A new approach for the synthesis of bioactive quinuclidine and imidazole compounds

U okviru ovog rada pripravljena je knjižnica od 63 derivata potencijalno bioaktivnih oksima, etera i karbamata oksima, te α-acilamino-amida koji sadrže imidazolijevu ili kinuklidinijevu jezgru. Dodatno, sintetizirani su i α-acilamino-amidi koji sadrže i druge heterocikličke podjedinice (piridin, indol, tetrazol i tiofen) kako bi se dobila što raznovrsnija knjižnica novih spojeva koji do sada nisu opisani u literaturi. U sintezi spojeva primijenjene su klasične metode sinteze, mehanokemijske i sinteze potpomognutim mikrovalnim zračenjem. Varirani su uvjeti te uspoređene brzine i iskorištenja reakcija, ali i stereokemija nastalih produkata kod etera oksima. Optimirani su uvjeti za stereospecifičnu sintezu četiri etera oksima kinuklidina mehanokemijskom sintezom bez otapala i uz natrijev hidroksid kao bazu (nastaje anti izomer). Za određivanje omjera izomera etera oksima te konformera α-acilamino-amida u otopini primijenjena je spektroskopija nuklearne magnetske rezonancije. Mehanizam i stereokemija nastanka etera oksima kinuklidin-3-ona te konformacijski prostor α-acilamino-amida studirani su kvantno-kemijskim proračunima. In this work, a library of 63 derivatives of potentially bioactive oximes, oxime ethers, oximes carbamates, and α-acylamino-amides containing an imidazolium and/or quinuclidinium nucleus was prepared. In addition, α-acylamino-amides containing other heterocyclic subunits (pyridine, indole tetrazole and thiophene) were also synthesized in order to obtain the most diverse library of new compounds that have not been described in the literature so far. Classical methods of synthesis in solution, mechanochemical and microwave synthesis were used for the synthesis of compounds. The conditions were varied and the speed and yields of the reactions were compared, as well as the stereochemistry of the products formed in the case of ether oximes. The conditions for the stereospecific synthesis of four quinuclidine oxime ethers were optimized by mechanochemical synthesis without solvent and with sodium hydroxide as a base (anti isomer is formed). Nuclear magnetic resonance spectroscopy was used to determine the ratio of ether oxime isomers and α-acylamino-amide conformers in the solution. The mechanism and stereochemistry of quinuclidin-3-one oxime ether formation and the conformational space of α-acylamino-amide were studied by quantum-chemical calculations.