Structure-based drug design and combinatorial chemistry play important roles in the search for new drugs, and both these elements of medicinal chemistry were included in the present studies. This thesis outlines the synthesis of protease inhibitors against thrombin and the HCV NS3 protease, as well as the synthesis of a combinatorial library using solid phase chemistry.In the current work potent thrombin inhibitors were generated based on the D-Phe-Pro-Arg motif incorporating cyclopentene and cyclohexene scaffolds that were synthesized by ring-closing metathesis chemistry. A structure-activity relationship study was carried out using the crystallographic results for one of the inhibitors co-crystallized with thrombin. HCV NS3 protease inhibitors comprising the proline bioisostere 4-hydroxy-cyclopent-2-ene-1,2-dicarbboxylic acid were synthesized displaying low nanomolar activity. The stereochemistry and regiochemistry of the scaffolds were determined by NOESY and HMBC spectra, respectively. The final diastereomeric target compounds were isolated and annotated by applying TOCSY and ROESY NMR experiments. Furthermore, a 4-phenyl-2-carboxypiperazine targeted combinatorial chemistry library was synthesized to be used early in the lead discovery phase. This was done using a scaffold that was synthesized by palladiumcatalyzed aromatic amination chemistry and subsequently derivatized with eight electrophiles and ten nucleophiles.

This thesis describes original research aimed at the development of highly efficient polymer functionalization strategies by introducing orthogonal chemistry within polymeric systems. The primary hypothesis of this thesis is that the use of click chemistries or noncovalent interactions can provide new and easy pathways towards the synthesis of highly functionalized polymers thereby addressing the shortcomings of traditional covalent functionalization approaches. To verify the hypothesis, the work presented in the following chapters of this thesis further explores previous methods of either covalent or noncovalent polymer functionalization described in Chapter 1. Chapters 2 and 3 present advanced methods of covalent polymer functionalization based on high-yielding and orthogonal click reactions: 1,3-dipolar cycloaddition, hydrazone formation, and maleimide-thiol coupling. All three click reactions employed can be orthogonal to one another and conversions can be quantitative, leading to the easy and rapid synthesis of highly functionalized polymers without interference among functional handles along the polymer backbones. The next two chapters focus on the noncovalent functionalization strategies for creating supramolecular block copolymers via the main-chain self-assembly of telechelic polymers. Novel synthetic methods to prepare telechelic polymers bearing terminal recognition motifs were developed through a combination of ROMP using functionalized ruthenium initiators and functionalized chain-terminators, and the resulting polymers were self-assembled to form supramolecular block copolymers. Chapter 4 demonstrates the formation of supramolecular multiblock copolymers via self-assembly of symmetrical telechelic polymers using metal coordination, while Chapter 5 demonstrates that supramolecular ABC triblock copolymers can be prepared by the self-assembly of a heterotelechelic polymer as the central block with two other complementary monotelechelic polymers using two orthogonal hydrogen bonding interactions. Chapter 6 presents a unique application of noncovalent functionalization approaches. The ultimate goal of this research is to develop a controlled polymerization method based on noncovalent templation. The initial attempts at the metal coordination-based template polymerization are presented in this chapter. Finally, Chapter 7 summarizes the findings in each chapter and presents the potential extensions of the orthogonal functionalization strategies developed in this thesis.

Taxol™, isolated from the bark of Taxus brevifolia in the late 1960s, and the semisynthetic analog Taxotere™ have proven clinical importance for the treatment of ovarian and breast cancer. Taxol™ exerts its biological effect by binding to polymerized tubulin and stabilizing the resulting microtubules. Studies aimed at understanding the biologically active conformation of taxol and its binding environment on β-tubulin are described. This knowledge is important because it could lead to the design of structurally less complicated drugs with better efficacy and better bioavailability. Moreover, the information can be extended to other natural products that possess microtubule-stabilizing properties similar to Taxol™. In this work, the synthesis of a triply labeled taxol analog is described as well as REDOR studies of this compound complexed to tubulin are in progress. Macrocyclic analogs of taxol have been prepared and their biological activities were evaluated. Chemical modeling of these analogs and their activities agrees with the hypothesis that Taxol™ adopts T-shaped conformation. Difficulties were encountered with the key ring-closing metathesis strategy, suggesting that a more flexible and efficient macrocyclization method will be needed to synthesize additional macrocyclic analogs. / Ph. D.

Ru-catalyzed olefin metathesis is an exceptionally powerful, versatile methodology for the assembly of carbon–carbon bonds. The N-heterocyclic carbene (NHC)-stabilized, “second-generation” Ru catalysts have enabled groundbreaking recent advances, ranging from the RCM assembly of cyclic peptides as hepatitis C virus therapeutics, to the elaboration of renewable seed oils and phenylpropanoids into value-added products and chemicals. However, key limitations arise from facile catalyst decomposition. Despite a plethora of studies on the synthesis of new catalysts, and on the decomposition processes accessible to the precatalyst and resting-state species, the underlying principles that govern decomposition of the active intermediates have been surprisingly little examined. One important reason for this is their incredible reactivity: the four-coordinate methylidene intermediate RuCl2(H2IMes)(=CH2) is too short-lived to be observed, while the metallacyclobutane (MCB) intermediate RuCl2(H2IMes)(2-C3H6) can only be observed below –40 °C. This makes them extremely challenging, but also fascinating targets for study. Understanding the underlying chemistry that dictates their reactivity and decomposition is essential for informed catalyst and process redesign, and is thus of fundamental interest, but also considerable practical importance. This thesis work thus aims at understanding the decomposition of active intermediates relevant to the highly-active, second-generation class of catalysts. Emphasis is placed on examining a variety of metathesis contexts, as well as providing solutions. Treated first are the decomposition pathways that arise during metathesis of electron-deficient olefins, a frontier area in organic synthesis, and in the utilization of renewable resources. An unexpected correlation is revealed between rapid catalyst decomposition, and the presence of a stabilizing PCy3 ligand in the standard catalyst for this reaction. The nucleophilic phosphine ligand is shown to attack an acrylate olefin, forming enolates that function as potent Brønsted bases. Literature evidence suggests that such strong bases are innocuous towards the precatalyst, pointing towards a key role for the active intermediates in Brønsted base-induced catalyst decomposition. Precisely which intermediate is involved, as well as the site of deprotonation, is elucidated next. Prior to this work, the NHC ligand was widely believed to be the target for attack. However, through labelling experiments, analysis of the Ru and organic byproducts, and computational studies, deprotonation is shown to occur at the MCB ring. Moreover, MCB deprotonation is revealed to be unexpectedly general, and not contingent on the presence of either an exceptionally strong base, or an electron-deficient substrate. This understanding is key, given recent reports from pharma highlighting the adverse impact of base contaminants, as well as current interest in metathesis of amine-containing substrates. Next examined are the intrinsic decomposition pathways operative for the MCB and four-coordinate methylidene. Prior to this work, the only reported pathway for decomposition of these two species involved beta-elimination of the MCB ring as propene. However, beta-elimination is shown to play an unexpectedly minor role in catalyst decomposition: less than 40% propenes are observed, even under conditions expected to favour MCB elimination. Bimolecular coupling of the methylidene, with loss of the methylidene moiety as ethylene, is proposed to account for the difference. Thus, transiently-stabilized adducts RuCl2(H2IMes)(=CH2)(L)n (L = o-dianiline or pyridine) are synthesized at temperatures down to –120 °C. On warming, these adducts lose Ln and rapidly decompose via bimolecular coupling, with loss of the methylidene moiety as ethylene. These experiments provide the first unambiguous evidence for bimolecular coupling in the important "second-generation" Ru systems, nearly two decades after which this pathway was dismissed in leading papers and reviews. The last two sections focus on solutions. First, a powerful, straightforward solution to the “enolate problem” is developed, whereby the acrylate enolates are quenched and sequestered via reaction with a polyphenol resin. Then, methods for preventing catalyst decomposition during matrix-assisted laser desorption / ionization mass spectrometry (MALDI-MS) are developed, via elucidation of the instrumental and experimental factors that promote successful analysis. As one of the only MS methods capable of affording insight into neutral metal complexes and catalysts, MALDI has unique potential to enable routine analysis of catalyst speciation and decomposition in situ, under real catalytic conditions, for a wide range of catalytic reactions. Collectively, the findings in this thesis offer a much more complete understanding of the fundamental pathways accessible to the important, highly-active metathesis intermediates, and offer strategies likely to inform practice in both academic and industrial settings. This understanding is key to harnessing the full potential of metathesis methodologies.

This diploma thesis is focused on the preparation of enantiomerically pure compounds based on organocatalytic allylic substitution using Baylis-Hillman carbonates. As selected substrates for the allylic substitution were chosen α-azidoketones such as azidoacetophenone, 2-azido-1-indanone and then heterocyclic compounds (N-phenylrhodanine and its derivate) belonging to the pharmaceutical privileged compounds. Other substrate for allylic substitution was allylmalononitrile. In addition, this thesis includes with synthesis of cyclic compounds based on the reaction of products of allylmalononitrile with B-H carbonates using olefin metathesis.

As reações de metatese assim como o desenvolvimento de complexos metal-carbeno (W, Mo, Ru) se tornaram amplamente conhecidos na química graças aos avanços que trouxeram. Na química orgânica, possibilitou a síntese de macrocíclos por meio da RCM e na química de polímeros a ROMP permitiu um alto grau de controle da polimerização além da alta reatividade dos catalisadores. Isso fez desta reação uma poderosa ferramenta no desenvolvimento de novos materias. A tentativa de combinar a processabilidade dos polímeros com as propriedades luminescentes de determinandos compostos tem sido tema de muitas pesquisas.O objetivo deste trabalho é derivatizar compostos luminescentes , como o complexo metálico [Ru(bpy)3] (PF6)2e a porfirina tetrakis-(pentafluorfenil)porfirina (TPPF20), com o monômero norborneno (NBE) para obtenção de monômeros lumiscentes passíveis de serem polimerizados via ROMP. Aqui será apresentado e discutido a síntese e a caracterização desses compostos partindo-se dos reagentes: ácido-5-norborneno-2carboxílico; etilenodiamina e o ácido-2,2\'-bipiridina-4,4\'-dicarboxílico, cis-[RuCl2(bpy)2] e a porfirina TPPF20. Os compostos foram sintetizados com rendimentos superiores a 60%, com exceção da obtenção da porfirina, e caracterizados por RMN - 1H e 13C; FTIR; UV-vis. Os estudos de copolimerização entre NEN (norborneno-etilenodiamina-norborneno), NBE-TPPF e [Ru(bpy)2(NBbpy)](PF6)2 foram feitos usando o catalisador de Grubbs segunda gereação. Os polímeros gerados foram caracterizados usando TG-FTIR e RMN-1H, as massas moleculares não puderam ser calculadas por GPC porém os estudos indicam obtenção de baixo peso molelcular. O material obtido foi testado como sensibilizador em vidro condutor ITO, porém não houve adsorção do composto necessitam algumas modificações no metalomonômero. / The metathesis reactions as well as the development of metal-carbene complexes (W, Mo, Ru) became widely known in chemistry thanks to advancements brought. In organic chemistry, it enabled the synthesis of macrocycle by RCM. Useful for the synthesis of natural products. In polymer chemistry, ROMP, allow a high degree of polymerization control. This made the ROMP reaction a powerful tool in the development of new materials. In attempt to combine the processability of polymers with luminescent properties of such compounds has been the subject of several researchs. The aim of this work is to synthesize luminescent compounds based on [Ru(bpy)3] (PF6)2 metal complex and on the porphyrin tetrakis-(pentafluorphenyl)porphyrin (TPPF20), funcionalized with pendant norbornene monomer (NBE) to obtain lumiscentes monomers which can undergo ROMP polymerization. Here will be discussed the synthesis and characterization of these compounds using as starting materials: 5-norbornene-2-carboxylic acid; ethylenediamine; 2,2\'-bipyridine-4,4\'dicarboxylic acid, cis-[RuCl2(bpy)2] and the porphyrin TPPF20. The compounds were synthesized with yields higher than 60%, with the exception of the porphyrin, and characterized by 1H and 13C-NMR; FTIR; UV-vis. Copolymerization reaction between NEN (Norbornene-Ethylenediamine-Norbornene), NBE-TPPFe [Ru(bpy)2(NBbpy)] (PF6)2 were performed using Grubbs second generation catalyst. Resultinf polymers were characterized by TG-FTIR and 1H-NMR, molecular weight could not be measured by GPC, since polymers were insoluble, but studies indicate low molelcular weight. The material obtained was tested as sensitizer in conductive glass ITO. The polymer didn\'t adsorb in to the ITO surface. Some changes in the compound molecular structure are required to improve adsorption.

As reações de metatese assim como o desenvolvimento de complexos metal-carbeno (W, Mo, Ru) se tornaram amplamente conhecidos na química graças aos avanços que trouxeram. Na química orgânica, possibilitou a síntese de macrocíclos por meio da RCM e na química de polímeros a ROMP permitiu um alto grau de controle da polimerização além da alta reatividade dos catalisadores. Isso fez desta reação uma poderosa ferramenta no desenvolvimento de novos materias. A tentativa de combinar a processabilidade dos polímeros com as propriedades luminescentes de determinandos compostos tem sido tema de muitas pesquisas.O objetivo deste trabalho é derivatizar compostos luminescentes , como o complexo metálico [Ru(bpy)3] (PF6)2e a porfirina tetrakis-(pentafluorfenil)porfirina (TPPF20), com o monômero norborneno (NBE) para obtenção de monômeros lumiscentes passíveis de serem polimerizados via ROMP. Aqui será apresentado e discutido a síntese e a caracterização desses compostos partindo-se dos reagentes: ácido-5-norborneno-2carboxílico; etilenodiamina e o ácido-2,2\'-bipiridina-4,4\'-dicarboxílico, cis-[RuCl2(bpy)2] e a porfirina TPPF20. Os compostos foram sintetizados com rendimentos superiores a 60%, com exceção da obtenção da porfirina, e caracterizados por RMN - 1H e 13C; FTIR; UV-vis. Os estudos de copolimerização entre NEN (norborneno-etilenodiamina-norborneno), NBE-TPPF e [Ru(bpy)2(NBbpy)](PF6)2 foram feitos usando o catalisador de Grubbs segunda gereação. Os polímeros gerados foram caracterizados usando TG-FTIR e RMN-1H, as massas moleculares não puderam ser calculadas por GPC porém os estudos indicam obtenção de baixo peso molelcular. O material obtido foi testado como sensibilizador em vidro condutor ITO, porém não houve adsorção do composto necessitam algumas modificações no metalomonômero. / The metathesis reactions as well as the development of metal-carbene complexes (W, Mo, Ru) became widely known in chemistry thanks to advancements brought. In organic chemistry, it enabled the synthesis of macrocycle by RCM. Useful for the synthesis of natural products. In polymer chemistry, ROMP, allow a high degree of polymerization control. This made the ROMP reaction a powerful tool in the development of new materials. In attempt to combine the processability of polymers with luminescent properties of such compounds has been the subject of several researchs. The aim of this work is to synthesize luminescent compounds based on [Ru(bpy)3] (PF6)2 metal complex and on the porphyrin tetrakis-(pentafluorphenyl)porphyrin (TPPF20), funcionalized with pendant norbornene monomer (NBE) to obtain lumiscentes monomers which can undergo ROMP polymerization. Here will be discussed the synthesis and characterization of these compounds using as starting materials: 5-norbornene-2-carboxylic acid; ethylenediamine; 2,2\'-bipyridine-4,4\'dicarboxylic acid, cis-[RuCl2(bpy)2] and the porphyrin TPPF20. The compounds were synthesized with yields higher than 60%, with the exception of the porphyrin, and characterized by 1H and 13C-NMR; FTIR; UV-vis. Copolymerization reaction between NEN (Norbornene-Ethylenediamine-Norbornene), NBE-TPPFe [Ru(bpy)2(NBbpy)] (PF6)2 were performed using Grubbs second generation catalyst. Resultinf polymers were characterized by TG-FTIR and 1H-NMR, molecular weight could not be measured by GPC, since polymers were insoluble, but studies indicate low molelcular weight. The material obtained was tested as sensitizer in conductive glass ITO. The polymer didn\'t adsorb in to the ITO surface. Some changes in the compound molecular structure are required to improve adsorption.

Among Nature's creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionalities. This phenomenal structural diversity of terpenes makes them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The thesis entitled “Synthetic Approaches to Herbertenoid and Cuperenoid Sesquiterpenes" describes the application of ring-closing metathesis and Claisen rearrangement based approach to some herbertenoid and cuparenoid natural products. The results are described in five different sections, viz., a) First Total Synthesis of (±)-γ-Herbertenol; b) First Total Synthesis of (±)-HM-2; c) First Total Synthesis of (±)-HM-4 and HM-3; d) First Total Synthesis of Herbertenones A and B; and e) Total Synthesis of Lagopodin A. Complete details of the experimental procedures and the spectroscopic data were provided in a different section. A brief introduction is provided wherever appropriate to keep the present work in proper perspective. The compounds are sequentially numbered (bold), references are marked sequentially as superscripts and listed in the last section of the thesis. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. To begin with, the first total synthesis of γ-herbertenol, an herbertene isolated from a non-herbertus source, has been accomplished starting from 3,5-dimethylphenol. Claisen rearrangement of 3-(3-methoxy-5-methylphenyl)but-2-en-1-ol, obtained in eight steps from 3,5-dimethylphenol, furnished a γ,δ-unsaturated ester, which was transformed into 4-aryl-4,5,5-trimethylcyclopent-2-enone employing RCM reaction as the key step, which was further transformed into (±)-γ-herbertenol, which exhibited spectral data identical to that of the natural product. An alternative RCM reaction based methodology was also developed for the synthesis of γ-herbertenol methyl ether starting from ethyl 3-aryl-3-methylpent-4-enoate, an intermediate in the first sequence. The methodology has been extended for the synthesis of the putative structure of HM-2 starting from 2,4-dimethoxy-5-methylacetophenone via the corresponding ethyl 3-aryl-3-methylpent-4-enoate. However, the spectral data of the synthetic compound was found to be different from that reported for the natural product. A new cuperenoid structure for HM-2 was proposed. Total synthesis of cuparene-1,4-diol starting from toluhydroquinone, followed by its conversion to mono methyl ether and mono acetyl derivative confirmed the structures of HM-1 and the revised structure of HM-2. In a similar manner, total synthesis of the putative structure of HM-3 starting from 4-methylresorcinol dimethyl ether proved it to be wrong. A cupereniod structure, HM-4 monoacetate was proposed for HM-3. Synthesis of HM-4, and its conversion to mono acetate confirmed the structures of HM-4 and the revised structure of HM-3. The methodology has been further extended to the first total synthesis of herbertenones A and B starting from 2,5-dimethoxybenzaldehyde. By readily identifying the similarity between lagopodin A and HM-1 and HM-2, an intermediate in the synthesis of HM-1 and HM-2 has been further transformed in to (±)lagopodin A.

Among Nature's creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionalities. This phenomenal structural diversity of terpenes makes them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The thesis entitled “Ireland-Claisen Rearrangement Based Strategy to Sesquiterpenes Containing Vicinal Quaternary Carbon Atoms” demonstrates the utility of the Ireland ester Claisen rearrangement and RCM reactions for the synthesis of a variety of sesquiterpenes containing vicinal quaternary carbon atoms. The results are described in five different sections, viz., (a) Synthesis of herbertene-1,13-diol and α-herbertenol; (b) Total syntheses of herbertenolide, herberteneacetal, herbertene-1,14-diol and herbertene-1,15-diol; (c) First total synthesis of the spirobenzofuran isolated from Acremonium sp. HKI 0230; (d) Total synthesis of lagopodin A; and (e) Synthesis of Laurencenone C, α- and β-chamigrenes. Complete details of the experimental procedures and the spectroscopic data were provided in a different section. A brief introduction is provided wherever appropriate to keep the present work in proper perspective. The compounds are sequentially numbered (bold), references are marked sequentially as superscripts and listed in the last section of the thesis. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. To begin with a short and efficient synthesis of herbertene-1,13-diol and α-herbertenol has been achieved starting from 2-allyl-4-methylanisole. Ireland ester Claisen rearrangement of the dimethylallyl 2-arylpent-4-enoate, obtained from p-cresol in seven steps, followed by RCM reaction of the resultant diene generated 1-aryl-1,2,2-trimethylcyclopent-3-enecarbo-xylate, which on functional group transformations provided (±)-herbertene-1,13-diol and (±)-α-herbertenol. Ireland ester Claisen rearrangement of E-3-(2-methoxy-5-methylphenyl)but-2-en-1-yl 2-methylpent-4-enoate furnished a stereoisomeric mixture of the dieneesters, which on RCM reaction generated an epimeric mixture of 2-aryl-1,2-dimethylcyclopent-3-enecarboxylates. These esters were further elaborated into (±)-herbertene-1,14-diol, (±)-herbertene-1,15-diol and (±)-herberteneacetal via epi-herbertenolide and (±)-herbertenolide. First total synthesis of a spirobenzofuran isolated from Acremonium sp. HKI 0230 has been accomplished starting from 2,5-dimethoxy-4-methylphenylacetate, confirming the structure of the natural product. Ireland ester Claisen rearrangement of dimethylallyl 2-(2,5-dimethoxy-4-methylphenyl)pent-4-enoate followed by RCM reaction and demethylation furnished a lactone, cyclopentaspirobenzofuranone, which on further functional group transformations completed the first total synthesis of the spirobenzofuran. 1-(2,5-Dimethoxy-4-methylphenyl)-1,2-dimethylcyclopent-3-enecarboxylate, an intermediate in the synthesis of spirobenzofuran, has been further elaborated into 1-aryl-1,2,2-trimethylcyclopent-3-ene, which on functional group transformations transformed into (±)lagopodin A and (±)-enokipodins A and B. Efficient total syntheses of laurencenone C, α-chamigrene and β-chamigrenes have been accomplished employing an Ireland ester Claisen rearrangement and RCM reaction as key steps starting from the Diels-Alder adduct of isoprene and acrylic acid. Ireland ester Claisen rearrangement of dimethylallyl cyclohex-3-enecarboxylate generated methyl 1-(1',1'-dimethylallyl)cyclohex-3-enecarboxylate, which was further elaborated into 5,5,9-trimethyl-spiro[5.5]undeca-3,8-dien-1-ol employing an RCM reaction as the key step. The spirodienol on further functional group transformations generated (±)-laurencenone C, (±)-α-chamigrene and (±)-β-chamigrene.

Les macrocycles ont longtemps attiré l'attention des chimistes. Malgré cet intérêt, peu de méthodes générales et efficaces pour la construction de macrocycles ont été développés. Récemment, notre groupe a développé un programme de recherche visant à développer de nouvelles voies vers la synthèse de paracyclophanes et ce mémoire présente l pluspart des efforts les plus récents dans ce domaine. Traditionnellement, la synthèse de paracyclophanes rigides est facilitée par l'installation d'un groupe fonctionnel capable de contrôler la structure de la molécule en solution (ex un élément de contrôle de conformation (ECC)). Cependant, cette approche utilisant des auxiliaires exige que le ECC soit facilement installé avant macrocyclisation et facilement enlevé après la cyclisation. Le présent mémoire décrit une méthode alternative pour guider la macrocyclisations difficile à travers l'utilisation d'additifs comme ECC. Les additifs sont des hétérocycles aromatiques N-alkylé qui sont bon marché, faciles à préparer et peuvent être facilement ajoutés à un mélange de réaction et enlevés suite à la macrocyclisation par simple précipitation et de filtration. En outre, les ECCs sont recyclables. L'utilisation du nouveau ECC est démontré dans la synthèse des para-et métacyclophanes en utilisant soit la métathèse de fermeture de cycle (RCM) ou couplage de Glaser-Hay. / Macrocycles have long attracted the attention of chemists. Despite that interest, few general and efficient methods for the construction of macrocycles have been developed. Recently our group has developed a research program aimed at developing novel routes towards the synthesis of paracyclophanes and the present thesis details the most recent efforts in this area. Traditionally, the synthesis of rigid paracyclophanes is aided by the installation of functional groups capable of controlling the solution state structure of the molecules (ie. a conformational control element (CCE)). However, this auxiliary-like approach requires that the CCE be readily installed prior to macrocyclization and easily removed following the cyclization. In the present thesis describes an alternative method to guiding difficult macrocyclizations through the use of additives as CCEs is described. The additives are N-alkylated aromatic heterocycles that are cheap, easily prepared and can be easily added to a reaction mixture and removed following the macrocyclization through simple precipitation and filtration. In addition, the CCEs are recyclable. The use of the new CCEs is demonstrated in the synthesis of para- and metacyclophanes using either ring closing metathesis (RCM) or Glaser-Hay couplings.