We have successfully developed an efficient approach to 3,4-disubstituted £\,£]-unsaturated £_-lactams from glutarimide, and proved to be applicable for the synthesis of hydrocinchonine and hydrocinchonidine.

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.

The known 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones 122 were dehydrogenated using thallium(III) p-tolylsulfonate in dimethoxyethane under reflux to afford the 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136. Palladium-catalyzed Sonogashira cross-coupling of the 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones with terminal alkynes in the presence of PdCl2(PPh3)2-CuI (as homogeneous catalyst source) and 10% Pd/C-PPh3-CuI (as heterogeneous catalyst source) catalyst mixture and NEt3 as a base and co-solvent in ethanol under reflux afforded the corresponding 6,8-dialkynyl-2-aryl-2,3-dihydroquinolin-4(1H)-ones 138 and 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones 137, respectively. PdCl2-catalyzed electrophilic cyclization of the 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones in acetonitrile under reflux afforded the 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 or the 2-aryl-6-bromo-8-(4-hydroxybutanoyl)-2,3-dihydroquinolin-4(1H)-ones 140 from the 4-phenylethynyl-substituted or 4-alkylethynyl-substituted precursors, respectively. The 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136 wturn, subjected to similar homogeneous and heterogeneous palladium catalyst sources using NEt3 as a base in DMF-water mixture under reflux and K2CO3 as a base in dioxane under reflux afforded 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 143 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142, respectively. The monoalkynylated 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142 were subsequently transformed using palladium-catalyzed Suzuki-Miyaura cross-coupling with arylboronic acids in the presence of PdCl2(PPh3)2-PCy3 catalyst mixture and K2CO3 as a base in dioxane-water mixture to afford the corresponding novel 8-substituted 2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 141 and 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 144, respectively. All the new compounds were characterized using a combination of 1H NMR, 13C NMR, IR, mass spectroscopic techniques and X-ray crystallography. / Chemistry / D. Phil. (Chemistry)

This thesis focuses on the design and development of novel versatile diamido ligands for transition metal and main group element chemistry. The central concept of this work deal relied on the design of N, N'-disubstituted-1,8-diaminonaphthalene (H2RR’-DAN) as proligands to dianionic diamido ligand scaffolds. These ligands would then be employed for stabilization of main group element (e.g. Li, B, Al) and transition metal (e.g. Ti, Zn) compounds.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第20303号 / 薬科博第72号 / 新制||薬科||8(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 川端 猛夫, 教授 高須 清誠, 教授 竹本 佳司 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DGAM

This thesis focuses upon pacidamycin, a member of the uridyl peptide antibiotics, a family of antibiotics which exhibit an, as yet, clinically unexploited mode of action, against MraY. The Goss group has previously demonstrated the ease of accessing N and C-termini analogues of pacidamycin utilizing precursor directed biosynthesis. The central diamino acid is key to pacidamycin's activity, yet little work has been carried out, to date, to investigate the SAR around this moiety. Particularly this thesis describes work toward generating pacidamycin analogues using the complementary tools of organic synthesis and biosynthesis. Chapter 1 introduces natural compounds and their importance in clinical use, provides a brief overview of the history of antibiotics and focuses on the urgent need for new antibiotics displaying new chemical architectures and possessing novel modes of action. This chapter also introduces uridyl peptide antibiotics and overviews the SAR studies around these unusual peptides, focusing on pacidamycin in particular. Diaminobutyric acid is central to these structures and a discussion of a selection of published methods to synthesis α, β-diaminobutyric acid (DABA) is also presented. Chapter 2 describes the synthesis of DABA and two analogues, in which the C-methyl moiety has been substituted by an ethyl or a cyclopropyl group. The mutasynthesis approach utilised in the attempt to generate novel pacidamycins and discussion around the results observes is also described. Chapter 3 demonstrates a three step one-pot reaction to access 1,3-disubstituted urea molecules. The chapter starts with a brief overview of previously established methods in the literature to access these useful molecules, and then moves towards a discussion about the reaction optimisation. The chapter also describes a family of analogues generated utilising this novel approach; and exploring the use of these analogues in the mutasynthesis of pacidamycin. In order to access the desired pacidamycin analogues with the modified diamino acid residue, it was determined that it is currently not possible to use a mutasynthesis approach, instead an approach of total synthesis needed to be employed. Chapter 4 describes this total synthesis. The C- terminal urea motif was generated using a novel 1-pot phosphine free route developed during this study. To access the central native (2S, 3S)- DABA, a variation of the route of Merino et al's via Garner's aldehyde was initially utilised. Subsequently, a shorter and more flexible approach from Soloshonok et al via a Ni (II) Schiff base complex of glycine was adopted. Unpublished results from the Goss group have shown that the 2',3'dihydroxy uridine analogues in pacidamycin conferred broader spectra of activity. Work towards the synthesis of these analogues has been conducted. The order of assembly of the peptide and the nucleoside fragments was in alignment with Boojamra et al's approach. If the de-protection chemistry had worked according to plan, this would have resulted with a synthesis that is at least 6 steps shorter and higher yielding then Boojamra's. The introduction in this chapter reports the various methods previously reported in the literature for the total synthesis of pacidamycin. A discussion about the current progress in the total synthesis highlighting the difficulties faced is also shown. Chapter 5 demonstrates utilising semi-synthesis as a useful tool to generate novel pacidamycins by applying a Pictet-Spengler reaction on pacidamycin 4. This chapter starts with an overview of this phosphate mediated Pictet-Spengler reaction. In addition, a discussion about the large-scale fermentation of Streptomyces coeruleorubidus, the wild type producer of pacidamycin, and the generation of pacidamycin analogues utilising a semi-synthesis approach is also presented. Chapter 6 describes the future work following on from this study building upon each of the above chapters.

No description available.

This work is mainly concentrated on the development of new versatile ligand based on N,N’-disubstituted-1,8-diaminonaphthalene (1,8-DAN) for main group chemistry. Therefore, our initial efforts were made on the design of new ligand scaffold by using 1,8-DAN. Following that, new ligand family supported by 1,8-DAN was applied as ligands to main group elements (B, Al, In, Ga, and C). Furthermore, six-membered ring carbenes which are derived from the reaction between N,N’-disubstituted-1,8-diaminonaphthalene and carbon are also investigated. In addition, the stable carbenes were implied as a new ligand system for palladium, leading to the formation of metal ligand complexes. Therefore, the synthesis and reactivity of these complexes are also reported. Chapter I gives an explanation on the basic concepts in terms of the ligand designs and reports the reasons why N,N’-disubstituted-1,8-diaminonaphthalene has been chosen as the framework of for these ligands. Chapter II presents the approach to synthesize ligands depending on the substitution. Regarding this, three methods were successfully used: reductive amination, application of acyl halide followed by reduction, and copper catalyzed C-N coupling reactions. Chapter III describes the reactions between the N,N’-disubstituted-1,8-diaminonaphthalene and main group elements B, Al, Ga, and In in 13 group. In this chapter, a variety of mononuclear and dinuclear complexes are investigated and fully characterized. Furthermore, some computational studies are also reported for the comparison with experimental results. Chapter IV deals with new ligand family, carbene, which is derived from N,N’-disubstituted-1,8-diaminonaphthalene. Therefore, not only fundamental concepts for the NHC (N-heterocyclic carbene) are discussed but also synthetic pathways are introduced. Moreover, interesting features of free carbene are presented as well. Chapter V reports the potential of this new carbene ligand family as ligands for transition metal compound, especially, Pd(II) compounds. Several different pathways for synthesizing the desired metal carbene complexes are presented.

Darmstadt, Techn. Universiẗat, Diss., 2004. / Dateien im PDF-Format.

Les chimistes organiciens disposent à l'heure actuelle des outils de la biocatalyse afin d'accéder aux produits de la chimie fine et en particulier à des synthons et des molécules optiquement enrichies. Dans ce cadre, le travail de thèse présenté dans ce mémoire a été conduit afin d'enrichir notre connaissance sur une époxyde hydrolase (EH) découverte après analyse métagénomique d'un bio-filtre. Afin de pouvoir mener une étude de mutagénèse dirigée de sorte à améliorer certaines propriétés de cette enzyme appelée Kau2-EH, un modèle de l'enzyme a été élaboré sur la base de la structure tridimensionnelle de l'EH de souris. Le choix de cette matrice fait suite à des études d'inhibition comparées visant à déterminer laquelle des trois EHs, dont la structure tridimensionnelle était connue (pomme de terre, souris, homme) et dont la séquence était proche de celle de Kau2-EH, présentait l’inhibition la plus proche de celle observée pour Kau2-EH. Il avait été montré précédemment que Kau2-EH présentait un intérêt en biocatalyse permettant une résolution cinétique quasi-parfaite de l'oxyde de trans-méthyl-styrène et une transformation énantioconvergente, elle aussi quasi-parfaite, de l'oxyde de cis-méthyl-styrène. Ainsi des études de bioconversion dédiées à l'évaluation de la diversité des substrats de Kau2-EH ont été réalisées. Cette enzyme se révéla être particulièrement performante lors de l'utilisation d'époxydes cis- et trans-1,2-disubstitués portant sur un des atomes de carbone de la fonction époxyde un groupement phényle ou p-méthoxy-phényle et sur l'autre un groupement variable (méthyl- ou éthyl-ester, cyano, bromo- ou chloro-méthyle, phényle). Pour neuf des dix substrats testés des énantiosélectivités très élevées ont été trouvées permettant des résolutions cinétiques quasi-parfaites de huit d'entre eux et la désymétrisation quasi-parfaite du neuvième. Seul le cis-méthyl-glycidate ne fut pas un substrat de Kau2-EH. Dans les neufs cas précédents une réaction préparative à l'échelle du gramme a pu être conduite à très haute concentration en substrat (de 25 à 75 g/L) et sur une courte période de temps (de 1 à 4h) sauf pour l'oxyde de cis-stilbène (24 h). Finalement et afin d'accéder aux constantes cinétiques fondamentale, une étude préliminaire de « stopped-flow » du comportement de Kau2-EH a été réalisée en utilisant l'oxyde de trans-stilbène comme substrat. / Biocatalysis is nowadays an important tool available to organist chemist to get access to fine chemicals and especially enantiomerically enriched synthons and molecules. Within this framework, the PhD work described in this dissertation was conducted in order to get insights about a newly discovered epoxide hydrolase (EH) from a metagenomic analysis of a biofilter. In order to conduct directed mutagenesis on the so-called Kau2-EH, a model of the enzyme was constructed based on the 3D structure of murine EH. The choice of this template was dictated by comparative inhibition studies aimed at differentiating three otherwise closely Kau2-sequence-related EHs with known crystal structure (potato-, murine- and human-EHs) and showing inhibition behavior the closest to the one found for Kau2. The enzyme was previously shown to display interesting biocatalytic properties such a nearly perfect kinetic resolution of trans-methyl-styrene-oxide and a nearly perfect enantioconvergent transformation of cis-methyl-styrene-oxide. Thus, bioconversion studies dedicated to the evaluation Kau2-EH substrate chemical space were undertaken. The enzyme proved to be particularly useful when using 1,2-disubstituted cis- or trans-aromatic epoxides bearing an aromatic ring (phenyl, p-methoxy-phenyl) on one of the epoxide-bearing carbon atom and various chemical groups (methyl- or ethyl-esters, cyano, chloro- or bromo-methyl or phenyl) on the second carbon atom. For nine of the ten tested substrates very high enantioselectivities were observed allowing nearly perfect kinetic resolutions of eight of them and a nearly perfect desymmetrization of the ninth. Only cis-methyl-glycidate proved to be not a substrate of Kau2-EH. In the all other nine cases a preparative scale reaction could be conducted on the 1g scale, at high to very high substrate concentration (25 to 75 g/L) and in short periods of time (1 to 4h) except for cis-stilbene-oxide (24 h). Finally and in order to get access to fundamental kinetic constants, a preliminary stopped-flow analysis of Kau2-EH behavior was undertaken using trans-stilbene-oxide as substrate.