We have developed an one-pot reaction procedure to polysubstituted pyroglutamates with three contiguous chiral centers. The results were applied to the synthetic studies toward kainic acid and lycorane.

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Carbon skeleton of polysubstituted pyroglutamates with three contiguous asymmetric centers was built up in one base-induced coupling/cyclization reaction of £\-sulfonylacetamide with 2-bromo-2-propenoates and has been used as the key step in the formal synthesis of isoguvacine paroxetine, and psudoheliotridane.

Reaction of 3-sulfonyl acetamides with various substituted methyl acrylate derivatives furnished pyroglutamate and glutarimidess via [3+2] and [3+3] cycloaddition respectively. The results were applied to the synthesis of pyrrolizidine skeleton, tylophorine, cryptopleurine and fused bicyclic glutarimides.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第20192号 / 理博第4277号 / 新制||理||1615(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 依光 英樹, 教授 丸岡 啓二, 講師 西村 貴洋 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第20944号 / 理博第4396号 / 新制||理||1631(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 依光 英樹, 教授 丸岡 啓二, 教授 大須賀 篤弘 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Brevisamide was isolated from the red tide dinoflagellate Karenia brevis in 2007. Key features of brevisamide include a substituted tetrahydropyran core and conjugated 3,4-dimethylhepta-2,4-dienal side chain. Total synthesis of brevisamide was highlighted by a stereoselective [4+2]-annulation of a (Z)-crotyl silane to furnish the substituted pyran core and Negishi cross-coupling to construct the conjugated dienal side chain. Successful application of the silane-based annulation methodology provided brevisamide in overall 17 steps and 6.4% overall yield from the known (Z)-crotyl silane. Isatisine A was isolated from the leaf and roots of Isatis indigotica in 2007. Total synthesis of isatisine A commenced with the development of a silyl-directed Mukaiyama-type [3+2]-annulation of an ethoxy allylsilane to construct a tetrahydrofuran core. [3+2]-Annulation reaction of an ethoxy allyl silane with 2-bromocinnamylaldehyde afforded the furan core as a single diastereomer. Further substrate-controlled indole addition and intramolecular copper(I)-mediated amidation provided (+)-isatisine A in overall 12 steps. One-pot Diels-Alder/annulation sequence was developed utilizing a silane-substituted 1,3-diene to give a fused-cyclic scaffold. In this reaction sequence, initial Lewis-acid-promoted Diels-Alder reaction between the silyl-substituted diene and a naphthoquinone constructed an intermediate cyclic allylsilane, and subsequent addition of aldehyde and Lewis acid triggered the annulation to construct a complex cyclic compound with high diastereoselectivity. This one-pot three component reaction sequence allowed for a simple access to various fused-polycyclic compounds, which bear a tetrahydropyran core. Leiodolide A was isolated from the deep-water marine sponge Leiodermatium. Leiodolide A was found to be significantly cytotoxic against HCT-116 human colon carcinoma with IC50 values = 1.4 ug/mL (2.5 uM). Since the natural product leiodolide A was found to comprise less than 0.001% of the dry weight of the sponge, establishing an efficient synthetic method to provide a significant amount of the natural product would be valuable to further biological studies. Our effort to synthesized upper fragment of leiodolide A was conducted through a series of cross-coupling reactions involving Stille coupling. Although proper conditions for the oxidation of (Z)-olefin to introduce the contiguous C15-17 triol system in leiodolide A were not achieved, this synthetic pathway would be useful in the total synthesis of leiodolide A.

This thesis deals with the development and application of new synthetic methodology for stereo- or regioselective construction of carbon-carbon bonds in organic synthesis. The first part of this thesis describes the development of a divergent protocol for stereoselective synthesis of chiral aminodiols by employing Mukaiyama aldol additions to syn- and anti-α-amino-β-silyloxy aldehydes. The stereoselectivity of the nucleophilic attack is governed by either chelation to the α-amino moiety or by nucleophilic attack in the Felkin-Anh sense. This study is also directed towards the elucidation of the factors that dictate aldehyde π-facial selectivity in substrate-controlled nucleophilic additions to these and similar systems. In the second part, a highly stereoselective [3 + 2]-annulation reaction of N-Ts-α-amino aldehydes and 1,3-bis(silyl)propenes for stereoselective construction of densely functionalized pyrrolidines is presented. In addition, this methodology is also implemented as a keystep in a synthetic approach towards the polyhydroxylated pyrrolidine and pyrrolizidine alkaloids DGDP and (+)-alexine from a common late pyrrolidine intermediate. Finally, a divergent protocol for regioselective opening of vinyl epoxides using alkyne nucleophiles is described, in which the regioselectivity of the nucleophilic attack is controlled by the choice of reaction conditions. The regioselectivities of the SN2 and SN2’ processes are, however, significantly influenced by the nature of the alkyne substituents and the best results are obtained using ethoxyacetylene. The SN2 opening of vinyl epoxides with ethoxyacetylene as nucleophile is also shown to provide a straightforward entry to functionalized γ-butyrolactones. / QC 20100917

Cette thèse est constituée de trois parties : 1) Le contexte bibliographique, 2) le développement de réactions domino cupro-catalysées et 3) une approche vers la synthèse totale des raputindoles.La première partie introduit d’abord le concept de réactions domino ainsi que leurs applications, puis les réactions catalysées par du cuivre permettant de former des liaisons C-N sont passées en revue en incluant les couplages de Ullmann, Goldberg et de Chan-Lam, les séquences d’activation oxydante de liaisons C-H/formation de liaison C-N, l’insertion de nitrènes et l’hydroamination de liaisons C-C multiples. En se basant sur ces réactions élémentaires permettant de former une liaison C-N unique, les développements récents de réactions domino sont ensuite détaillés.La deuxième partie peut être subdivisée en 3 sections : 1) la synthèse de benzimidazoles, 2) la synthèse d’imidazoles and 3) la synthèse de guanidines. Un rappel des méthodes existantes pour la synthèse de ces motifs est proposé dans chaque section. Notre travail, basé sur la formation de liaisons C-N multiples selon une séquence cupro-catalysée domino, est ensuite détaillé. Celui-ci nous a permis d’aboutir au développement de voies d’accès aux benzimidazoles, en utilisant une réaction séquentielle catalysée par du cuivre en présence d’oxygène à partir d’acides boroniques et d’amidines, à la synthèse d’imidazoles par une réaction de di-amination d’alcynes vrai par des amidines et à l’obtention de guanidines et de 2-aminobenzimidines par une réaction à 3 composant. Ces réactions domino montrent une bonne efficacité et permettent d’assembler des hétérocycles à partir de précurseurs aisément accessibles.La dernière partie est consacrée à la synthèse des raputindoles. La structure, les activités et les réactions clé pour la construction de ces alcaloïdes sont discuté d’abord, nous amenant à proposer une rétrosynthèse pour accéder à ces molécules. Les réactions qui ont retenues notre attention pour construire ces molécules sont une annelation [3+2] irido-catalysée d’acides o-formylarylboronique et de 1,3-diènes, la synthèse de Leimgruber-Batcho pour obtenir des indoles et une séquence d’alkylboration-protodéboration. A partir de cela 3 stratégies ont été évaluées, montrant que l’accès à ce type de composé naturel est envisageable en combinant ces étapes. / This thesis consists in three parts: bibliographic background, copper-catalyzed reactions for synthesis of N-containing compounds, approach to the synthesis of raputindoles.The first part introduces the domino reactions and their applications, then, copper-mediated reactions for construction of C-N bond formation are reviewed including Ullmann, Goldberg and Chan-Lam coupling, oxidative C-H activation/C-N formation, insertion of nitrenes and carbenoids, and hydroamination of multi-C-C bonds. This can be used as guides to design domino reaction. Following these copper-mediated single C-N bond formation reactions, recent developments of copper-catalyzed domino reactions for synthesis of heterocycles are described.The second part can be divided into three sections: 1) synthesis of benzimidazoles, 2) synthesis of imidazoles and 3) synthesis of guanidines. Each section summarizes the existing methods used for their synthesis. Following it, our synthetic work involving copper-catalyzed C-N bond formation domino reactions is discussed in detail. Our objectives include the synthesis of benzimidazoles through copper-catalyzed sequential reaction of benzamidines and boronic acids, synthesis of imidazoles via copper-catalyzed domino reaction of benzamidines and acetylenes, and synthesis of guanidines and 2-aminobenzimidazoles by Cu-catalyzed three-component reaction of cyanamides, boronic acids and amines. These copper-catalyzed domino reactions show high efficiencies from readily available and simple starting materials.The last part is about the total synthesis of raputindoles. The structure and bioactivities of raputindoles and key reactions for the total synthesis of raputindoles are introduced first, the synthetic strategies are then proposed on basis of relative synthetic methods. The key reactions we use for the synthesis of raputindoles are iridium catalyzed [3+2] annulation of o-formylarylboronic acids and 1,3-dienes, Leimgruber-Batcho indole synthesis, transition-metal catalyzed SN2 substitution and alkylborylation-protondeborylation. According to the three strategies we proposed, lots of relative reactions were investigated. The results show that it is possible to synthesize the raputindole molecules based on the iridium catalyzed [3+2] annulation of 2-formylarylboronic acids and 1,3-dienes.