Small molecule libraries have become essential for the development of drug discovery campaigns and chemical genetics. The studies towards the synthesis of a small molecule library, based upon the cis-ring fused phenanthridine core I, will be described. The first section of this thesis examines the development and application of a novel intramolecular Heck cyclisation to the synthesis of core phenanthridine structure II, via precursor III (Chapter 2).The second section (Chapter 3) describes the extension of this methodology towards the development of a library of phenanthridines IV. This includes methodology designed to incorporate the key principles of diversity-oriented synthesis, namely appendage, stereochemical and skeletal diversity. The final part of this thesis (Chapter 4) describes the merging of these various methodologies to generate a small library of novel phenanthridine analogues. Preliminary biological evaluation of the phenanthridine library using whole organism zebrafish phenotyping, will also be discussed.

Thesis advisor: Marc L. Snapper / Chapter 1: The design of a novel first aid smart fabric that is linked to a biologically active molecule through an event specific cleavable linker is described. Successful functionalization of a cellulose filter paper fabric mimic and the synthesis of a linker which is potentially selectively cleavable in the presence of blood have been achieved. Chapter 2: Synthetic studies towards the total synthesis of Torilin, a sesquiterpene guaiane natural product with interesting biological activities are described. The synthesis of the hydroazulene core of Torilin is accomplished through a cyclopropanation/ Lewis acid mediated fragmentation of a highly functionalized polycyclic system which is rapidly accessed through the intramolecular cycloaddition of cyclobutadiene. / Thesis (MS) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Galanthamine is one of only a few drugs that is licenced for the treatment of Alzheimer's disease. It is manufactured through an inefficient synthetic process or extracted from members of the Amaryllidaceae plant family. In this work a range of structurally related alkaloids was semisynthesised from galanthamine and used as standards to assist with the search for alkaloids that may make a good starting point in the semisynthesis of galanthamine. The search was targeted on the effluent from the production line of Alzeim Ltd., a company that extracted galanthamine from members of the Narcissus genus. In addition to the above there was an examination of specific areas of galanthamine chemistry; focusing on the application of synthetic methodologies to open new chemical space. By far the most successful of these was the use of galanthamine in a urea-mediated intramolecular aryl migration. A rare example of lithiation chemistry being applied to a natural product and also the most complicated structure to date on which the intramolecular aryl migration has been performed.

The construction of benzylic quaternary stereocentres via the enantioselective copper-catalyzed 1,4-addition of dialkylzinc reagents to Meldrum’s acid acceptors in the presence of a phosphoramidite ligand is reported. Meldrum’s acid acceptors can be easily accessed and numerous derivatives have been prepared to investigate the scope of the enantioselective 1,4-addition. The reaction is tolerant to a wide range of heteroaromatic and functional groups. The significance of substituting the position para, meta, and ortho to the electrophilic centre is also highlighted. Primary and secondary organozinc reagents are shown to be compatible in this reaction. A highly enantioselective synthesis of carboxylic acid derivatives having an -quaternary centre through copper-catalyzed 1,4-addition of dialkylzinc reagents to aryl acetate derivatives is also described. This method employs a commercially available phosphoramidite ligand and readily accessible Meldrum’s acid acceptors. A brief insight into the observed selectivity is also discussed. The significance of this method was established by the expedient preparation of chiral diesters, succinimides, γ-butyrolactones, and isocyanates from highly functionalized benzyl Meldrum’s acids. In addition to 1,4-addition, the enantioselective asymmetric synthesis of benzylic tertiary and quaternary stereogenic centres via 1,6-addition of dialkylzinc reagents to Meldrum’s acid acceptors is outlined. This work represents one of the early examples of 1,6-asymmetric conjugate addition reactions and discussions on the regioselectivity of the process are disclosed. On a different subject matter, the occurrence and persistence of C–H•••X (O, S, Br, Cl, and F) bond in solution using 1H NMR spectroscopy is discussed for a large number of benzyl Meldrum’s acids. The latter are novel and reliable probes for the evaluation of this type of non-classical interactions in solution. The persistence of the C–H•••X bond in solution is demonstrated to be dependent upon structural features present on the aromatic moiety and the benzylic position of the benzyl Meldrum’s acid derivatives. The observations presented highlight the large potential of Meldrum’s acid in developing an understanding of the function and nature of C–H•••X interactions.

The construction of benzylic quaternary stereocentres via the enantioselective copper-catalyzed 1,4-addition of dialkylzinc reagents to Meldrum’s acid acceptors in the presence of a phosphoramidite ligand is reported. Meldrum’s acid acceptors can be easily accessed and numerous derivatives have been prepared to investigate the scope of the enantioselective 1,4-addition. The reaction is tolerant to a wide range of heteroaromatic and functional groups. The significance of substituting the position para, meta, and ortho to the electrophilic centre is also highlighted. Primary and secondary organozinc reagents are shown to be compatible in this reaction. A highly enantioselective synthesis of carboxylic acid derivatives having an -quaternary centre through copper-catalyzed 1,4-addition of dialkylzinc reagents to aryl acetate derivatives is also described. This method employs a commercially available phosphoramidite ligand and readily accessible Meldrum’s acid acceptors. A brief insight into the observed selectivity is also discussed. The significance of this method was established by the expedient preparation of chiral diesters, succinimides, γ-butyrolactones, and isocyanates from highly functionalized benzyl Meldrum’s acids. In addition to 1,4-addition, the enantioselective asymmetric synthesis of benzylic tertiary and quaternary stereogenic centres via 1,6-addition of dialkylzinc reagents to Meldrum’s acid acceptors is outlined. This work represents one of the early examples of 1,6-asymmetric conjugate addition reactions and discussions on the regioselectivity of the process are disclosed. On a different subject matter, the occurrence and persistence of C–H•••X (O, S, Br, Cl, and F) bond in solution using 1H NMR spectroscopy is discussed for a large number of benzyl Meldrum’s acids. The latter are novel and reliable probes for the evaluation of this type of non-classical interactions in solution. The persistence of the C–H•••X bond in solution is demonstrated to be dependent upon structural features present on the aromatic moiety and the benzylic position of the benzyl Meldrum’s acid derivatives. The observations presented highlight the large potential of Meldrum’s acid in developing an understanding of the function and nature of C–H•••X interactions.

The molecular conformations, potential energy functions and vibrational spectra of several cyclic molecules have been investigated by ab initio and density functional theory calculations and by infrared and Raman spectroscopy. The ab initio computations of 3-cyclopenten-1-ol predict that its lowest energy conformer has a weak pi-type intramolecular hydrogen bonding. The three other conformers lie 301 to 411 cm^-1 higher in energy. The infrared and Raman spectra of this molecule confirm the presence of the four conformers. The energy difference between the two conformers of lowest energy was also determined from the experimental spectroscopic data and was found to be 435 plus/minus 160 cm^-1, in reasonable agreement with the ab initio computations results. Ab initio calculations for cyclopentane and d1, 1,1-d2, 1,1,2,2,3,3-d6, and d10 isotopomers confirm cyclopentane confirmed that has twist and bent structures and that these differ in energy by less than 10 cm^-1. The bending angle is 41.5 degrees and the twisting angle is 43.2 degrees. A complete vibrational assignment for each of the isotopomers was achieved. Ab initio calculations were also carried out for methylcyclopropane, cyclopropylsilane, cylopropylgermane, cyclopropylamine, cyclopropanethiol and cyclopropanol. The structure and the potential energy function for internal rotation was calculated for each and compared to available experimental results determined from infrared and Raman spectra. The calculated barriers to internal rotation agree very well with the experimental data. The structures, relative energies, and frequencies for the lowest energy vibrations of the twisted, bent, and planar forms of cyclohexene and four of its oxygen analogs were calculated and compared to experimental results. The calculated structural data agree very well with that from the microwave work, but the computed barriers are somewhat lower than those based on far-infrared data. 4-Silaspiro-(3,3)-heptane possesses two four-membered rings, each puckered with and angle of 34 degrees. The molecule possesses a two-dimensional ring-puckering potential energy surface with four equivalent minima. The ab initio calculations predict a barrier to planarity of each ring of 582 cm^-1 while the energy of the structure with both rings planar is 1220 cm^-1 higher. The calculated infrared and Raman spectra were compared to those previously published, and the agreement is excellent.

In the last decade, there has been a surge of interest from the chemistry community in developing synthetic catalysts that emulate the remarkable rate accelerations observed for enzymatic reactions. One approach utilized by enzymes involves preorganization of substrate(s) using a favourable binding event to orient the substrate(s) in a reactive arrangement. Although the “induced intramolecularity” is entropically unfavourable, it is facilitated by the enzymes and utilized to accelerate the subsequent chemical transformation. Chemists have often used a conceptually related stepwise approach in which temporary tethers are assembled to induce a temporary intramolecularity. This preorganization often enables difficult intermolecular reactions, and typically leads to increased regio-, chemo-, and stereoselectivity in chemical reactions. Seeking to develop a catalytic approach, we focused our efforts in developing a mild, carbonyl-catalyzed hydration protocol for - and -amino nitriles to give the corresponding - and -amino amide and acid. This work highlights the value of employing induced intramolecularity in accessing structurally important chemical motifs that otherwise require harsh reaction conditions. Additionally, this thesis presents the background material, design process, optimization and scope of this reactivity.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第13828号 / 工博第2932号 / 新制||工||1433(附属図書館) / 26044 / UT51-2008-C744 / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 檜山 爲次郎, 教授 大嶌 幸一郎, 教授 松原 誠二郎 / 学位規則第4条第1項該当

Neste trabalho, realizou-se a síntese e a caracterização de quatro novas bases de Tröger. Estes compostos pertencem à classe de heterociclos 2-hidroxifenibenzazóis, que caracterizam-se por apresentar uma forte emissão de fluorescência, devido à reação de transferência protônica intramolecular no estado excitado -ESIPT- por eles sofrrida quando excitados por luz ultravioleta. Os heterociclos sintetizadosapesentam ligações de hidrogênio intramolecular entrte o nitrogênio azólico e a hidroxila fenólica e um granded deslocamento de Stokes, características tíicas de compostos que sofrem a ESIPT. As bases de Tröger, que são quirais, são bem conhecidas como receptores moleculares devido a concavidade que estas moléculas apresentam, Os compostos obtidos são os primeiro exmeplos de bases de Tröger fluorescentes, via ESIP, na literatura, por isso, despertam grande interesse na síntese de sondas biológicas moleculares fluorescentes. A partir da resolução quiral das bases de Tröger, estas potencialmente podem vir a ser utilizadas como indutores quirais e/ou par ao reconhecimento enantiosseletivo do DNA. A resolução quiral foi feita para uma das bases de Tröger sintetizadas.