Nature’s biodiversity is complex and filled with beauty and wonder which are all observable on the macroscopic scale. This exquisiteness of nature’s intricacies are mirrored on the molecular level such that substances, large or small, are assembled to serve as signaling molecules, protective agents, and fundamental composites of higher-order frameworks for the operation and survival of life. Over the years, chemists have isolated and synthesized these molecules, known as natural products, to understand and evaluate their functions in biology and potential for medicinal applications. Although bioactive natural products demonstrate medicinal promise, poor pharmacological effects require further derivatization because semisynthesis is not sufficient to refine adverse pharmacokinetics. For some active molecules, isolation results in poor yields. In addition to small quantity isolation, many natural products, reflecting the immense complexity of biology itself, pose difficult synthetic challenges to organic chemists because of skeletal heterogeneity, stereochemical complexity, and substitution divergence. As a result of these synthetic obstacles to natural product utilization, improvements are needed in current chemical approaches, and new innovative methodologies for synthesis and chemical space exploration are necessary. Pharmaceutically relevant frameworks, natural products, and synthetic biologically active molecules are comprised of polycarbocyclic and heterocyclic scaffolds. Traditionally, cycloadditions, transannular transformations, and annulation reactions serve as powerful methods for polycyclic formation. In order to assemble diverse polycycles, donor-acceptor cyclopropanes are useful, versatile synthetic equivalents for C-C bond formations. By taking advantage of the strain within these unique, polarized systems, differing molecular architectures can be accessed directly to perform contemporary organic synthesis. Moreover, the donor-acceptor cyclopropanes initially utilized in these studies provided a fundamental basis for new methods to synthesize other relevant scaffolds. Unique, efficient, Lewis acid-catalyzed intramolecular cyclization strategies for the construction of functionalized polycycles using Friedel-Crafts-type alkylation sequences are presented to expand the reaction repertoire of the molecular architect. Generally, products were formed from commercially-available starting materials in high yields with broad scope. The methodologies were demonstrated to be modular, operationally simple, and amenable to different substitution patterns and functional groups to afford tetrahydroindolizines, heteroaromatic cyclohexenones, hydropyrido[1,2-a]indoles, pyrrolo[1,2-a]indoles, pyrrolo[3,2,1-ij]quinolines, pyrrolizines, and tetrahydrobenzo[ij]quinolizines. To demonstrate the utility of the methodologies devised, progress toward, (±)-rhazinicine, a natural product, is discussed. This dissertation is organized into six chapters: (1) an introduction, paradoxical stress and molecular strain’s utility in synthesis; (2) annulation reactions for the formation of heteroaromatic cyclohexenones; (3) hydropyrido[1,2-a]indole formation via an In(III)-catalyzed cyclopropane ring-opening/Friedel-Crafts alkylation sequence; (4) tetrahydroindolizine formation and progress toward the total synthesis of (±)-rhazinicine (5) pyrrolo[1,2-a]indole synthesis using a Michael-type Friedel-Crafts cyclization approach; and (6) a versatile protocol for the intramolecular formation of functionalized pyrrolo[3,2,1-ij]quinolines.

This PhD thesis is focused on the development of novel low-oxidation state main group catalysis for organic synthesis. More specifically, the major objective has been to explore and design non-toxic and effective catalysts based on the following isoelectronic species: nitreones [nitrogen(I)], carbones [carbon(0)], and silylones [silicon(0)]; the corresponding central nonmetal atom in these molecules is in the formal low-oxidation state ‘+I’ and ‘0’, respectively. These species have been calculated to be strong Lewis and Brønsted bases. In addition, compared with established base catalysts such as N-heterocyclic carbenes (NHCs), nitreones, carbones, and silylones formally possess an additional lone pair of electrons at the central atom. In turn, these species may be used in base catalysis or as ligands in metal catalysis, and in the context of frustrated Lewis pair (FLP) or dual catalysis. The Lewis basicity of these N(I), C(0), and Si(0) compounds has been assessed with 11B NMR analysis using a variety of boron Lewis acids. These boron binding data have been compared with results obtained using NHCs as a Lewis base. Nitreones –more specifically cyclopropen-imines– have been explored in base catalysis. These N(I) Lewis bases have been uncovered to catalytically activate a variety of silicon-based pro-nucleophiles for subsequent bond formation with carbonyl and imine derivatives as well as aziridines. Successfully used pro-nucleophiles include TMS–CN, TMS– CF3, TMS–N3, and TMS–Cl. The characteristic features of this unprecedented cyclopropenimine Lewis base catalysis include low catalyst loading, mild reaction conditions, and broad substrate scopes. Various “normal” imines have proved to be catalytically inactive under the same conditions. In a similar context, carbones and silylones have been used to develop novel catalytic umpolung reactions, which turned out to be too challenging at this stage. Importantly though, silylones have been shown to activate the B–H bond of suitable pro-nucleophiles. Finally, several carbone–metal complexes have been synthesized and characterized. These novel species may be used in Lewis acid or dual catalysis after appropriate activation of the corresponding metal site.

The first comprehensive account of Diels-Alder reactions occurring by a simultaneous self-assembly of the components and catalysis of the reaction via a Lewis Acid (LA) is presented in this study. The synthetic usefulness of the intramolecularity achieved by temporary connection of DA reaction components has been combined with the benefits of LA catalysis to overcome the regio- and stereochemical diversities associated with DA reactions of unsymmetrically substituted dienes and dienophiles. LA's employed in this study act both as temporary connectors (by binding to LB sites of the diene and dienophile) and as catalysts (by complexation to oxygen of carbonyl moieties of the dienophiles). Formation of the tether, cycloaddition; and removal of the transient linker all occurs in a single operation.* To illustrate the high selectivity accomplished in this approach, an experimental model system consisting of unsymmetrically substituted dienol 6 and methoxy diene 397 and an unsymmetrically substituted dienophile (methyl acrylate, MAC) was designed. Thermal combination of either of these two dienes with MAC produces nearly equimolar mixtures of all four possible adducts illustrating the unselective nature of the reactions. Use of LA's to mediate the reaction between dienol 6 and MAC results in exclusive regio- and stereoselective formation of a single adduct. In contrast, application of the same LA's for the reaction between the methoxy diene and MAC either results in the formation of two 'endo' regioisomers in low yield or no reaction at all.* Exclusive formation of a single adduct for the reactions of 6 is attributed to a process in which the LA both pre-organizes the reactants and catalyzes the cycloaddition. This phenomenon is not expected to be observed in the reactions of the methoxy diene. The difference in the behavior of the two dienes is ascribed to the difference in their interactions with the LA's. Dienol 6 is able to bind covalently and irreversibly to the LA's while methoxy diene 397 is only able to co-ordinate to the LA's in a reversible manner. Mechanistic studies strongly support the self-assembled pathway and exclude other potential routes. Reactions of dienol 6 with other structurally suitable dienophiles under similar LA mediated conditions exhibit higher selectivities and reactivities in comparison with their uncatalyzed counterparts. Use of a structurally similar chiral dienol induces a highly diastereoselective cycloadditions with different dienophiles, whereas the thermal versions of the reactions again produce all possible adducts. The strategy has also been used for DA reactions of ' 2H'-thiopyran dienols with dienophiles 'N'-acroyl-2-oxazolidinone (NAO), ('E')-3-[3-(methoxycarbonyl)propenoyl]-1,3-oxazolidin-2 -one (MCPO), and 'N'-phenylmaleimide (NPM). Use of MgII is demonstrated to be effective to stereoselectively catalyze reactions which are unselective thermally or do not proceed at all. *Please refer to dissertation for diagrams.

A series of new “frustrated Lewis pairs” (FLPs), including chiral versions, with a predefined spatial relationship between the basic and acidic centers is proposed. Several synthetic protocols toward the targets were investigated: through an aryllithium-haloborane coupling; using organotin reagents and a chiral diazaborolidine; and through organoboranes RBH₂ as the boron component. Further development of the project is discussed in light of the discovered data. The intermolecular system consisting of 8-bromo-2-methylquinoline and (C₆F₅)₃B was shown to exist in the form of an FLP. This FLP is not capable of heterolytic H-H bond cleavage with formation of an isolable adduct either at 1 atm or at 4 atm of H₂.

Improved procedures for the glycosylation of serine and threonine utilizing Schiff base activation are reported. The procedures are less expensive and more efficient alternatives to previously published methods. The Schiff bases exhibited ring-chain tautomerism in CDCl₃ as shown by ¹H NMR. Acting as glycosyl acceptors, the Schiff bases reacted at RT with simple sugar peracetate donors with BF₃•OEt₂ promotion to provide the corresponding protected amino acid glycosides in good yields. With microwave irradiation, the reactions were complete in 2-5 minutes. Glycosylation with the dipeptide Schiff base shows the potential of this method in the preparation of peptide building blocks. To investigate this reaction further, direct glycosylation of sugar acetates with FMOC-Ser-OH/OBZl under BF₃•OEt₂ promotion in a microwave provided glycosides in high yield. In addition to the expected glycoside products acetylated side products resulting from acetate migration were isolated, suggesting that activation of the anomeric sugar acetates with a Lewis acid such BF₃•OEt₂ led to an oxocarbenium ion, which rearranged to a 1,2-dioxocarbenium ion because of the acetate participating group at C-2. Solvent participation was also illustrated with acetate migration being more pronounced when CH₃CN was used as a solvent and resulted in less product yield and higher amounts of the acetylated product. The acyl transfer products in these reactions where sugar acetates serve as glycosyl donors is reported for the first time, which also implies that ortho-ester like intermediates are important in the reaction mechanism. Keeping the message segment constant in the sequence H-Tyr-DThr-Gly-Phe-Leu- Ser-CO-NH₂ and modification of the address segment with different carbohydrate moieties had little effect on selectivity for binding at the μ, δ, or κ-opiod receptors. However, substitution of D-threonine with D-serine or the less polar D-alanine in the message segment resulted in a loss of κ-receptor affinity. Further replacement of D-threonine with the more hydrophobic D-valine resulted in complete loss of κ-binding affinity generating pure μ-δ agonists. These data suggests that changes in the message segment of the pharmacophore results in the glycopeptide adopting a conformation that is less favorable for 􀀁-binding receptor activity. Finally, the peripheral administration and i.c.v. tests of the drugs suggest that modifications in the message segment of the pharmacophore influences the potency of these compounds.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第22454号 / 工博第4715号 / 新制||工||1736(附属図書館) / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 松原 誠二郎, 教授 杉野目 道紀, 教授 中尾 佳亮 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

<p> This thesis describes an investigation into the effects of Lewis acid complexation on the photochemistry of α,β unsaturated carbonyl compounds.</p> <p> Initial studies involved the use of Nuclear Magnetic Resonance (NMR) and Ultraviolet (UV) spectroscopy in examining Lewis acid modification of the photostationary state for E/Z isomerization of various acyclic enones. The results obtained provide a good understanding of the origin of the perturbation of the photostationary state of these systems. In the course of these investigations, the question also arose as to the possible effects of complexation upon the photochemistry of cyclic enone systems where E/Z isomerization cannot occur, particularly whether this would catalyze [2+2] cycloadditions to the enone carbon/carbon double bond. Lewis acid complexed enones are widely used as activated dienophiles in Diels Alder reactions, and have been recently reported to serve as activated 'enophiles' in a photochemical dimerization of coumarin.</p> </p> The examination here is focused upon endo-tricyclo [5.2.1.02,6] deca-4,8-dien-3-one. (See Diagram in thesis). </p> <p> Reported here is a detailed investigation of the photochemistry of the AlEtCl2 complex of this compound, and the results are interpreted mechanistically. The reaction gives rise to a single product which reaches a photostationary state with the reactant complex. The isomerization is formally a [1,3] sigmatropic shift involving the isolated double bond. It seems likely however, to proceed by the formation of an allyl cation intermediate.</p> / Thesis / Master of Science (MSc)

Design and development of novel one-step reactions that produce nitrogen-containing scaffolds is an invaluable area of chemistry due to the abundance of these moieties in natural products and biologically active molecules. Discovering novel methods using uncommon substrates and rare earth metals to access these significant scaffolds present a challenge. Over the course of my doctoral studies, I have designed, developed and optimized novel reactions by using rarely known substrates and rare earth metals that have afforded important nitrogen-containing scaffolds. The products obtained allow access to otherwise long-to-synthesize molecules and expeditious construction of biologically active molecules.

No description available.

京都大学 / 新制・課程博士 / 博士(工学) / 甲第24813号 / 工博第5156号 / 新制||工||1985(附属図書館) / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 山子 茂, 教授 辻井 敬亘, 教授 大内 誠 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM