This thesis describes the development of the [RuCl₂(P N N)L] catalytic system for asymmetric hydrogenation. It has been demonstrated that the current system is efficient in preparing a range of bulky chiral alcohols in good enantioselectivity, many of which are likely to be inaccessible using the more classic [RuCl₂(P P)N N)] system developed by Noyori and coworkers. It has been shown that the current system is tolerant of a range of substrate electronic effects as well as the presence of heteroaromatic functionality, thus showing its applicability in synthesis. This has been extended to prepare a number of bulky derivatives of synthetically important molecules. The demonstration of this is significant as in drug design, for example, studies that aim to extend lipophilicity or steric bulk make the ability to prepare alcohols across the full range of steric properties important. We have shown that chiral alcohols with adjacent gem-dimethyl groups can be prepared in high enantioselectivity and their conversion into other valuable molecules, such as chiral lactones has been demonstrated. Detailed mechanistic studies have been undertaken for the present system in order to aid rational design of new, more active and selective catalysts. A number of achiral variants of the original system have been prepared and the key features of ligand structure for efficient catalysis have been identified. This was accomplished by rigorous kinetic analysis of each complex, using specialist gas-uptake monitoring equipment. The key features of catalyst structure and optimal reaction conditions for efficient asymmetric hydrogenation have been identified. Our greater understanding of the present system allowed us to rationally design new catalysts of for enantioselective hydrogenation. Our aim was to be able to tune the catalyst structure to carry out hydrogenation of a greater variety of ketone substrate with high activity and selectivity. We have successfully prepared second generation catalysts that show enhanced enantioselectivity for a variety of substrates, many of which were problematic with the Noyori system.

In Michael J. Krische research group we are developing new transition metal catalyzed Carbon-Carbon (C-C) forming reactions focusing on atom economy and byproduct free, environmental friendly approaches. We have developed a broad family of C-C bond forming hydrogenations with relative and absolute stereocontrol which provide an alternative to stoichiometric organometallic reagents in certain carbonyl and imine additions. Inspiring from the group work my goal was to develop new reactions, extend the scope of our group chemistry and their application towards synthesis of biologically active natural products. I have been part of enantioselective Rh catalyzed Aldol reaction of vinyl ketones to different aldehydes. Also, we have found that iridium catalyzed transfer hydrogenation of allylic acetates in the presence of aldehydes or alcohols results in highly enantioselective carbonyl allylation under the conditions of transfer hydrogenative. Based on this reactivity a concise enantio- and diastereoselective synthesis of 1,3-polyols was achieved via iterative chain elongation and bidirectional iterative asymmetric allylation was performed, which enables the rapid assembly of 1,3-polyol substructures with exceptional levels of stereocontrol. The utility of this approach stems from the ability to avoid the use of chirally modified allylmetal reagents, which require multistep preparation, and the ability to perform chain elongation directly from the alcohol oxidation level. This approach was utilized for the total synthesis of (+)-Roxaticin from 1,3-propanediol in 20 longest linear steps and a total number of 29 manipulations. Further, advancements were made in iridium catalyzed C-C bond formation under transfer hydrogenation. While methallyl acetate does not serve as an efficient allyl donor, the use of more reactive leaving group in methallyl chloride compensate for the shorter lifetime of the more highly substituted olefin π-complex. Based on this insight into the requirements of the catalytic process, highly enantioselective Grignard-Nozaki-Hiyama methallylation is achieved from the alcohol or aldehyde oxidation levels. Also, a catalytic method for enantioselective vinylogous Reformatsky- type aldol addition was developed in which asymmetric carbonyl addition occurs with equal facility from the alcohol or aldehyde oxidation level. Good to excellent levels of regioselectivity and uniformly high levels of enantioselectivity were observed across a range of alcohols and aldehydes. / text

A set of five new C3-symmetric phosphites were synthesized and tested in palladium-catalyzed asymmetric Suzuki coupling. The observed reactivity and selectivity were dependent upon several factors. One of the phosphites was able to achieve some of the highest levels of enantioselectivity in asymmetric Suzuki couplings with specific substrates. Different hypotheses have been made for understanding the ligand effects and reaction selectivities, and those hypotheses were tested via various methods including DOSY NMR experiments, X-ray crystallography, and correlation of catalyst selectivity with Tolman cone angles. Although only modest enantioselectivities were observed in most reactions, the ability to synthesis these phosphites in only three steps on gram scales and to readily tune their properties by simple modification of the binaphthyl 2´-substituents makes them promising candidates for determining structure-selectivity relationships in asymmetric transition metal catalysis, in which phosphites have been previously shown to be successful. A series of novel chiral oxazoline-based carbodicarbene ligands was targeted for synthesis. Unfortunately, the chosen synthetic route could not be completed due to unwanted reactivity of the oxazoline ring. However, a new and efficient route for Pd-catalyzed direct amination of aryl halides with oxazoline amine was developed and optimized during these studies. Chiral binaphthyl based Pd(II) ADC complexes with different substituent groups have been synthesized and tested in asymmetric Suzuki coupling reactions. Although only low enantioselectivities were observed in Suzuki coupling, this represents a new class of chiral metal-ADC catalysts that could be tested in further catalytic.

Pyrrolidine and pyrrolidinone rings are common motifs found in many biologically active natural products and drugs. Accordingly, our work focuses on the development of new methodologies for their one-pot synthesis. An efficient diastereoselective nitro-Mannich / lactamisation reaction cascade of methyl 3-nitropropanoate with cyclic and acyclic imines for the direct preparation of trans-monocyclic and fused tricyclic pyrrolidinone derivatives was developed. The reaction is easy to perform, broad in scope and tolerates a wide variety of functional groups. For the monocyclic methodology, 28 examples with a very good average yield of 72% and excellent diastereocontrol (typical dr >98:2) were obtained using optimized conditions and varying the amine and the aldehyde reagents. The methodology has been extended to the synthesis of 1,3,5-trisubstituted 4-nitropyrrolidinone derivatives using α-substituted 3-nitropropanoate. Using a one-pot protocol, 22 derivatives were synthesised in good yields (65% average) and diastereomeric ratios ranging from 3:1 to 30:1 in favor of the trans/trans diastereoisomer. In addition, the nitro-Mannich / lactamisation cascade of methyl 3-nitropropanoate was developed further to allow the rapid synthesis of 5-isopropyl-4-nitropyrrolidin-2-one from reaction with ammonium acetate and 1-butyl-4-nitropyrrolidin-2-one from reaction with formaldehyde. Also, the synthetic utility of the nitro-pyrrolidinones formed was exemplified through various functional group modifications: the selective reduction of the lactam carbonyl, the reduction of the nitro group in the presence or absence of a carbonyl group and the reductive removal of the nitro group. The development of an enantioselective version of the cascade under chiral Brönsted acid catalysis provided promising results (up to 90% ee). Moreover, various studies were undertaken to understand the mechanism of the reaction and the nitro-Mannich / latamisation cascade is now well understood. Furthermore, a formal synthesis of rac-Slaframine in 8 steps and 15% overall yield was achieved and it inspired additional work towards a nitro-Mannich / epoxide ring opening cascade.

This diploma thesis deals with the scope of organocatalytic concept for the preparation of enantiomerically pure organic compounds, containing fluorine atom. Our attention was focused on the use of easily available α,β-unsaturated aldehydes and ketones as starting materials and commercially available secondary amines as catalysts. The first part of the work is dedicated to the enantioselective cyclization reaction of hydrazone (24) with cyclohex-2-enone (25). The second part describes a study of enantioselective nucleophilic addition of diethyl 2-fluoromalonate (31a) to α,β-unsaturated aldehydes (30) via enamine activation.

Development of new asymmetric processes is one of the objectives of catalysis in organic chemistry. These processes can provide access to chiral building blocks applicable in syntheses of various natural substances that can be used for medical purposes. One such process is the preparation of chiral homoallyl alcohols, which have been used for syntheses of variety of biologically active compounds. In view of the aforementioned, suitably substituted homoallyl alcohols could be used as intermediates in syntheses of koibacins A-D, which have a number of interesting biological properties. Natural koibacins A-D are metabolites isolated from the marine cyanobacterium Oscillatoria sp. that exhibits selective antileishmanial activity and potent antïinflammantory properties. Our synthetic plan is focused on an approach through the allylation of aldehydes, esterification, ring closing metathesis and finally cross metathesis with different lipophilic fragments. Key words: enantioselective allylation, asymmetric synthesis, natural compounds, coibacins.

No description available.

Thesis advisor: Amir H. Hoveyda / Chapter 1 Enantioselective Conjugate Additions of Carbon Nucleophiles to Activated Olefins: Preparation of Enantioenriched Compounds Containing All-Carbon Quaternary Stereogenic Centers. Methods for enantioselective conjugate addition of nucleophiles to activated olefins generating products containing all-carbon quaternary stereogenic centers are critically reviewed. Enantioselective conjugate addition has been shown to be a powerful and concise approach to construct carbon-carbon bonds to prepare compounds containing sterically hindered stereogenic centers and has seen great advances in the past several years. Owing to the difficult nature of additions to relatively unreactive conjugate acceptors, compared to additions generating tertiary stereogenic centers, and construction of a sterically-hindered bond, in many cases, new and active catalysts had to be developed. The review discusses the areas where significant advances have been made as well as current limitations and future outlook. Chapter 2 Development of New and Active Catalysts for Cu-Catalyzed Enantioselective Conjugate Addition of Alkyl- and Arylzinc Reagent. Through development of new chiral catalysts, we have found an active and enantiodiscriminating bidentate, sulfonate-containing NHC-Cu catalyst that effects enantioselective conjugate addition of alkyl- and arylzinc reagents on notoriously difficult trisubstituted cyclic enones. Products are prepared with high levels of selectivity and participate in a variety of further functionalizations. The enantioselective additions are efficient and practical, not requiring rigorously anhydrous or oxygen-free conditions. Chapter 3 Cu-Catalyzed Enantioselective Conjugate Addition of Alkyl- and Arylaluminum Reagents to Trisubstituted Enones. Outlined in this chapter is the first effective solution for Cu-catalyzed enantioselective addition of alkyl and aryl nucleophiles to trisubstituted cyclopentenones generating products bearing a &beta;-all-carbon quaternary stereogenic center. Products are obtained in up to 97% yield and 99:1 er, only requiring 5 mol % of an in situ generated Cu-NHC catalyst. The methodology was highlighted as one of the key steps in the total synthesis of clavirolide C. Not only five-membered rings, but six- and seven-membered rings serve as proficient partners in the enantioselective process. Moreover, in cases for the enantioselective aryl addition, in situ prepared Me₂AlAr can be used without purification, filtration, or isolation, only requiring the corresponding aryl halides. The additions have also been extended to trisubstituted unsaturated lactones and chromones. Chapter 4 Cu-Catalyzed Enantioselective Conjugate Addition of Vinylaluminum Reagents to Cyclic Trisubstituted Enones. An enantioselective protocol for the formation of &beta;,&beta;-disubstituted cyclic ketones containing a synthetically versatile vinylsilane is disclosed. Enantioselective conjugate addition of in situ prepared silyl-substituted vinylaluminum reagents to &beta;,&beta;-unsaturated ketones promoted by 5 mol % of chiral Cu-NHC complexes delivers desired products with high efficiency (up to 95% yield after purification) and enantioselectivities (up to >98:<2 er). Several functionalizations utilizing the vinylsilanes, vicinal to an all-carbon quaternary stereogenic center, are shown, including an oxidative rearrangement, vinyl iodide formation and protodesilylation, accessing products not previously attainable. Furthermore, the enantioselective protocol is demonstrated as the key transformation in the total synthesis of riccardiphenol B. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Zopiclona (ZO) é um hipnótico não-benzodiazepínico da classe ciclopirrolonas, indicada para o tratamento da insônia. A ZO é um fármaco quiral administrada como uma mistura racêmica; no entanto, a sua atividade farmacológica está principalmente relacionada com o enatiômero (+)-(S)-ZO, também conhecido como eszopiclona. A ZO é extensivamente metabolizada e os metabólitos principais são a N-desmetil zopiclona (N-Des) e zopiclona-N-óxido (N-Ox). A N-Ox também é uma impureza encontrada na matéria prima. Além dessa impureza, outras oriundas do processo de síntese ou devido à degradação também podem ser encontradas: impureza B (RP29307), impureza C (2-amino-5-cloropiridina, ACP ou RP26695) e RP 48497. Sendo assim, o objetivo desse estudo foi desenvolver métodos de análise enantiosseletiva da ZO, metabólitos e impurezas em formulações farmacêuticas e materiais biológicos. Um método empregando a cromatografia líquida de alta eficiência com detecção por espectrometria de massas (LC-MS-MS) foi desenvolvido e validado para a quantificação simultânea da ZO e de seus metabolitos em plasma de ratos. Os analitos foram isolados das amostras por extração líquido-líquido e separados na coluna CHIRALPAK AD-RH, empregando a fase móvel constituída por etanol:metanol:acetonitrila (50:45:5, v/v/v) mais 0,025 % de dietilamina, na vazão de 1,0 mL min-1. A moclobemida foi utilizada como padrão interno. O método desenvolvido foi linear no intervalo de concentração plasmática de 7,5-500 ng mL-1. As recuperações médias absolutas foram de 74,6 e 75,7; 61,6 e 56,9; 72,5 e 70,7 % para os enantiômeros da ZO, N-Des e N-Ox, respectivamente, e 75,9 % para o padrão interno. A precisão e a exatidão apresentaram resultados dentro de níveis aceitáveis (<15 %). A aplicação do método em um estudo piloto de disposição cinética da ZO em ratos mostrou que os níveis de (+)-(S)-ZO foram sempre superiores aos de (-)-(R)-ZO. Concentrações mais elevadas também foram observadas para (+)-(S)-N-Des e (+)-(S)-N-Ox, confirmando a disposição cinética estereosselectiva da ZO. Outro método desenvolvido utilizando LC-MS-MS permitiu a determinação da ZO no cérebro de ratos. O tratamento das amostras foi realizado empregando a extração em fase sólida, obtendo-se recuperações elevadas de 89,6 e 91,7 % para cada enantiômero. Os enantiômeros foram separados em uma coluna CHIRALPAK AD, com a fase móvel constituída por acetonitrila:etanol:metanol (60:20:20, v/v/v), na vazão de 1,3 mL min-1. A moclobemida também foi utilizada como padrão interno. O método validado mostrou linearidade no intervalo de 0,29-344,8 ng g-1, com limite de quantificação de 0,29 ng g-1. Pôde-se observar que os níveis de (+)-(S)-ZO, o enantiômero mais ativo, foram sempre superiores aos de (-)-(R)-ZO. Finalmente, um terceiro método foi desenvolvido para análise enantiosseletiva da ZO e das suas impurezas N-Ox e ACP em comprimidos, empregando a eletroforese capilar com detecção UV (CE-UV). Os analitos foram extraídos dos comprimidos utilizando acetonitrila e foram separados em um capilar não revestido de sílica fundida (50 um, 42 cm de comprimento efetivo, 50 cm de comprimento total), utilizando tampão fosfato de sódio 80 mmol L-1, pH 2,5, contendo 5 mmol L-1 de ?-ciclodextrina carboximetilada. Os analitos e o padrão ii interno (trimetropina) foram detectados em 305 e 200 nm, respectivamente. Uma tensão de 27 kV foi aplicada e a temperatura do capilar foi mantida em 25 °C. Todos os analitos foram analisados em até 8 min e as curvas analíticas foram lineares no intervalo de concentração de 0,4-0,8 mg mL-1 para cada enantiômero da ZO, 0,8-1,6 ?g mL-1 para ACP e 0,4-0,8 ?g-1 mL para cada enantiômero da N-Ox. Os coeficientes de variação e erros relativos obtidos na avaliação da precisão e exatidão foram inferiores a 2% para todos os analitos. Este método validado foi utilizado para estudar a degradação e racemização da ZO sob condições de stress. As duas impurezas avaliadas foram formadas nas condições de estresse mas a racemização não foi observada. / Zopiclone (ZO) is a non-benzodiazepine hypnotic drug of the cyclopyrrolone class, indicated for the treatment of insomnia. ZO is a chiral drug administered as a racemic mixture, however its pharmacological activity is mainly related to (+)-(S)-ZO, also known as eszopiclone. It is extensively metabolized and the main metabolites are N-desmethyl zopiclone (N-Des) and zopiclone-N-oxide (N-OX). N-Ox is also found as an impurity in the raw material. Other impurities, coming from the synthetic procedure or due to degradation can also be found: impurity B (RP29307), impurity C (2-amine-5-chloropyridine, ACP or RP26695) and RP 48497. Therefore, the aim of this study was the development of methods for the enantioselective analysis of ZO, metabolites and impurities in pharmaceutical formulations and biological materials. A high-performance liquid chromatographic method with triple quadrupole mass spectrometry detection (LC-MS-MS) was developed and validated for the simultaneous quantification of ZO and its metabolites in rat plasma samples. The analytes were isolated from rat plasma by liquid-liquid extraction and separated using a CHIRALPAK AD-RH column, and ethanol:methanol:acetonitrile (50:45:5, v/v/v) plus 0.025 % diethylamine as mobile phase, at a flow-rate of 1.0 mL min-1. Moclobemide was used as internal standard. The developed method was linear over the concentration range of 7.5-500 ng mL-1. The mean absolute recoveries were 74.6 and 75.7; 61.6 and 56.9; 72.5 and 70.7 % for ZO enantiomers, for N-Des enantiomers and for N-Ox enantiomers, respectively, and 75.9 % for the internal standard. Precision and accuracy were within acceptable levels of confidence (<15 %). Method application in a pilot study of ZO kinetic disposition in rats showed that the levels of (+)-(S)-ZO were always higher than those of (-)-(R)-ZO. Higher concentrations were also observed for (+)-(S)-N-Des and (+)-(S)-N-Ox. Another method was developed for the determination of ZO in rat brain using LC-MS-MS. The sample treatment procedure was carried out employing solid-phase extraction yielding recoveries of 89.6 and 91.7 % for each ZO enantiomer. The ZO enantiomers were resolved on a CHIRALPAK AD column with a mobile phase consisting of acetonitrile:ethanol:methanol (60:20:20, v/v/v) at a flow rate of 1.3 mL min-1. Moclobemide was used as internal standard. The validated method showed linearity in the range of 0.29 - 344.8 ng g-1, with quantification limit of 0.29 ng g-1. It could be observed that the levels of (+)-(S)-ZO were always higher than those of (-)-(R)-ZO. Finally, a third method was developed for the enantioselective analysis of ZO and its impurities N-Ox and ACP in tablets using capillary electrophoresis with UV detection (CE-UV). The analytes were extracted from the tablets using acetonitrile and were separated in an uncoated fused-silica capillary (50 ?m, 42 cm effective length, 50 cm total length) using 80 mmol L-1 sodium phosphate buffer, pH 2.5, and 5 mmol L-1 carboxymethyl-?-cyclodextrin as running buffer. The analytes and the internal standard (trimethoprim) were detected at 305 and 200 nm, respectively. A tension of 27 kV was applied and the capillary temperature was maintained at 25 ºC. All analytes were analyzed within 8 min and linear calibration curves over the iv concentration range of 0.4-0.8 mg mL-1 for each ZO enantiomer, 0.8-1.6 ?g mL-1 for ACP and 0.4-0.8 ?g mL-1 for each N-Ox enantiomer were obtained. The coefficients of correlation obtained for the linear curves were greater than 0.99. The intra-day and inter-day accuracy and precision were lower than 2% for all analytes. This validated method was employed to study the degradation and racemization of ZO under stress conditions. The results obtained showed that ACP and N-Ox were both formed under the stress conditions used, but racemization was not observed.

A hidroxicloroquina (HCQ) é um importante fármaco quiral usado, principalmente, no tratamento de artrite reumatóide, lupus eritematoso sistêmico e malária e cujas propriedades farmacocinéticas e farmacodinâmicas são estereosseletivas. Em relação às propriedades farmacocinéticas, alguns estudos prévios indicam que o metabolismo estereosseletivo parece ser função da espécie estudada, o que implica na necessidade de métodos seletivos para a determinação de seus enantiômeros em materiais biológicos. Assim, propôs-se o desenvolvimento e a validação de métodos para análise dos enantiômeros do fármaco inalterado e de seus principais metabólitos em frações microssomais de homogeneizados de fígado de ratos e camundongos. Para tanto foram empregadas as técnicas de eletroforese capilar (CE) e de cromatografia líquida de alta eficiência (HPLC). Inicialmente foi desenvolvido um método por HPLC, em uma etapa, para a quantificação dos enantiômeros de dois metabólitos da HCQ, desetilcloroquina (DCQ) e desetilhidroxicloroquina (DHCQ) em microssomas de fígado de ratos e camundongos. A separação foi efetuada utilizando-se a coluna Chiralpak AD-RH e hexano:isopropanol (92:8, v/v) acrescido de 0,1% de dietilamina como fase móvel. O procedimento de extração líquido-líquido foi utilizado para a preparação das amostras. A metodologia desenvolvida resultou na completa resolução dos enantiômeros da HCQ, DCQ e DHCQ e pode ser considerada adequada, visto que os parâmetros de validação mostraram valores dentro dos limites exigidos na literatura. O segundo método desenvolvido permitiu a quantificação dos enantiômeros dos três metabólitos da HCQ: DCQ, DHCQ e bisdesetilcloroquina (BDCQ) em microssomas de fígado de camundongos. A separação foi efetuada utilizando-se um tubo capilar de sílica fundida e solução do eletrólito tris(hidroximetil)aminometano 100 mmol/L, ajustada a pH 9,0 com ácido fosfórico e acrescida de 1% (m/v) de &#946; –CD - sulfatada e 30 mmol/L de &#946; –CD - hidroxipropilada. O procedimento de extração líquido-líquido foi eficiente para remover interferentes e os parâmetros de validação mostraram valores dentro dos limites exigidos na literatura. Os métodos desenvolvidos foram aplicados no estudo in vitro do metabolismo da HCQ em frações microssomais de fígado dos animais, verificando-se que o principal metabólito formado é o (-)-(R)-DHCQ, para ambas espécies estudadas. / Hydroxychloroquine (HCQ) is an important chiral drug used specially in the treatment of rheumatoid arthritis, systemic lupus erythematosus and malaria, with stereoselective pharmacokinetic and pharmacodinamic properties. Concerning these properties, some previous studies indicate that the stereoselective metabolism seems to be a function of the studied species, therefore selective methods are required for the determination of its enantiomers in biological matrix. Thus, the present work reports the development and validation of methods for the analysis of the enantiomers of HCQ and its main metabolites in microsomal fraction of rats and mice liver homogenates. Capillary electrophoresis (CE) and high-performance liquid chromatography (HPLC) were used for this purpose. Initially, a one-step HPLC method was developed for the quantification of the enantiomers of two HCQ metabolites, desethylchloroquine (DCQ) and desethylhydroxychloroquine (DHCQ) in microsomal fraction of rats and mice liver homogenates. The separation was performed on a Chiralpak AD-RH column using hexane:isopropanol (92:8, v/v) plus 0.1% diethylamine as the mobile phase. Liquid-liquid extraction procedure was used for sample preparation. The developed methodology resulted in the complete resolution of HCQ, DCQ and DHCQ enantiomers and can be considered suitable because the validation parameters are in accordance with the limits established in the literature. The second developed method allowed the quantification of the enantiomers of the three HCQ metabolites, DCQ, DHCQ and bisdesethylchloroquine (BDCQ) in microsomal fraction of mice liver homogenates. The separation was performed using a fused-silica capillary tube and tris (hydroxymethyl) aminometane 100 mmol/L electrolyte solution, adjusted at pH 9.0 with phosphoric acid, containing 1% (w/v) sulfated- &#946; -CD and 30 mmol/L hydroxypropyl- &#946; -CD. The liquid-liquid extraction procedure was efficient to remove interferents and the validation parameters showed values within accordance to the literature. The developed methods were applied in the in vitro metabolism study of HCQ in microsomal fractions of the liver of the animals and it was verified that the main metabolite formed is (-)-(R)-DHCQ for both animal species studied.