We use stepwise [3+3] annulation to prepare the asymmetric glutarimides, and then we can build substituent group in C6 position after choosing regioselective addition reaction. And we establish a new approach to benzo[h]quinoline skeleton starting from glutarimides via ring-closing reaction. Finally, we applied this method to the synthetic studies toward benzo[h]quinoline derivatives.

As reações de adição aldólica entre a cetimina 1 e aldeídos aromáticos foram inicialmente efetuadas à temperatura ambiente, em sistema bifásico constituído por uma fase aquosa básica (KOH 10% ou NaOH 5% m/v) e por uma fase orgânica (aldeído), na ausência de solventes e de catalisadores, observando-se baixa conversão em produto. Porém, quando se utilizou o catalisador aliquat®-336, foi possível reduzir a concentração da base (NaOH 1%), com conversão total da imina em produto que, na maioria dos casos, era uma mistura de duas oxazolidinas isoméricas de estereoquímica cis e trans. Esses compostos puderam ser isolados e purificados por recristalização de etanol ou metanol. Em todas as reações efetuadas com benzaldeído, m-clorobenzaldeído e p-nitrobenzaldeído, não se observou excesso diastereomérico significativo. No entanto, as reações com p-clorobenzaldeído mostraram-se diastereosseletivas, conduzindo, à temperatura ambiente, quase que exclusivamente à oxazolidina de estereoquímica cis. A comparação entre o resultado de reações efetuadas a curto e longo tempo de reação, ou em diferentes temperaturas, permitiu concluir que o aldol de estereoquímica anti é o produto cinético, o qual se transforma lentamente na oxazolidina cis. O produto termodinâmico (aldol syn) cicliza rapidamente, não sendo observado nos espectros de RMN de H dos produtos brutos de reação, mas sim seu produto ciclizado, a oxazolidina trans. Tentativas de obter os produtos de reação com excesso enantiomérico, pelo emprego de catalisadores de transferência de fase assimétricos, não foram bem sucedidas. / The aldol addition reactions of ketimine 1 with four aromatic aldehydes could be performed at room temperature, in the presence of an alkaline aqueous solution (KOH 10% or NaOH 5% m/v), and in the absence of organic solvents or catalysts. Under this conditions, conversion to product was often incomplete. However, when the reaction was performed in the presence of aliquat®-336, the base concentration could be reduced (1% m/v), and the ketimine was completely converted into a mixture of diastereomeric oxazolidines, that could be isolated and purified by crystallization from ethanol or methanol. Although no significative diastereomeric excess was observed for the reactions of 1 with benzaldehyde, m-chlorobenzaldehyde or p-nitrobenzaldehyde, for reactions with p-chlorobenzaldehyde the cis oxazolidine was almost exclusively formed. The comparison of diastereomeric ratio at shorter or longer reaction times seems to indicate that the aldol anti adduct is the kinetic product and that cyclization to the corresponding cis oxazolidine is slower than the retro-aldol reaction. On the other hand, in lieu of the thermodynamic product (aldol syn), only the corresponding cyclized product (oxazolidine trans) could be visualized in the H NMR spectra of the crude product, as a result of a fast cyclization step. Attempts to produce enantiomeric enriched oxazolidines by performing the aldol reactions in the presence of chiral catalysts were unsuccessful.

We can construct asymmetric glutarimide while using [3+3] annulation.Then we can build substituent group in C6 position after choosing regioselective addition reaction, and then apply it to synthetic studies toward polysubstituted pyridin-2-ones and Vitamin B6 derivatives.

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As reações de adição aldólica entre a cetimina 1 e aldeídos aromáticos foram inicialmente efetuadas à temperatura ambiente, em sistema bifásico constituído por uma fase aquosa básica (KOH 10% ou NaOH 5% m/v) e por uma fase orgânica (aldeído), na ausência de solventes e de catalisadores, observando-se baixa conversão em produto. Porém, quando se utilizou o catalisador aliquat®-336, foi possível reduzir a concentração da base (NaOH 1%), com conversão total da imina em produto que, na maioria dos casos, era uma mistura de duas oxazolidinas isoméricas de estereoquímica cis e trans. Esses compostos puderam ser isolados e purificados por recristalização de etanol ou metanol. Em todas as reações efetuadas com benzaldeído, m-clorobenzaldeído e p-nitrobenzaldeído, não se observou excesso diastereomérico significativo. No entanto, as reações com p-clorobenzaldeído mostraram-se diastereosseletivas, conduzindo, à temperatura ambiente, quase que exclusivamente à oxazolidina de estereoquímica cis. A comparação entre o resultado de reações efetuadas a curto e longo tempo de reação, ou em diferentes temperaturas, permitiu concluir que o aldol de estereoquímica anti é o produto cinético, o qual se transforma lentamente na oxazolidina cis. O produto termodinâmico (aldol syn) cicliza rapidamente, não sendo observado nos espectros de RMN de H dos produtos brutos de reação, mas sim seu produto ciclizado, a oxazolidina trans. Tentativas de obter os produtos de reação com excesso enantiomérico, pelo emprego de catalisadores de transferência de fase assimétricos, não foram bem sucedidas. / The aldol addition reactions of ketimine 1 with four aromatic aldehydes could be performed at room temperature, in the presence of an alkaline aqueous solution (KOH 10% or NaOH 5% m/v), and in the absence of organic solvents or catalysts. Under this conditions, conversion to product was often incomplete. However, when the reaction was performed in the presence of aliquat®-336, the base concentration could be reduced (1% m/v), and the ketimine was completely converted into a mixture of diastereomeric oxazolidines, that could be isolated and purified by crystallization from ethanol or methanol. Although no significative diastereomeric excess was observed for the reactions of 1 with benzaldehyde, m-chlorobenzaldehyde or p-nitrobenzaldehyde, for reactions with p-chlorobenzaldehyde the cis oxazolidine was almost exclusively formed. The comparison of diastereomeric ratio at shorter or longer reaction times seems to indicate that the aldol anti adduct is the kinetic product and that cyclization to the corresponding cis oxazolidine is slower than the retro-aldol reaction. On the other hand, in lieu of the thermodynamic product (aldol syn), only the corresponding cyclized product (oxazolidine trans) could be visualized in the H NMR spectra of the crude product, as a result of a fast cyclization step. Attempts to produce enantiomeric enriched oxazolidines by performing the aldol reactions in the presence of chiral catalysts were unsuccessful.

De nos jours, une des stratégies majeures dans la modulation de la pharmacocinétique des composés bioactifs est leur vectorisation et l’obtention de formes prodrogues. Ce travail est centré sur la vectorisation d’antitumoraux phosphorés à l’aide de peptides favorisant le passage membranaire. Nous avons alors réalisé la conjugaison d’aminoalkyl-bisphosphonates avec des séquences peptidiques afin de modifier leur temps de rétention dans l’organisme et d’augmenter leur internalisation cellulaire. Différents espaceurs possédant un motif carbonylé insaturé ont été évalués dans le couplage par la réaction d’addition aza- et thiaMichael afin d’aboutir à l’obtention d’un conjugué peptide-alendronate. Une approche prodrogue a également été réalisée avec la synthèse de dérivés de type bisphosphinates et l’obtention d’un analogue de l’alendronate. / Nowadays, one of the main strategies for pharmacokinetic modifications of bioactive compounds is their vectorization and the synthesis of prodrug derivatives. This work is focused on the vectorization of phosphorus antitumor agents with cell-penetrating peptides. We have then conjugated aminoalkyl-bisphosphonates with peptidic sequence to modify their retention time and increase their cellular internalization. Several linkers bearing an insaturated carbonyl moiety have been evaluated in conjugation by aza- and thia-Michael addition reaction to obtain a conjugated peptide-alendronate compounds. A prodrug approach has been conducted with the synthesis of bisphosphinate derivatives and an analog of alendronate has been obtained.

Aminoalcohols are very important compounds used in various asymmetric transformations as chiral ligands or chiral auxiliaries. In this thesis, four novel heterocyclic amine substituted chiral 1,4-aminoalcohols were synthesized. In the synthetic strategy, amide esters were synthesized from (2S, 3R)-3-methoxycarbonylbicyclo[2.2.1]hept-5-ene-2-carboxylic acid by DCC coupling method. Subsequent reduction of these amide esters lead to target 1,4-aminoalcohols. The activities of these novel chiral 1,4-aminoalcohols were tested in enantioselective diethylzinc addition, Mukaiyama aldol and Diels-Alder reactions. The enantioselectivities were measured by HPLC. All the products were identified by H NMR and C NMR spectroscopy

Amino alcohols are valuable bioactive substances and frequently used as chiral catalyst in various asymmetric transformation reactions. In the synthetic route, the asymmetric synthesis of novel chiral N,N-dialkyl substituted chiral 1,4-amino alcohols are performed starting with meso-anhydride 38. Quinine-mediated desymmetrization of the anhydride with methanol afforded (2S,3R)-cis-monoester 39 with a high enantiomeric excess (up to 98% ee). Chemoselective amidation of hemiester with various N,N-dialkyl substituted amines resulted in amido esters and they were subjected to LAH reduction to afford chiral 1,4-amino alcohol ligands. The activities of the chiral ligands, (2S,3R)-43, (2S,3R)-44, (2S,3R)-45, (2S,3R)-46 were tested in various asymmetric transformation reactions, i.e. asymmetric diethylzinc addition and asymmetric Diels-Alder reactions. Keywords: 1,4-Amino alcohols, chiral ligand, asymmetric diethylzinc addition reaction, Diels-Alder reaction

Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第16808号 / 工博第3529号 / 新制||工||1534(附属図書館) / 29483 / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 杉野目 道紀, 教授 村上 正浩, 教授 吉田 潤一 / 学位規則第4条第1項該当

The synthesis of a series of 2-chloropyrimidine derivatives is described. The synthesis began with a nucleophilic addition of lithiated heterocyclic molecules to the 4 position of 2-chloropyrimidine to give dihydropyrimidine intermediates. The intermediates were oxidized to the pyrimidine ring using the DDQ method. This was followed by an addition-elimination reaction of an amine to the 2-chloropyrimidine derivative. The structure and properties of the final compounds were analyzed by melting point, combustion analysis, and 13C-NMR and 1H-NMR spectroscopy. Biological activities in vitro of the synthesized compounds as antagonists of the 5-HT2a and 5-HT7 receptors were determined by an independent laboratory.