The synthesis and characterization of a series of chiral indium complexes bearing a tridentate NNO ligand are reported. The ligand 2-[[[(dimethylamino)cyclohexyl]amino]methyl]- 4,6-bis(tert-butyl) phenol (H₂NNO) was synthesized via a previously published procedure and bound to indium by both a protonolysis and salt metathesis route. A dimethylated indium complex (NNO)InMe₂ (1) was isolated by reaction of InMe₃ with H₂NNO. A one-pot saltmetathesis route was used to produce a unique mixed-bridge dinuclear indium complex [(NNO)InCl] ₂(μ-OEt)(μ-Cl) (3) from a mixture of indium trichloride, potassium ethoxide and the monopotassiated salt of the ligand, KH(NNO). Direct reaction of KH(NNO) and indium trichloride resulted in the formation of (NNO)InCl₂ (4) which was carried forward to 3 by reaction with sodium ethoxide. The complex 3 is active for the ROP of β-butyrolactone ε-caprolactone and lactide and is the first reported indium-based catalyst for lactide or β-butyrolactone ROP. Kinetic studies of 3 for ROP of LA revealed that catalyst was well-behaved, and that the rate was first order with regard to lactide and catalyst. The enthalpy and entropy of activation for the ROP were experimentally determined. Polymer produced by ROP by 3 has narrow molecular weight distribution and a good correlation is seen between the observed moleular weight and monomer loading. A mechanism was proposed for 3 acting as a catalyst for the ROP of lactide; however further experiments are required to confirm this mechanism. Polymer samples isolated from the ROP of rac-lactide by rac-3 show isotactic enrichment. It is postulated that the chiral catalyst 3 is exerting stereocontrol via an enantiomorphic site control mechanism.

This thesis describes the development and rationalization of processes involved in a new methodology developed in our group, minor enantiomer recycling. The first part of the thesis addresses mechanistic studies of one of the reactions involved in minor enantiomer recycling, dual Lewis acid-Lewis base catalyzed acetylcyanation of aldehydes. The methodology uses a combination of a chiral titanium-salen  complex with a tertiary amine as a catalytic  system  in  the enantioselective  synthesis  of  O-acylated  cyanohydrins from aldehydes and ketonitriles. Mechanistic investigations revealed that the rate-determining step in the reaction changes, depending on the nature of the aldehyde that was used. It was also concluded that cyanohydrin is coordinated to the Lewis acid in the acylation step. The second part of the thesis deals with minor enantiomer recycling, a highly selective one-pot recycling system. In a first step the product is formed as a minor and a major enantiomer by asymmetric catalysis. Recycling of the minor enantiomer, by selective kinetic resolution, regenerates the starting material. Continuous addition of a second reagent, also involved in a coupled exergonic process, leads to an increase of both yield and enantiomeric excess. Recycling procedures for the synthesis of O-acylated and O-formylated cyanohydrins have been developed with high yield and high enantiomeric excess of the products. The study includes development of the systems, comparison to other methodologies in asymmetric catalysis, and attempts to understand the processes involved. / <p>QC 20141202</p>

This thesis is divided into four chapters that describe the new development in rhodium-catalyzed addition reactions and asymmetric ring opening (ARO) reactions of strained alkenes. Chapter 1 describes a regioselective Rh(I)-catalyzed addition reaction of arylboronic acids to unactivated alkenes - protected allylic amines and allyl sulfones. These formal hydroarylation processes have significantly advanced the substrate scope. Comprehensive studies were carried out to optimize the reaction conditions and a wide range of arylboronic acids were employed. The reaction was found to be linear-selective and a mechanism based on functional group- directing effects has been proposed. Chapter 2 discloses the discovery of Rh(I)-catalyzed addition of arylboronic acids to (benzyl- /arylsulfonyl)acetonitriles. Novel β-sulfonylvinylamine products were formed in a stereoselective fashion (Z-alkene). Upon hydrolysis, β-keto sulfones were obtained with a broad scope of aryl and sulfonyl substituents. These (Z)-β-sulfonylvinylamines were useful synthons in the synthesis of unsymmetrical polysubstituted pyridines via 1-aza-allyl anion intermediates as well as 1,4- benzothiazine derivatives via intramolecular cyclization. Chapter 3 reports the use of two new nucleophiles in Rh(I)-catalyzed ARO of oxabicyclic alkenes - water and triethylamine trihydrofluoride. In the water-induced ARO, an unprecedented domino ARO/isomerization process was discovered which led to the formation of 2-hydroxy-1- tetralones. By modifying the reaction conditions, trans-1,2-diols can be obtained in excellent enantioselectivity. Using triethylamine trihydrofluoride as a nucleophile, an aliphatic C-F bond was constructed enantioselectively in the ring-opening process which provided fluorinated building blocks containing both allylic fluoride and fluorohydrin units. Finally, Chapter 4 details the development of a one-pot synthesis of a chiral dihydrobenzofuran framework using Rh-catalyzed asymmetric ring opening and Pd-catalyzed C-O coupling. The product can be obtained in excellent enantioselectivity without isolation of intermediates. Systematic metal-ligand studies were carried out to investigate the compatibility of each catalytic system using product enantiopurity as an indicator.

This thesis is divided into four chapters that describe the new development in rhodium-catalyzed addition reactions and asymmetric ring opening (ARO) reactions of strained alkenes. Chapter 1 describes a regioselective Rh(I)-catalyzed addition reaction of arylboronic acids to unactivated alkenes - protected allylic amines and allyl sulfones. These formal hydroarylation processes have significantly advanced the substrate scope. Comprehensive studies were carried out to optimize the reaction conditions and a wide range of arylboronic acids were employed. The reaction was found to be linear-selective and a mechanism based on functional group- directing effects has been proposed. Chapter 2 discloses the discovery of Rh(I)-catalyzed addition of arylboronic acids to (benzyl- /arylsulfonyl)acetonitriles. Novel β-sulfonylvinylamine products were formed in a stereoselective fashion (Z-alkene). Upon hydrolysis, β-keto sulfones were obtained with a broad scope of aryl and sulfonyl substituents. These (Z)-β-sulfonylvinylamines were useful synthons in the synthesis of unsymmetrical polysubstituted pyridines via 1-aza-allyl anion intermediates as well as 1,4- benzothiazine derivatives via intramolecular cyclization. Chapter 3 reports the use of two new nucleophiles in Rh(I)-catalyzed ARO of oxabicyclic alkenes - water and triethylamine trihydrofluoride. In the water-induced ARO, an unprecedented domino ARO/isomerization process was discovered which led to the formation of 2-hydroxy-1- tetralones. By modifying the reaction conditions, trans-1,2-diols can be obtained in excellent enantioselectivity. Using triethylamine trihydrofluoride as a nucleophile, an aliphatic C-F bond was constructed enantioselectively in the ring-opening process which provided fluorinated building blocks containing both allylic fluoride and fluorohydrin units. Finally, Chapter 4 details the development of a one-pot synthesis of a chiral dihydrobenzofuran framework using Rh-catalyzed asymmetric ring opening and Pd-catalyzed C-O coupling. The product can be obtained in excellent enantioselectivity without isolation of intermediates. Systematic metal-ligand studies were carried out to investigate the compatibility of each catalytic system using product enantiopurity as an indicator.

The study of catalysis is a fundamental aspect of chemical engineering, as its implications affect all chemical transformations. Traditionally, catalysis has been subdivided into two areas: homogeneous and heterogeneous catalysis. Homogeneous catalysis refers to single-sited catalysts that exist in the same phase as the reaction media. These catalysts tend to be highly active and selective but often difficult to recover and reuse. In contrast, heterogeneous catalysts are typically multi-sited catalysts that exist in a different phase from the reaction media. These catalysts tend to be less active and selective than their homogeneous counterparts. However, the vast majority of industrial scale catalysts are heterogeneous because they can be easily separated, making them easily implemented in continuous processes, allowing for efficient, large scale operations. Due to the limitations of traditional homogeneous and heterogeneous catalysts, researchers have increasingly investigated hybrid catalysts that incorporate aspects of homogeneous and heterogeneous catalysis. This is accomplished via immobilization of homogeneous catalyst analogues onto solid-phase supports, thereby preserving the activity and selectivity of homogeneous catalysts while allowing for facile recovery and reuse from the insoluble, heterogeneous support. A variety of systems is presented here including organic and organometallic catalysts immobilized on organic and inorganic supports. Five cases are included. The first discusses utilization of supported acid and base catalysts for use in one-pot cascade reactions. The second example illustrates use of silica-coated magnetic nanoparticle supported acid catalysts for organic transformations. The third case presents novel polymer brush supported Cobalt-salen catalysts for the enantioselective, hydrolytic kinetic resolution of epoxides. A fourth case presents novel, magnetic polymer brush supported organic and organometallic catalysts for organic transformations. The fifth example illustrates polymer and silica supported ruthenium-salen catalysts for the asymmetric cyclopropanation of olefins. The overall goal of this thesis work is to develop novel supports and immobilization techniques to advance the field of hybrid organic/inorganic catalysts for the production of fine chemical and pharmaceutical intermediates.

The development of ligands derived from natural amino acids for asymmetric transfer hydrogenation (ATH) of prochiral ketones is described herein. In the first part, reductions performed in alcoholic media are examined, where it is found that amino acid-derived hydroxamic acids and thioamides, respectively, are simple and versatile ligands that in combination with [RhCp*Cl2]2 efficiently catalyze this particular transformation. Selectivities up to 97% ee of the corresponding secondary alcohols are obtained, and it is furthermore observed that the two different ligand classes, albeit based on the same amino acid scaffold, give rise to products of opposite configuration. The highly interesting enantioswitchable nature of the two abovementioned catalysts is studied in detail by mechanistic investigations. A structure/activity correlation analysis is performed, which reveals that the diverse behavior of the catalysts arise from different interactions between the ligands and the metal. Kinetic studies furthermore stress the catalyst divergence, since a difference in the rate determining step is established from initial rate measurements. In addition, rate constants are determined for each step of the overall reduction process. In the last part, catalyst development for ATH executed in water is discussed. The applicability of hydroxamic acid ligands is further extended, and catalysts based on these compounds are found to be efficient and compatible with aqueous conditions. The structurally even simpler amino acid amide is also evaluated as a ligand, and selectivities up to 90% ee are obtained in the reduction of a number of aryl alkyl ketones. The very challenging reduction of dialkyl ketones is moreover examined in the Rh-catalyzed aqueous ATH, where a modified surfactant-resembling sulfonylated diamine is used as ligand, and the reaction is carried out in the presence of SDS-micelles. A positive effect is to some extent found on the catalyst performance upon addition of phase-transfer components, especially regarding the catalytic activity in the reduction of more hydrophobic substrates. / At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: In press.

The synthesis and characterization of a series of chiral indium complexes bearing a tridentate NNO ligand are reported. The ligand 2-[[[(dimethylamino)cyclohexyl]amino]methyl]- 4,6-bis(tert-butyl) phenol (H₂NNO) was synthesized via a previously published procedure and bound to indium by both a protonolysis and salt metathesis route. A dimethylated indium complex (NNO)InMe₂ (1) was isolated by reaction of InMe₃ with H₂NNO. A one-pot saltmetathesis route was used to produce a unique mixed-bridge dinuclear indium complex [(NNO)InCl] ₂(μ-OEt)(μ-Cl) (3) from a mixture of indium trichloride, potassium ethoxide and the monopotassiated salt of the ligand, KH(NNO). Direct reaction of KH(NNO) and indium trichloride resulted in the formation of (NNO)InCl₂ (4) which was carried forward to 3 by reaction with sodium ethoxide. The complex 3 is active for the ROP of β-butyrolactone ε-caprolactone and lactide and is the first reported indium-based catalyst for lactide or β-butyrolactone ROP. Kinetic studies of 3 for ROP of LA revealed that catalyst was well-behaved, and that the rate was first order with regard to lactide and catalyst. The enthalpy and entropy of activation for the ROP were experimentally determined. Polymer produced by ROP by 3 has narrow molecular weight distribution and a good correlation is seen between the observed moleular weight and monomer loading. A mechanism was proposed for 3 acting as a catalyst for the ROP of lactide; however further experiments are required to confirm this mechanism. Polymer samples isolated from the ROP of rac-lactide by rac-3 show isotactic enrichment. It is postulated that the chiral catalyst 3 is exerting stereocontrol via an enantiomorphic site control mechanism.

143 f. / Submitted by Ana Hilda Fonseca (anahilda@ufba.br) on 2013-09-24T14:26:15Z No. of bitstreams: 1 Dissertação Maria Candeia Kuliakita.pdf: 4339184 bytes, checksum: 54063fe95edeaa2662c649acf009c9ae (MD5) / Approved for entry into archive by Ana Hilda Fonseca(anahilda@ufba.br) on 2013-09-24T14:27:50Z (GMT) No. of bitstreams: 1 Dissertação Maria Candeia Kuliakita.pdf: 4339184 bytes, checksum: 54063fe95edeaa2662c649acf009c9ae (MD5) / Made available in DSpace on 2013-09-24T14:27:50Z (GMT). No. of bitstreams: 1 Dissertação Maria Candeia Kuliakita.pdf: 4339184 bytes, checksum: 54063fe95edeaa2662c649acf009c9ae (MD5) Previous issue date: 2012 / CNPq / Desenvolveram-se neste trabalho atividades experimentais empregando as reações de Mannich, utilizando-se o dímero di-hidróxi-acetona, um derivado da glicerina. A glicerina obtém-se como co- produto da produção de biodiesel. Sem êxitos nas tentativas feitas para a reação de Mannich, partiu-se então para reações aldólicas organocatalisadas. Nesta rota preparou-se a di-hidroxi-acetona sililada (97% de rendimento), que foi empregada como reagente na reação aldólica com o 4-nitrobenzaldeído. O aldol foi obtido como mistura enantiomérica enriquecida, na proporção diastereoisomérica de 5:1 (syn/anti). Posterior acetilação em 90% de rendimento permitiu avaliar, através de HPLC com coluna quiral, o excesso enantiomérico em cerca de 90%. O aldol acetilado teve seu grupo TBS primário removido (96-100 % de rendimento). No entanto, as tentativas de oxidação e preparação do ácido não foram exitosas. Como alternativa, reações de redução para a obtenção de dióis foram feitas obtendo-se dióis com estreoquímica relativa 1,3-anti em rendimento de 80%. Reações de redução por aminação também foram realizadas, mas sem resultados satisfatórios. Em paralelo a estas reações foram preparados derivados de ácidos triterpênicos (ácidos betulínico e ursólico), triterpenos (lupeol) e esteroides (estigmasterol e β-sitosterol) com ácidos oleico e hexanoico, preparando-se compostos com potencial atividade anticâncer e anti-AIDS. / Salvador

The total syntheses of isomeric aglain natural products (±)-foveoglin A and (±)-perviridisin B have been achieved via ESIPT (excited states intramolecular proton transfer)-mediated selective (3+2) photocycloaddition of 3-hydroxyflavone with trans,trans-1,4-diphenyl-1,3-butadiene (DPBD). Using TADDOLs or Pirkle’s alcohol as chiral hydrogen-bonding additives, enantioselective ESIPT photocycloaddition was performed providing access to (+)-foveoglin A which also enabled confirmation of its absolute configuration. Photophysical studies have been conducted for ESIPT photocycloadditions revealing the possibility for exergonic electron transfer from the excited triplet state of 3-hydroxyflavones to dipolarophiles with appropriate redox potentials, which also provided a rationale for the observed selectivity. Further application of ESIPT photocycloaddition using 1-alkyl-2-aryl-3-hydroxyquinolinones (3-HQ’s) to synthesize nitrogen-containing analogues of flavaglines, aza-rocaglates, will be described. Differential photoreactivity between 2-aryl-3-hydroxyquinolinones (N-H-3-HQ’s) and 1-alkyl-2-aryl-3-hydroxyquinolinones (N-alkyl-3-HQ’s) was observed. A rationale for this observation was also provided based on photophysical measurements. A novel method to synthesize N-alkyl-3-hydroxyquinolinones using sodium hydride as base was discovered to overcome limited access to photoreaction substrates. A recirculating photoflow reactor was applied to the ESIPT photocycloaddition to increase the efficiency of the reaction. Initial biological testing indicates that aza-rocaglates do not possess activity in comparison to related rocaglates which also provides further information on the SAR of the natural product scaffold. Computational studies were conducted in collaboration with Prof. David Coker’s group using Metadynamics simulation to study tetrakis-9-phenanthrenyl TADDOL-mediated asymmetric ESIPT photocycloadditions. With a choice of collective variables based on hydrogen-bonding interactions between TADDOL and 3-hydroxyflavone, the free energy surfaces associated with formation of the hydrogen-bonding complexes between TADDOL and the 3-hydroxyflavone/methyl cinnamate or 3-hydroxyflavone/stilebene pairs were obtained. The representative three-component model from the obtained free energy minimum indicate that in addition to hydrogen-bonding interactions, π-π stacking between the phenanthren-9-yl groups of TADDOL and the 3-hydroxyflavone substrate also facilitate the asymmetric photocycloaddition which has provided information for future asymmetric catalyst designs. / 2020-11-06T00:00:00Z

In recent years, the exploitation of flow technologies as an enabling tool to access unique chemical reactivity has flourished. This dissertation describes the utilisation of these flow methods to access new sets of highly versatile, unstable diazo compounds and their application in coupling reactions. In the first chapter, an introduction into the structure and reactivity of diazo compounds is provided, as well as a discussion of currently available methods for their generation. The second chapter describes the coupling of flow-generated, semi-stabilised diazo compounds with terminal alkynes for the synthesis of racemic di- and trisubstituted allenes, using copper(I) catalysis. The third chapter follows with an account of creating chiral disubstituted allenes by asymmetric coupling of flow-generated, semi-stabilised aryl aldehyde-derived diazo compounds with terminal alkynes, using a copper(I) catalyst and a newly developed pyridine(bisimidazoline) ligand. The fourth chapter describes the generation of new, highly reactive non-stabilised diazo compounds and their reaction with arylboronic acids to allow metal-free ‘protodeboronative’ and ‘oxidative’ C(sp2)-C(sp3) cross-couplings. Finally, the fifth chapter describes the experimental procedures relevant for the results described in Chapters 2-4.