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V okviru magistrske naloge sem sintetiziral nove spojine z biciklo[2.2.2]oktenskim skeletom. Z Diels–Alderjevo reakcijo 2H-piran-2-onov z maleinanhidridom sem pripravil dva biciklo[2.2.2]oktena s pripojenima sukcinanhidridnima fragmentoma, ki sem ju uporabil pri nadaljnjih reakcijah derivatizacije. Z reakcijo nukleofilne substitucije s hidrazinom na dianhidridnih obročih in nadaljnjo reakcijo N-substituirane aminske spojine z aromatskimi ali heteroaromatskimi aldehidi sem sintetiziral serijo osemnajstih biciklo[2.2.2]oktenov s pripojenimi hidrazonskimi fragmenti. Za razliko od sintez z aldehidi je reakcija s ketonom potekla slabše, saj je željeni produkt kljub daljšem reakcijskem času nastal le v sledovih. Pripravil sem tudi biciklo[2.2.2]oktene s pripojenimi acilhidrazidnimi fragmenti, vendar produktov ni bilo mogoče izolirati v čisti obliki. Za sintezo teh spojin sem izhodne acilhidrazide pripravil iz analognih etilnih estrov z reakcijo s hidrazin hidratom. Karakterizacijo produktov s pripojenimi acilhidrazidi je ovirala otežena rotacija vezi v DMSO, zaradi katere so bili signali na 1H NMR in 13C NMR spektrih razširjeni. Omenjeno težavo sem poskušal rešiti z merjenjem spektrov pri višji temperaturi ali z uporabo devteriranega topila z manjšo gostoto. Reakcije sinteze obeh tipov produktov so potekale s segrevanjem reakcijske zmesi v zaprtih debelostenskih ACE cevkah, kot topilo pa sem uporabil n-BuOH. V obeh primerih so 1H NMR spektri pokazali nastanek asimetričnih stranskih produktov, ki sem jih potrdil z MS analizo. Za metodo čiščenja produktov sem uporabil prekristalizacijo iz EtOH ali MeOH, kar je bilo v večini primerov uspešno. Sinteze tiosemikarbazidnih derivatov biciklo[2.2.2]oktenov niso bile uspešne. Pri pogojih refluksa so produkti nastali v sledovih, pri pogojih segrevanja reakcijske zmesi v zaprtih debelostenskih ACE cevkah pa je prišlo do razpada in nastanka biciklo[2.2.2]oktenov s pripojenimi N-aminosukcinimidnimi obroči. Prav tako je bila neuspešna sinteza biciklo[2.2.2]oktena z N-acetaldehidnima fragmentoma. The main emphasis of this master degree thesis is synthesis of novel compounds with bicyclo[2.2.2]octene framework. Two starting bicyclo[2.2.2]oct-7-enes with two fused succinanhydride moieties, which were used in all further derivatization reactions, were synthesized with Diels–Alder reaction of 2H-pyran-2-ones with maleic anhydride. Synthesis of a series of eighteen novel bicyclo[2.2.2]octenes with fused hydrazone moiety was achieved with nucleophilic substitution of hydrazine on cyclic anhydride fragments and subsequent reaction of N-substituted amine group with various aromatic and heteroaromatic aldehydes. In contrast to reactions of aldehydes reactions of ketones were less successful, after long reaction times only traces of desired products were observed. Bicyclo[2.2.2]octenes with fused acylhydrazide fragments were also prepared, although I was unable to isolate them in pure form. For synthesis of these compounds I prepared starting acylhydrazides from corresponding ethyl esters in reaction with hydrazine hydrate. Characterisation of acylhydrazide derivatives of bicyclo[2.2.2]octenes with 1H NMR and 13C NMR analysis was complicated by restricted rotation of acylhydrazide moieties in DMSO-d6 solution, which caused broadening of signals in the spectrum. I tried to solve this problem with measuring NMR spectra at higher temperature or in deuterated solvents with lower density. The syntheses of all aforementioned final compounds were carried out with heating the reaction mixture in closed heavy wall pressure ACE tubes. The n-BuOH was used as the solvent. In all cases the 1H NMR analysis showed the presence of asymetric by- products, which were further confirmed with MS analysis. In most cases these were removed from crude products with recrystalisation in EtOH or MeOH. The preparation of thiosemicarbazide derivatives of bicicylo[2.2.2]octenes was not successful. After refluxing reaction mixture only traces of desired products were found. When same reactions were carried out in closed heavy wall pressure ACE tubes degradation of compounds present in the reaction mixture occured, leading to the formation of bicyclo[2.2.2]octene with fused succinimide fragments. Synthesis of bicyclo[2.2.2]octene with two fused N-acetaldehyde moieties was also unsuccessful with no traces of desired products observed.

V magistrskem delu sem raziskoval Diels–Alderjevo reakcijo med substituiranimi 2H-piran-2-oni in maleinanhidridom. Izhodne 2H-piran-2-one sem pripravil z enoločno sintezo, pri čemer so nastali različno substituirani 3-benzoilamino-2H-piran-2-oni. Slednji pri reakcijah z maleinanhidridom pod termičnimi pogoji običajno tvorijo enega izmed dveh možnih produktov: biciklični dvojni adukt (derivatiziran biciklo[2.2.2]okten) ali termodinamsko stabilnejši aromatski produkt (derivat izobenzofurana). Z optimizacijo reakcijskih pogojev sem poskušal pripraviti ter izolirati obe vrsti produktov. Izkazalo se je, da je reaktivnost 2H-piran-2-onov, ki vsebujejo elektron donorske substituente, pri reakciji z maleinanhidridom večja kot je reaktivnost 2H-piran-2-onov z elektron privlačnimi substituenti v obeh primerih nastanejo biciklični dvojni adukti z dobrimi izkoristki, v drugem primeru pa tudi aromatizirani izobenzofuranski produkti. 2H-piran-2-oni z elektron donorskimi substituenti torej preferenčno tvorijo biciklične adukte, ki se v večini primerov tudi po daljšem reakcijskem času in višji reakcijski temperaturi slabo pretvarjajo v aromatske. In the present work I investigated the Diels–Alder reaction between substituted 2H-pyran-2-ones and maleic anhydride. The starting 2H-pyran-2-ones were synthesised by “one pot” synthesis, resulting in various substituted 3-benzoylamino-2H-pyran-2-ones. The latter when reacted with maleic anhydride under thermal conditions usually form one of the two possible products: a bicyclic double adduct (derivatized bicyclo[2.2.2] octene) or a thermodynamically more stable aromatic product (isobenzofuran derivative). By optimizing the reaction conditions, I tried to prepare and isolate both types of products. The reactivity of 2H-pyran-2-ones with electron donor substituents in the reaction with maleic anhydride has been shown to be greater than the reactivity of 2H-pyran-2-ones with electron-withdrawing substituents, resulting in the formation of bicyclic double adducts (with good yields) in the former case and aromatic isobenzofuran products in the latter. In contrast, 2H-pyran-2-ones with electron donor substituents preferentially form a bicyclic adduct, which in most cases is poorly converted to aromatic even after a long reaction time and higher reaction temperature.

The syntheses and crystal structures of the two title compounds, C11H10O3 (I) and C17H14BrNO2 (II), both containing the bicyclo[2.2.2]octene ring system, are reported here [the structure of I has been reported previously: White & Goh (2014). Private Communication (refcode HOKRIK). CCDC, Cambridge, England]. The bond lengths and angles of the bicyclo[2.2.2]octene ring system are similar for both structures. The imide functional group of II features carbonyl C=O bond lengths of 1.209 (2) and 1.210 (2) Å, with C—N bond lengths of 1.393 (2) and 1.397 (2) Å. The five-membered imide ring is nearly planar, and it is positioned exo relative to the alkene bridgehead carbon atoms of the bicyclo[2.2.2]octene ring system. Non-covalent interactions present in the crystal structure of II include a number of C—H...O interactions. The extended structure of II also features C—H...O hydrogen bonds as well as C—H...π and lone pair–π interactions, which combine together to create supramolecular sheets.

V okviru magistrske naloge sem sintetiziral osem različno substituiranih biciklo[2.2.2]oktenskih sistemov z dvojno termično Diels–Alderjevo cikloadicijo maleinanhidrida na različno substituirane 2H-piran-2-one. V prvi stopnji s cikloadicijo maleinanhidrida v vlogi dienofila nastanejo oksabiciklo[2.2.2]oktenski intermediati, ki pod reakcijskimi pogoji spontano eliminirajo molekulo ogljikovega dioksida in tako tvorijo naslednji cikloheksadienski intermediat, ki služi kot nov dien za napad nove molekule dienofila (maleinanhidrida). Z molekulskim modeliranjem sem raziskal ali je v prvi stopnji cikloadicij različnih dienofilov (maleinanhidrida in substituiranih vinil etrov) reakcijski napad preferenčno ekso ali endo. Rezultate, dobljene z računsko metodo PM6, sem primerjal z eksperimentalnimi podatki, vključno z že objavljenimi v literaturi. In this master's degree I have synthesized eight variously substituted bicyclo[2.2.2]octene systems by using Diels–Alder cycloaddition of maleic anhydride on differently substituted 2H-pyran-2-ones. In the first stage of the cycloaddition of maleic anhydride as the dienophile oxabicyclo[2.2.2]octene intermediates are formed, which under the reaction conditions spontaneously eliminate a molecule of carbon dioxide and thus form the next cyclohexadiene intermediate, which serves as the diene for the attack of the second molecule of dienophile (maleic anhydride). Using molecular modelling I explored the endo/exo attack preference of various dienophiles (maleic anhydride and substituted vinyl ethers) of the first stage of the cycloaddition reaction. I compared the results, obtained with the computational method PM6, with experimental data in the literature.

V okviru diplomskega dela so predstavljene sinteze nekaterih 2H-piran-2-onov, primer zamenjave zaščitne skupine na izbranem 2H-piran-2-onu ter sinteza biciklo[2.2.2]oktenskega adukta, ki sem ga pripravil iz maleinanhidrida in 3-benzoilamino-6-(2-tienil)-2H-piran-2-ona. Slednja sinteza je bila izvedena na dva različna načina – pod refluksom ter z uporabo mikrovalov. Namen je bil ugotoviti, ali bosta obe poti vodili do željenega končnega produkta, ter katera pot bo vodila do produkta z boljšim izkoristkom. V sklopu diplomskega dela je vključen tudi pregled literaturnih podatkov o regio- in stereoselektivnosti [4+2] cikloadicij, v katerih so kot dieni pogosto zastopani 2H-piran-2-oni. Te zaradi edinstvenih značilnosti 2H-piran-2-onov predstavljajo izredno močno sintezno orodje za tvorbo kompleksnejših molekul in strukturno izredno raznolikih sinteznih gradnikov. In the context of this Diploma work, syntheses of some 2H-pyran-2-ones are presented. Additionally, an example of the replacement of a protecting group on a selected 2H-pyran-2-one and the synthesis of a byciclo[2.2.2]octene adduct prepared from maleic anhydride and 3-benzoylamino-6-(2-thienyl)-2H-pyran-2-one are included. The latter was performed in two different ways - under reflux conditions and by using irradiation with microwaves. The purpose was to determine whether both paths would lead to the desired end product and to find out which path would result in a better yield. This Diploma work also presents the literature data on regio- and stereoselectivity of [4+2] cycloadditions, in which 2H-pyran-2-ones are often represented as diene compounds. Due to the unique characteristics of 2H-pyran-2-ones, these reactions represent an extremely powerful synthetic tool for the formation of more complex molecules and structurally extremely diverse synthetic building blocks.

Five new neolignans with a bicyclo[2.2.2]octene framework were isolated from an ethanolic extract of the bark of Cordia americana. The structures and relative configurations of the compounds were elucidated by a combination of spectroscopic methods. All the isolated compounds showed good antioxidant activities in the DPPH radical scavenging (0.5–100 µg/mL) and Ferric-reducing antioxidant power (FRAP, 1–100 µg/mL) assays. One of the compounds displayed mild fungistatic activity at 0.1 µmol/spot against Fusarium virguliforme while, at the same time, all compounds were inactive against several strains of Gram (+) and Gram (−) bacteria at all assayed concentrations (10–1000 µg/mL). Fil: Fernandez, Lucia Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Cirigliano, Adriana Monica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Fabani, Maria Paula. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Lima, Beatriz Viviana. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Alberti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Kramer, Fernando Luis. Universidad Nacional de Misiones. Facultad de Ciencias Exactas, Químicas y Naturales; Argentina Fil: Tapia, Alejandro A.. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina Fil: Cabrera, Gabriela Myriam. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Palermo, Jorge Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Sánchez, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina