This thesis describes stereoselective syntheses of four amino acids, three of which are C-glycosidic analogues of glycosylated amino acids. The overall goal of the project was to probe the interactions between MHC molecules, glycopeptide antigens and T cell receptors, that are essential for development of collagen induced arthritis. Collagen induced arthritis is a frequently used mouse model for rheumatoid arthritis, an autoimmune disease that attacks joint cartilage and leads to a painful and eventually crippling condition. The thesis is based on four studies. The first study describes the synthesis of hydroxylysine, an amino acid that is found in collagen and is an important constituent of the glycopeptide proposed as an antigen in collagen induced arthritis. During the synthesis of hydroxylysine some new insight into the mechanism of the reductive opening of p-methoxybenzylidene acetals was obtained. The remaining three studies deals with the synthesis of C-glycosidic analogues of glycosylated amino acids, hydroxy norvaline, threonine and hydroxylysine.The synthesis of each amino acid required control of several stereogenic centra and utilizes a variety of approaches such as use of stereoselective reactions, chiral auxilaries, chiral templates and asymmetric catalysis. The C-glycosidic analogues of galactosylated hydroxynorvaline and hydroxylysine were incorporated in glycopeptides from type II collagen and evaluated in T cell response assays. It was found that the T cells were stimulated by the C-glycopeptides, but that higher concentrations were required than for the native O-glycopeptide

This thesis is divided into four separate parts with amino alcohols as the common feature. The first part of the thesis describes the development of an efficient three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters are formed in high yields and excellent diastereoselectivities. An asymmetric version was also developed by employing chiral α-methylbenzyl imines as dipolarophiles yielding enantiomerically pure syn-α-hydroxy-β-amino esters. This methodology was also applied on a short asymmetric synthesis of the paclitaxel side-chain as well as in an asymmetric synthetic approach towards the proteasome inhibitor omuralide. Furthermore, the use of chiral Rh(II) carboxylates furnishes the syn-α-hydroxy-β-amino esters in moderate enantioselectivity (er up to 82:18), which indicates that the reaction proceeds via a metal-associated carbonyl ylide. The second part describes the development of a 1,3-dipolar cycloaddition reaction of azomethine ylides to aldehydes for the synthesis of α-amino-β-hydroxy esters. Different methods for the generation of the ylides, including Vedejs’ oxazole methology and an Ag(I)/phosphine-catalyzed approach have been evaluated. The best results were obtained with the Ag(I)/phosphine approach, which yielded the desired α-amino-β-hydroxy ester in 68% yield and 3.4:1 syn:anti-selectivity. The last two parts deals with the total synthesis of the amino alcohol-containing natural products D-erythro-sphingosine and (−)-stemoamide. The key transformation in the sphingosine synthesis is a cross-metathesis reaction for the assembly of the polar head group and the aliphatic chain. In the stemoamide synthesis, the key feature is an iodoboration/Negishi/RCM-sequence for the construction of the β,γ-unsaturated azepine core of stemoamide followed by a stereoselective bromolactonization/1,4-reduction strategy for the installation of the requisite C8-C9 trans-stereochemistry. / QC 20100820

The natural product celastrol (1) possesses a wide array of promising biological activities related to diseases characterized by protein misfolding including those associated with neuronal degradation, inflammation, and cancer. Relevant to cancer, celastrol functions as a non-ATP-competitive inhibitor of heat shock protein-90, providing a potential lead for the development of new inhibitors with improved pharmacology. A laboratory preparation of the small molecule was undertaken to provide access to the unnatural enantiomer of celastrol. The lack of understanding of the chemistry and biology of the growing class of celastroids is attributed to the incompatibility of biologically inspired polyene cyclization strategies to assemble friedelin triterpenoids. As a result of these problems residing at the interface of chemistry and biology, a purely synthesis-based strategy for polyene cyclizations to rapidly construct the pentacyclic core of the friedelin and celastroid natural products has been developed. This efficient strategy is gram scalable culminating in the first total synthesis of wilforic acid (127) and an advanced intermediate capable of delivering celastrol (1) as well as numerous celastroid natural products. Phenols possess broad utility serving as key materials in all facets of chemical industries, especially the pharmaceutical industry. The ideal synthesis of a phenolic compound entails the direct oxidation of an aryl C-H bond remains to be a difficult synthetic challenge. Following our initial report describing the hydroxylation of arenes using phthaloyl peroxide, new peroxide derivatives were investigated to probe their reactivity in an effort to hydroxylate aromatics which were previously unreactive. Electronically poor to moderately rich arenes were successfully hydroxylated with a broad functional group tolerance using 4,5-dichlorophthaloyl peroxide. This protocol has been applied toward the rapid synthesis of phenolic analogs and metabolites of current pharmaceuticals as well as biocides. Mechanistic studies using kinetic isotope effect, competition, and benzylic oxidation experiments indicate that a novel diradical reverse-rebound mechanism is the likely pathway. Further examination of the transition-state using linear free energy relationships with sigma vs. sigma+ values established a linear trend with a low negative rho value (- 3.92) corresponding best using sigma values supporting a diradical reverse-rebound addition. / text

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

No description available.

The Dong research group is interested in harnessing the power of transition metal catalysis to transform simple molecules and reagents (such as carbon monoxide, hydrogen gas, olefins, and C–H and C–O bonds) into valuable products (such as functionalized heterocycles, chiral carbonyl compounds and natural products). This thesis will describe our continual effort to achieve this goal. Part I describes the Pd-catalyzed functionalization of sp2 and sp3 C–H bonds. Carbon monoxide is used as a stoichiometric reductant in the cyclization of diarylnitroalkenes to afford biologically relevant 3-arylindoles and other N-containing heterocycles with carbon dioxide as the only stoichiometric byproduct. Also, an aryl sulfoxide moiety is shown to direct the arylation of sp3 C–H bonds to afford beta-functionalized amides. Part II describes the Ru-catalyzed sp3 C–O bond activation of alkoxypyridines and related heterocycles. In this transformation, an O- to N-alkyl migratory rearrangement occurs to afford N-alkylated pyridones which are structures found in many natural products and pharmaceutical agents. Part III describes our pursuit of metal-catalyzed asymmetric synthesis. Readily available benzylic bromides are carbonylated with carbon monoxide in alcoholic solvent mixtures. The resulting medicinally relevant 2-arylpropionic esters are obtained with moderate to good enantioselectivities. Preliminary results for the asymmetric hydrogenation of gem-diarylethylenes and novel ligand development are also disclosed. Part IV describes our efforts towards the total synthesis of 6-deoxyerythronolide B. Our retrosynthetic analysis of the macrolide antibiotic involves disconnections at the lactone linkage and between C7 and C8. The two equally complex fragments were prepared via reliable aldol, hydroboration, crotylation and redox chemistry. Rather than the typical macrolactonization method to form the 14-membered ring, we propose an alternative strategy where we plan to cyclize with a metal-catalyzed ring-closing metathesis event. Currently, this step is under investigation by other members in the group.

The Dong research group is interested in harnessing the power of transition metal catalysis to transform simple molecules and reagents (such as carbon monoxide, hydrogen gas, olefins, and C–H and C–O bonds) into valuable products (such as functionalized heterocycles, chiral carbonyl compounds and natural products). This thesis will describe our continual effort to achieve this goal. Part I describes the Pd-catalyzed functionalization of sp2 and sp3 C–H bonds. Carbon monoxide is used as a stoichiometric reductant in the cyclization of diarylnitroalkenes to afford biologically relevant 3-arylindoles and other N-containing heterocycles with carbon dioxide as the only stoichiometric byproduct. Also, an aryl sulfoxide moiety is shown to direct the arylation of sp3 C–H bonds to afford beta-functionalized amides. Part II describes the Ru-catalyzed sp3 C–O bond activation of alkoxypyridines and related heterocycles. In this transformation, an O- to N-alkyl migratory rearrangement occurs to afford N-alkylated pyridones which are structures found in many natural products and pharmaceutical agents. Part III describes our pursuit of metal-catalyzed asymmetric synthesis. Readily available benzylic bromides are carbonylated with carbon monoxide in alcoholic solvent mixtures. The resulting medicinally relevant 2-arylpropionic esters are obtained with moderate to good enantioselectivities. Preliminary results for the asymmetric hydrogenation of gem-diarylethylenes and novel ligand development are also disclosed. Part IV describes our efforts towards the total synthesis of 6-deoxyerythronolide B. Our retrosynthetic analysis of the macrolide antibiotic involves disconnections at the lactone linkage and between C7 and C8. The two equally complex fragments were prepared via reliable aldol, hydroboration, crotylation and redox chemistry. Rather than the typical macrolactonization method to form the 14-membered ring, we propose an alternative strategy where we plan to cyclize with a metal-catalyzed ring-closing metathesis event. Currently, this step is under investigation by other members in the group.

This thesis deals with the development and application of new synthetic methodology in organic chemistry. The first part describes the development of a new protocol for the synthesis of 3-pyrrolines by means of a microwave-assisted ring-expansion reaction of 2-vinylaziridines. In addition, this methodology is implemented as a key-step in a formal total synthesis of the antibiotic (-)-anisomycin. In the second part, a new methodology for the synthesis of arylglycines from Weinreb amides is described. In this procedure, a Grignard reagent is added to the iminium ion formed from the Weinreb amide upon treatment with a base. When a chiral amide is used, the nucleophilic addition proceeds with high diastereoselectivity. Finally, an easy and straightforward synthesis of α-amino amides via a base-mediated rearrangement of modified Weinreb amides into N,O-acetals is presented. Subsequent arylation, alkylation, alkenylation or alkynylation of this intermediate affords the corresponding α-amino amides in excellent yields. Furthermore, a more generalized protocol for the α-arylation of Weinreb amides lacking an α-amino moiety is also discussed. / QC 20100719

La cycloaddition [2+2] du dichlorocétène sur le 7-méthylcycloheptatriène conduit, après expansion de cycle au diazométhane et déshydrohalogénation, à une -chlorotriénone, ceci de manière très sélective. Cet intermédiaire s'est montré très efficace par le passé dans la synthèse de sesquiterpènes naturels possédant le squelette bicyclo[5.3.0]décane (guaianes, guaianolides, azulènes…). Nous avons utilisé cette méthodologie dans une approche synthétique des thapsigargines, des guaianolides naturels à la structure complexe dont un dérivé est à l'étude contre le cancer de la prostate. Nos recherches et notre savoir-faire nous ont permis d'accéder à un intermédiaire avancé pouvant mener à cette famille de composés, il possède les groupements, insaturations et configurations clé nécessaires. Il peut par ailleurs servir de plateforme idéale pour accéder à des azulènes naturels. Nous avons alors en paralèle synthétisé des azulènes bleu, violet et rouge (dont il s'agit de la première synthèse pour ces derniers) / The [2+2] cycloaddition of dichloroketene and 7-methylcycloheptatriene, followed by ring expansion with diazomethane and dehydrohalogenation, affords -chlorotrienone with high selectivity. In the past, this compound proved to be very efficient in the synthesis of natural sesquiterpenes containing the bicyclo[5.3.0]decane squeletton (guaianes, guaianolides, azulenes…). This methodology was used in an efficient synthetic approach of thapsigargins, which are complex guaianolides currently studied to treat prostate cancer via a derivative. Our work led us to get an advanced intermediate for this family, with key moities and configurations. It can also be used to access to natural azulenes. Then we synthetized blue, purple and red azulenes (the first ones for the latters).

A primeira parte deste trabalho teve como objetivo a síntese da (+)-baquenolida A empregando uma reação de contração de anel como etapa chave. A molécula alvo foi alcançada diastereosseletivamente em 15 etapas e com rendimento global de 6,2% a partir da cetona de Wieland-Miescher opticamente ativa, que foi preparada por meio de uma reação de anelação de Robinson assimétrica. Estudos realizados para a otimização da etapa chave exibiram melhores resultados quando trinitrato de tálio (TTN) foi empregado como oxidante. Contudo, o reagente de iodo(III) (diacetóxi)iodobenzeno (DIB) também pôde ser empregado para realizar esta transformação na presença de ácido ou quantidade catalítica de TTN, mas com baixos rendimentos. Foi estudada a oxidação de cis-octalinas e derivados com TTN em acetonitrila. A reação de diversos derivados de cis-octalinas com tálio(III) levou a diferentes produtos, dependendo principalmente do padrão de substituição do substrato. Os resultados mais promissores foram a obtenção de cis-hidrindanos funcionalizados a partir dos substratos 1,2,3,4,4a,5,8,8a-octa-hidro- 4a-metilnaftaleno e 1,2,3,4,4a,5,8,8a-octa-hidro-4a,7-dimetilnaftaleno. Considerando que o grupo metoxila é muito estável e mesmo assim a reação do substrato 1,2,3,4,4a,5,8,8a-octa-hidro-1- metóxi-6,8a-dimetilnaftaleno com TTN levou ao produto de contração em baixo rendimento, concluímos que a presença de grupos funcionais contendo oxigênio na posição C-1 prejudica o rearranjo oxidativo para a formação do produto de contração. A utilização de acetonitrila como solvente nas reações de oxidação de 1,2-dihidronaftalenos mediadas por TTN proporcionou a obtenção de produtos de contração a partir de substratos contendo ligação dupla trissubstituída. Uma vez que produtos de contração são isolados nas reações de di-hidronaftalenos trissubstituídos com tálio(III) ou com iodo(III) em acetonitrila, mas são obtidos apenas produtos de adição nas reações em metanol ou trimetilortoformiato, podemos concluir que o sucesso da reação de contração depende essencialmente da natureza do solvente. Finalmente, este trabalho apresenta os resultados obtidos durante a preparação do reagente de Koser [hidróxi(tosilóxi)iodobenzeno, HTIB] e derivados a partir de iodo molecular e arenos ou iodoarenos. O emprego de um procedimento \"one-pot\" em duas etapas foi uma boa alternativa para a preparação do HTIB a partir de benzeno, mas forneceu piores resultados que o procedimento em uma única etapa quando arenos contendo grupos doadores de elétrons foram utilizados como substratos. Não foi possível preparar derivados do reagente de Koser a partir de arenos contendo grupos retiradores de elétrons. De acordo com os resultados obtidos para a preparação de derivados do reagente de Koser a partir de iodoarenos, verificamos a promissora utilização de 1,1,1-trifluoroetanol (TFE) como co-solvente / The first part of this work aimed the synthesis of (+)-bakkenolide A employing a ring contraction reaction as key step. The target molecule was achieved, with high diastereoselectivity, in 15 steps and in 6.2% overall yield from the optically active Wieland-Miescher ketone, which was prepared by an asymmetric Robinson annulation. Studies to optimize the key step showed better results when thallium trinitrate (TTN) was used as oxidant. However, the iodine(III) reagent (diacetoxy)iodobenzene (DIB) could also be employed to promote this transformation in the presence of acid or catalytic amounts of TTN, but with low yields. We studied the oxidation of cis-octalins and derivatives with TTN in acetonitrile. The reaction of several cis-octalins derivatives with thallium(III) furnished different products, depending mainly on the substitution pattern of the substrate. The most promising results were the preparation of functionalized cis-hydrindanes from 1,2,3,4,4a,5,8,8a-octahydro-4amethylnaphthalene and from 1,2,3,4,4a,5,8,8a-octahydro-4a,7-dimethylnaphthalene. Since methoxy group is one of the more stable protecting groups for alcohols and still the reaction of the 1,2,3,4,4a,5,8,8a-octahydro-1-methoxy-6,8a-dimethylnaphthalene with TTN led to the ring contraction product in low yield, we conclude that the presence of oxygen-containing functional groups at the C-1 affect the oxidative rearrangement. The use of acetonitrile as solvent in TTN-mediated oxidation of 1,2-dihydronaphthalenes furnished ring contraction products from substrates containing trisubstituted double bond. Since ring contraction products are isolated in the reactions of trisubstituted dihydronaphthalenes either with thallium(III) or with iodine(III) in acetonitrile, but only addition products are obtained from reactions in methanol or in trimethylorthoformate, we concluded that the success of the ring contraction reaction dependes on the nature of the solvent. Finally, this thesis presents the results obtained during the preparation of the Koser\'s reagent [hydroxy(tosyloxy)iodobenzene, HTIB] and derivatives from molecular iodine and arenes or iodoarenos. The use of a one-pot two-step procedure was a good alternative for the preparation of HTIB from benzene, but gave worse results than the procedure in one-step when arenes containing electron donor groups were used as substrates. We could not prepare Koser\'s reagent derivatives from arenes containing electron-withdrawing groups. According to the results obtained for the preparation of Koser\'s reagent derivatives from iodoarenos, we could observe the promising use of 1,1,1-trifluoroethanol (TFE) as co-solvent.