Orientador: Anita Jocelyne Marsaioli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-07-27T06:42:42Z (GMT). No. of bitstreams: 1 Miranda_DomingosSaviode_D.pdf: 7629431 bytes, checksum: 2131de0ae02eb8177799e5d3058686a2 (MD5) Previous issue date: 1999 / Doutorado

The chemoselective hydrozirconation reaction of a series of 1-ene-3-yne molecules 51a-d, using the commercially available hydride reagent, Cp₂ZrCl(H) 1, provides an efficient route to the syntheses of 1,3-dienes 55a-d, substituted at the 1-position by the Cp₂ZrCl moiety. Similar chemoselectivity was observed in the hydrozirconation reaction of α, β-unsaturated nitriles, to generate the corresponding 1-azadienyl complexes 68-71. The complexes 55a-d were found to be useful general precursors in the preparation of other heterosubstituted 1,3-dienes. Thus, corresponding tin-, phosphorus-, boron-, selenium-and sulfur-heterosubstituted 1,3-dienes 77a-d, 79a-d, 87a-d, 88a-d and 89a-d were readily prepared in good to excellent yields by a stereoselective transfer reaction from zirconium. The 1-azadienyl complexes also served as useful starting materials in the preparation of selenium-and phosphorus-substituted 1-azadienes. The selenium-substituted 1,3-dienes 88a-d underwent a facile isomerization reaction when exposed to fluorescent light, and when thermolysed in the dark at 80°C in unsealed reactors. Mechanistic studies of this isomerization process suggested that an intermolecular pathway involving free radical intermediates was operable. A comparable photochemical isomerization reaction of the sulfur-substituted 1,3-dienes was also observed. When the cycloaddition reactions of 88a-b and 88d with maleic anhydride were performed in the absence of light at reson able temperatures, good yields of the expected endo-cycloadducts were obtained. However, when the same reactions were repeated in room light or at temperatures in excess of those required for formation of the endo-cycloadducts an, interesting, apparent [l,3]-shift of the phenylselenenyl moiety resulted. The results of a crossover experiment indicated that this rearrangment was intermolecular in nature. The preparation of the trialkylstannyl and phenylselenenyl 2-substituted 1,3-dienes (128 and 129) was achieved via a transmetalation reaction of the Grignard reagent 24. The Diels-Alder reactivity of 1,3-dienes 128 and 129, with a series of electron-deficient dienophiles, was successfully investigated. [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

The preparation of bicyclic dienes of the general structures (72), (82), (83) and (162) is described. These materials have been prepared via a novel annulation sequence involving (a) the alkylation of various carbonyl containing substances with the donor acceptor reagents (43), (44), (108)-(114) and (154), (b) the conversion of the alkylation products into the enol triflates, and (c) the palladium(O) catalyzed intramolecular coupling of the enol triflate-vinylstannane moieties via either a "one" or "two pot" process. The Diels-Alder reactions of the "parent" bicyclic diene (75), the cisoid cis diene (145) and the cisoid trans diene (146) are described. Four basic questions regarding the face selectivity, regioselectivity, stereoselectivity and comparative reactivity of the dienes in the formation of the Diels-Alder adducts of general structure (174) are addressed. The annulation sequences described above have been applied to the first total syntheses of the dolastane diterpenoids (±)-(14S)-dolasta-1(15),7,9-trien-14-ol (239) and (±)-amijitrienol (242). Thus, the substituted cycloheptanone (262), prepared in seven steps from the commercially available material (261), was converted via a series of transformations, including the newly developed annulation process, into the bicyclic diene (264). Introduction of the two appendages to (264) proceeded stereoselectively to provide the keto vinylstannane (265). Ring closure was effected with the desired stereochemistry to yield (±)-(239). A reduction, deprotection sequence afforded the ketone (249) from the diene ketal (263). A series of three steps involving an aldol condensation, Swern oxidation and stereoselective methylation provided the diketone (290). Chemo- and stereoselective reduction of (290) followed by protection of the alcohol moiety yielded the silyl ether (303). Cyclization, according to the methodology described herein, and deprotection of the silyl ether moiety produced (±)-(242). [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

The advancement of catalytic systems and the application thereof has proven to be the key to overcome traditional limitations of industrial-scale synthetic processes. Converging organometallic and biocatalytic principles lead to the development of Artificial Metalloenzymes (ArMs) that comprise a synthetic metal catalyst embedded in a protein scaffold, thereby combining the reactivity of the former with the versatility of the latter. This synergistic approach introduces rationally designed building blocks for the catalytic site and the host protein to assemble enzyme-like structures that follow regio-, chemo-, enantio- and substrate-selective principles. Yet, the identification of suitable protein scaffolds has thus far been challenging. Herein we report a rationally optimized fluorescent protein host, mTFP*, that was engineered to have no intrinsic metal binding capability and, owing to its robust nature, can act as scaffold for the design of novel ArMs. We demonstrate the potential of site-specific modifications within the protein host, use protein X-Ray analysis to validate the respective scaffolds and show how artificial mutant binding sites can be introduced. Transition metal Förster Resonance Energy transfer (tmFRET) methodologies help to evaluate micromolar dissociation constants and reveal structural rearrangements upon coordination of the metal centers. In conjunction with molecular insights from X-Ray crystallographic structure determination, dynamics of the binding pocket can be inferred. The versatile subset of different binding motifs paired with transition metal catalysts create artificial metalloenzymes that provide reactivities which otherwise do not exist in nature. As a proof of concept, Diels-Alder cycloadditions highlight the potential of the present mTFP* based catalysts by stereoselectively converting azachalcone and cyclopentadiene substrates. Screens indicate an enantiomeric excess of up to 60% and provide insights into the electronic and geometric constitution of the first coordination spheres binding the catalysts. We further apply two general principles to optimize selective conversions of the generated ArMs. 1) Utilizing site-specific mutagenesis, increased hydrophobicity is introduced to the second coordination sphere. 2) In-vitro post-expressional modification utilizing N-hydroxysuccinimide esters is anticipated to introduce a sterically more demanding second coordination sphere that influences substrate entry by favoring a particular stereoisomer. The latter approach however also enhances the host proteins robustness under processing conditions. The presented study investigates a novel approach to create artificial metalloenzymes based on non-enzymatic precursor proteins. It illustrates means of modification and functionalization. Further guidance to overcome the general problem of insufficient stereoselectivity and stability is also presented. In view of the insights gained we see the importance of further mutagenic studies, i.e. through means of guided evolution, to extend stereoselectivities. In-vivo applications of artificial metalloenzymes could thus be used to pursue metabolomic engineering.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Phthalocyanines (Pcs) are highly conjugated, 18π-electron cyclic molecules composed of four isoindoline units that exhibit unique optical, electrical and chemical properties. While originally used as dyes and pigments, the use of Pcs in modern technology has increased dramatically due to improved understanding and processing capabilities. Work in this dissertation outlines a number of methods to prepare Pc-containing materials for use in various applications. Chapter 1 provides a brief review of methods used to prepare Pc-containing polymeric materials from both symmetric and asymmetric macrocycles. Discussion will focus on methods that incorporate symmetric Pcs as the focal point, with particular attention being paid to the influence of the peripheral substitution of the Pc on macromolecular structure and properties. Further discussion will focus on the utilization of asymmetric Pcs as auxiliary functionalities, such as at the terminus or as pendant groups, of larger macromolecular materials. Chapter 2 describes the preparation of linear Pc-containing polymers through ring-opening metathesis polymerization of a Pc monomer. Through proper selection of catalyst, well-defined polymers with Pcs as pendant groups were prepared. Due to the controlled nature of ROMP, polymers of varying architectures, composition, and size were synthesized. The effect of Pc metallation, polymer composition and architecture on the site-isolation of the chromophore was investigated in both solution and condensed-phase thin films. Chapter 3 reports on efforts to prepare linear polymers with companion functionalities for post-polymerization coupling of asymmetric Pcs. Polymers with pendant furan groups were prepared for coupling with asymmetric Pcs through Diels-Alder cycloaddition. Investigation indicated that while coupling was achievable, the presence of the Pc in the resultant polymer promoted undesired crosslinking when stored at ambient conditions in light. Attempts to mitigate this problem through alternation of functionality locations were attempted by placing the furan functionality on the Pc, but degradation of the furan occurred to quickly to perform coupling sufficiently. Chapter 4 discusses the preparation of Pc-containing networks through Diels-Alder cycloaddition of furan and maleimide containing tetrasubstituted Pcs. Following preparation of the various Pcs, network formation in various states was conducted including solution, molded thick films, and patterned assemblies. Chapter 5 summarizes the results presented in Chapters 2-4 and provides an outlook for some future directions based upon the work herein. In addition, some preliminary results of some of these directions will also be presented.

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