity for the para position. A complete optimization of the reaction conditions and an evaluation of the scope allowed us to prepare a variety of diversely substituted aryltriflates (and nonaflates) in synthetically useful yields.