A risperidona é um medicamento antipsicótico que quando metabolizada da origem a dois metabólitos hidroxilados quirais, a 7-hidroxirisperidona (7-RispOH) e a 9-hidroxirisperidona (9-RispOH). A 9-RispOH apresenta as mesmas propriedades farmacológicas que a risperidona e já é comercializada como fármaco, com o nome genérico de paliperidona. Estudos em humanos mostram que existem diferenças na disposição cinética dos enantiômeros da 9-RispOH, com uma maior prevalência do enantiômero (+)-9-RispOH em plasma. Dessa forma, este trabalho teve como finalidade avaliar a capacidade de algumas espécies de fungos e também de catalisadores de Jacobsen em (bio)transformar enantiosseletivamente a risperidona em seu metabólito ativo 9-RispOH. Para tanto, foi desenvolvido um método de separação para a risperidona e seus metabólitos utilizando cromatografia líquida de alta eficiência quiral. Este método foi então aplicado nos estudos de biotransformação enantiosseletivo e nos estudos de catálise assimétrica. A separação cromatográfica foi realizada empregando a coluna Chiralcel OJ-H e metanol:etanol (50:50, v/v) + 0,2% de trietilamina como fase móvel. A vazão e temperatura utilizadas foram 0,8 mL min-1 e 25oC, respectivamente. Para extração dos analitos do meio de cultura, foi empregada a microextração em fase sólida (SPME) como técnica de preparação de amostra. O processo de SPME foi realizado utilizando uma fibra C18 mergulhando diretamente a fibra na amostra por 30 minutos e dessorvendo a fibra diretamente na fase móvel por 5 minutos. A validação e estudos de biotransformação foram realizados empregando a cromatografia líquida acoplada à espectrometria de massas (LC-MS/MS). O método foi validado e todos os parâmetros encontram-se de acordo com as recomendações da literatura. O estudo de biotransformação foi realizado com diferentes espécies de fungos e somente os fungos do gênero Cunninghamella foram capazes de biotransformar a risperidona em seu metabólito ativo. O fungo Cunninghamella echinulata foi capaz de biotransformar estereosseletivamente a risperidona no seu metabólito ativo (+)-9-RispOH com excesso enantiomérico de 100% e o fungo Cunninghamella elegans foi também capaz de biotransformar estereosseletivamente a risperidona nos dois enantiômeros da 9-RispOH em diferentes proporções. Os estudos preliminares de catálise assimétrica foram realizados empregando a cromatografia líquida e detecção por UV-Vis, injetando diretamente alíquotas no sistema cromatográfico. Esses estudos mostraram que na condição de reação 1:50:50 (em número de mols, catalisador:oxidante:substrato) houve uma catálise assimétrica da risperidona que demonstrou ser enantiosseletiva para o metabólito 7-RispOH (E1). / Risperidone is an atypical antipsychotic drug. Its metabolism yields in two hydroxylated chiral metabolites, 7-hydroxyrisperidone (7-RispOH) and 9-hydroxyrisperidone (9-RispOH). The 9-RispOH metabolite presents the same pharmacologic activity of the parent drug risperidone. This led this drug to be marketed as drug under the generic name paliperidone. Studies have shown differences in the kinetic disposition of the 9-RispOH enantiomers with higher prevalence of the (+)-9-RispOH enantiomer in plasma. Thus, this work aimed to evaluate the ability of some species of fungi and Jacobsen catalysts in the enantioselective (bio)transformation of risperidone into its active chiral metabolite 9-RispOH. To accomplish that, it was developed a separation method to analyze risperidone and its metabolites by chiral high-performance liquid chromatography. This method was employed in enantioselective biotransformation studies and in asymmetric catalysis studies. The chromatographic separation was performed on a Chiralcel OJ-H column using methanol:ethanol (50:50, v/v) plus 0.2% triethylamine as the mobile phase at a flow rate of 0.8 mL min-1. The SPME process was performed by immersing directly a C18 probe fiber in the culture medium during 30 min. The analytes were desorbed from the fiber directly in the mobile phase during 5 min. The method validation and the biotransformation studies were performed by high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The method was completely validated and all parameters were in agreement with the literature recommendations. The biotransformation studies were performed employing different species of fungi and only the Cunninghamella genus was able to biotransform risperidone into its active metabolite. The Cunninghamella echinulata fungus was able to biotransform risperidone into the active metabolite, (+)-9-RispOH, resulting in 100% of enantiomeric excess. The Cunninghamella elegans fungus was also able to biotransform stereoselectively risperidone into (+)- and ()-9-RispOH enantiomers at different rates. Preliminary studies of asymmetric catalysis were performed using high-performance liquid chromatography with UV-Vis detector (HPLC-UV). The aliquots were directly injected in the chromatography system. These studies showed that the reaction with 1:50:50 (catalyst:oxidant:substrate, in number of mols, in this sequence) presented an asymmetric catalysis of risperidone and that showed to be enantioselective to 7-RispOH (E1) metabolite.

O crescente interesse na avaliação da estereosseletividade na farmacocinética e farmacodinâmica de fármacos quirais, visando estabelecer as vantagens na produção de fármacos estereoquimicamente puros, tem levado ao desenvolvimento de métodos de análises com baixos limites de quantificação, seletividade e reprodutibilidade compatíveis com sua utilização em estudos de disposição cinética. Nesse contexto, um método empregando a cromatografia líquida de alta eficiência (HPLC) foi desenvolvido para a análise enantiosseletiva da mirtazapina em plasma humano. A mirtazapina foi selecionada para esse estudo por ser um novo antidepressivo, com propriedades farmacocinéticas e farmacodinâmicas estereosseletivas e em razão da carência de metodologia adequada para a quantificação individual dos seus enantiômeros. O procedimento de preparação das amostras envolveu tanto a extração líquido-líquido (LLE) quanto uma nova técnica de microextração em fase líquida empregando fibra cilíndrica microporosa de polipropileno (LPME), ambas usando tolueno como solvente de extração, seguido de análise cromatográfica, com detecção por absorção no UV, em 292 nm. A separação cromatográfica das formas (+)-(S)- e (-)-(R)- mirtazapina foi obtida em uma coluna Chiralpak AD protegida por coluna de guarda CN, usando hexano:etanol (98:2, v/v) + 0,1% de dietilamina como fase móvel. A recuperação média dos enantiômeros da mirtazapina empregando a LLE (96%) foi superior à obtida com a LPME (29%); apesar disso, os limites de quantificação foram muito próximos, isto é, 5,0 ng mL-1 para a LLE e 6,25 ng mL-1 para a LPME. Nos estudos de precisão e exatidão, os coeficientes de variação e erros relativos foram inferiores a 15% para todas as amostras avaliadas, empregando ambas as técnicas. O método de microextração baseado na LPME provou ser mais econômico e menos poluente e tão rápido, sensível e reprodutível quanto a LLE. As duas técnicas de preparação de amostras provaram ser adequadas e compatíveis para sua aplicações em estudos de disposição cinética. / The increased interest in enantioselective pharmacokinetic and pharmacodynamic properties of chiral drugs, aiming to establish the advantages in the production of estereochemically pure drugs, has led to the development of methods of analysis with low limits of quantification, selectivity and reproducibility, which are suitable to be used in kinetic disposition studies. On this basis, mirtazapine, a new antidepressant with estereoselective pharmacokinetic and pharmacodynamic properties but with few suitable methodologies for the separation and quantification of its enantiomers, was selected to evaluate two techniques of sample preparation. The procedure involved a classic liquid-liquid extraction and a new technique of liquid-phase microextraction using microporous polypropylene hollow fiber, both using toluene as extraction solvent. The analyses were carried out by high-performance liquid chromatography using chiral stationary phase and UV detection, at 292 nm. The chromatographic separation of (+)-(S)- e (-)-(R)- mirtazapine was performed on a Chiralpak AD column protected by a CN guard column, using hexane:ethanol (98:2, v/v) + 0.1% diethylamine as mobile phase. The mean recovery of mirtazapine enantiomers using LLE (96%) was higher than LPME (29%); in spite of this, the quantification limits have been very close, i.e, 5.0 ng mL-1 for LLE and 6.25 ng mL-1 for LPME. In precision and accuracy studies, coefficients of variation and relative errors were below 15% for all the evaluated samples in both LLE and LPME techniques. The microextraction method based on LPME proved to be more economic and less pollutant than LLE and as fast, sensible and reproducible as LLE. The two techniques of sample preparation have proved to be suitable for their application in kinetic disposition studies.

Nous avons développé de nouveaux accès pour la construction de molécules comportant les motifs Csp3-CF3 et Csp3-SCF3. Deux réactions de transfert d'hydrure sur des composés trifluorométhylés par catalyse avec des métaux de transition ont été réalisées : 1) l'isomérisation catalytique d'alcools allyliques trifluorométhylés par des complexes de fer (II); 2) le transfert d'hydrogéne énantiosélectif de céto-imines trifluorométhylées par des complexes chiraux de ruthénium en utilisant l'isopropanol comme source d'hydrure pour obtenir des amines trifluorométhylées optiquement actives avec de hauts rendements et de hautes énantiosélectivités. La trifluorométhylthiolation allylique nucléophile de dérivés de Morita-Baylis-Hillman a été étudiée. L'accès régio- et stéréosélectif aux produits SCF3 thermodynamiques a été réalisé par la combinaison de S8/CF3SiMe3/KF/DMF avec de bons rendements. Le produit cinétique a été obtenu en utilisant le réactif de Zard. / We have developed new accesses for the construction of molecules featuring Csp3-CF3 and Csp3-SCF3 motifs. Two atom-economical hydride transfer reactions of trifluoromethylated compounds by transition-metal catalysis were realized: 1) the isomerization of trifluoromethylated allylic alcohols by iron (II) complexes; 2) the enantioselective transfer hydrogenation of trifluoromethylated ketimines by a chiral complex of ruthenium and isopropanol as hydride source for the preparation of optically pure trifluoromethylated amines in high yields and high enantioselectivities. The nucleophilic allylic trifluoromethylthiolation of Morita-Baylis-Hillman derivatives was investigated. The regio- and stereoselective access to thermodynamic trifluoromethylthiolated products has been achieved by combination of S8/KFfMe3SiCF3/DMF in good yields. The kinetic trifluoromethylthiolated products were obtained by using Zard's trifluoromethylthiolating reagent.

Ph.D. (Chemistry) / Please refer to full text to view abstract

Ph.D. (Chemistry) / The bridged chiral benzopyrans were strategically ring opened via acetolysis to yield either galactose based chromenes or chromans, depending on the reaction conditions. A proposal relating to the mechanism of this selective ring opening acetolysis is discussed. The benzopyrans (chromenes, chromans and bridged chiral benzopyrans) were de-acetylated via triethyl amine catalysed transesterification. Interestingly, the chromenes did not yield the anticipated hydrolysis product (triol) but a new class of bridged chiral benzopyrans which were a result of intramolecular oxa-Michael addition. A chromene that formed during the selective ring opening of the bridged chiral benzopyrans was employed to develop a method for the synthesis of a carbohydrate derived oxepane. The oxepane synthesis was achieved, albeit in the face of numerous challenges from side reactions. The difficulties encountered in the synthesis are discussed...

The construction of tertiary alkylamines is a synthetic challenge exacerbated by the poor electrophilicity of imines. Due to the presence of this kind of building block in a large number of bioactive molecules, the development of new strategies to synthesise the quaternary carbon centre is essential. This thesis describes the work carried out on the rearrangement of lithiated vinyl ureas in order to form α-tertiary amines. The first part presents how vinyl ureas were synthesised, using the reaction between an imine and an aryl isocyanate. The development of one-pot process allows the synthesis of a range of ureas in large scale. These vinyl ureas present unusual reactivity: the electron-rich double bond can undergo syn umpolung carbolithiation followed by retentive aryl migration in order to generate highly substituted amines after cleavage of the urea. The complete mechanism is investigated to understand fully the diastereoselective pathway of the reaction. In the next part, the rearrangement of lithiated ureas is extended to the N to C vinyl transfer. Different vinyl migrating group are investigated and α-tertiary amines have been synthesised in high yields and enantiomerically pure form using this new rearrangement. The mechanistic insights of the reaction are also studied and a retentive mechanism will be identified. Finally, N to C vinyl transfer is applied toward the synthesis of Erythrina alkaloids.

Thesis advisor: X. Peter Zhang / Asymmetric C–H functionalization represents one of the central topics in modern organic chemistry, which allows for the direct installation of functional groups onto ubiquitous C–H bonds in organic molecules. Among numerous elegant strategies, transition metal-catalyzed C–H alkylation with diazo compounds represents one of the most powerful methods for C–C bond formation. Different from Fischer metallocarbene-based C–H insertion reactions, cobalt(II)-based metalloradical catalysis (MRC) is recently proven to be capable of activating acceptor/acceptor diazo compounds for radical C–H alkylation reactions via H-atom abstraction. In this dissertation, we have developed several systems by utilizing less-explored aryl and alkyl diazomethanes as new radical precursors for highly enantioselective radical C–H alkylation reactions, which permit the efficient synthesis of different optically active heterocyclic compounds. First, we have demonstrated the feasibility of using aryl aldehyde-derived sulfonylhydrazones as new radical precursors for enantioselective radical C–H alkylation to synthesis enantioenriched 2,3-dihydrobenzofuran derivatives. Notably, a general and mild way for in situ generation of diazo compounds have been identified by using 2,4,6-triisopropyl sulfonyl hydrazone as diazo precursor, which allow us to regulate the reaction temperature to achieve the high enantioselectivity for the desired radical reactions. Second, the utility of Co(II)-based MRC has been further highlighted by enantioselective indoline synthesis. Through the design and synthesis of new catalysts, the system is shown to have a broad spectrum of substrate scope, forming various 2-substituted indolines with up to 98% yield and 96% ee. A series of mechanistic studies further support the underlying stepwise radical alkylation pathway. Finally, we further expand the applicability of MRC to even more challenging diazo compounds, aliphatic diazomethanes. Starting from alkyl aldehyde-derived sulfonylhydrazones as diazo precursors, the Co(II)-based radical alkylation reactions allow for the enantioselective synthesis for common 2-substituted tetrahydrofuran structures with high yields and excellent enantioselectivities. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Catalytic enantioselective desymmetrization of meso-epoxides is widely used in many areas of chemistry. Such process is usually catalyzed by a transition metal complex with a chiral ligand. Recently, a synthesis of an analogue of Bolm's 2,2'-bipyridine ligand was developed and its combination with metal salts were tested in various reactions. In this master's thesis, a catalytic system composed of Sc(OTf)3/Bolm's ligand analogue was studied in alcoholysis and aminolysis of the meso- epoxides. The reaction has been extended to a broad range of alcohols providing 1,2-diol monoethers in excellent enantioselectivity up to 99% ee. The aminolysis of meso-epoxides has been optimized, as well. The catalyst loading could be lowered to 1 mol% with only marginal effects on the enantioselectivity. Key words: epoxides, enantioselective catalysis, chiral ligands.

Thesis advisor: Masayuki Wasa / This dissertation describes the development of novel catalyst systems that could promote the regio- and enantioselective transformations of C-H bonds contained in N-alkylamines and ethers through Lewis acid-mediated hydride abstraction processes. The progress made in C-H functionalization of N-alkylamines and ethers that served as the intellectual foundation of this dissertation research are summarized in Chapter 1. Despite notable advances, the development of broadly applicable, enantioselective, and catalytic protocols to functionalize C-H bonds in N-alkylamines and ethers with high regio- and stereo-selectivity was regarded as an unsolved problem when we started this dissertation research. In an effort to overcome these fundamental limitations, we first identified a B(C6F5)3/Cu-PyBOX cooperative catalyst system for the enantioselective conversion of a-amino C-H bonds through the generation of an iminium by (F5C6)3B-catalyzed hydride abstraction process (Chapter 2). We then envisioned that in situ generated iminium ions could be further deprotonated to furnish an enamine intermediate, which may react with electrophilic species for a-amino C-H functionalization. The design and development of such a catalyst system were discussed in Chapter 3. Finally, we disclose enantioselective Cu–BOX-catalyzed hetero Diels-Alder reactions of enol ethers generated through Ph3C+-mediated oxidation of alkyl ethers. (Chapter 4). / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Masayuki Wasa / This dissertation describes the development of cooperative catalyst systems for the functionalization of monocarbonyl compounds and stereoselective transformations of alpha-C–H bonds of N-alkylamines, inspired by the concepts of frustrated Lewis pairs (FLPs). Prior to this dissertation research, practical and broadly applicable C–C and C–heteroatom bond forming reactions involving the FLP complexes that provide synthetically desirable products with high enantioselectivity remained to be developed. Chapter 1 of this dissertation describes the recent advances in the transformations involving FLPs and B(C₆F₅)₃-catalyzed reactions. Inspired by the unique capability of FLP catalysts to activate otherwise unreactive molecules, and circumvent undesirable acid–base complexation, we have developed potent cooperative acid/base catalysts for C–C bond forming reactions of various monocarbonyl compounds and an appropriate electrophile, which will be discussed in Chapter 2. Another reactivity of FLPs to be explored has to do with the catalytic and enantioselective reactions of N-alkylamines, where two Lewis acid catalysts with potentially overlapping functions, work cooperatively to activate alpha-amino C–H bonds and promote the enantioselective C–C bond forming reaction between N-alkylamines and a nucleophilic species. In Chapter 3, B(C₆F₅)₃-catalyzed union of N-alkylamines and silicon enolates followed by the enantioselective B(C₆F₅)₃/Mg–PyBOX-catalyzed alpha-alkylation of N-alkylamines and alpha,beta-unsaturated compounds to form beta-amino carbonyl compounds will be described. In Chapter 4, B(C₆F₅)₃/Cu–PyBOX-catalyzed alpha-C–H alkynylation of N-alkylamines and the applications in late-stage functionalization and stereoselective synthesis will be discussed. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.