20.500.12556/RUL-128374 Sinteza in optimizacija aromatsko substituiranih nesimetričnih 1,2,4,5-tetraoksanov in peroksi-BODIPY analogov Synthesis and optimization of aromatically substituted 1,2,4,5-tetraoxanes and peroxy-BODIPY analogs V doktorskem delu smo predstavili nova spoznanja in poti sinteze s področja spiro fenil substituiranih 1,2,4,5-tetraoksanov (TO) ter kemijo organskih peroksidov razširili na BODIPY barvila ter s kristalografsko študijo okarakterizirali nove interakcije hidroperoksidnih skupin. Z In silico študijo smo ovrednotili spiro fenil substituirane tetraoksane kot potencialne biološko aktivne spojine za zdravljenje tuberkuloze. Raziskali smo peroksidacijo benzaldehid v gem-dihidroperokside (DHP) z vodikovim peroksidom z namenom njihove nadaljnje pretvorbe v biološko aktivne aril-substituirane TO. Razvili smo postopek peroksidacije deaktiviranih benzaldehidov z elektron privlačnimi substituenti in s pomočjo kislinske katalize pretvorili benzaldehide z nitro, trifluorometilno in ciano substituenti na p- in m-pozicijah v gem-dihidroperokside (DHP). Za peroksidacijo je potreben presežek koncentriranega peroksida, povišana temperatura 40 °C, ter reakcijski čas 24 ur. V reakciji nastajajo tudi hidroperoksi alkoholi in polimerne oblike peroksidnih spojin. DHP smo pripravili z 2−56 % pretvorbami. Zaradi nestabilnosti jih nismo izolirali ampak direktno uporabili za sintezo nesimetričnih aril-substituiranih spiro TO s 4-metilcikloheksanonom. V kislinsko katalizirani ciklizaciji smo jih z zmernimi izkoristki 19−32 % pretvorili v nesimetrične fenil-substituirane tetraoksane. Nadalje smo raziskali selektivnost sinteze TO glede na vrstni red peroksidacije in ciklizacije, saj lahko v DHP najprej pretvorimo cikloheksanon ali benzaldehid. Ugotovili smo, da so boljši izkoristki pri predhodni prevorbi cikloheksanona v DHP in sledeči ciklizaciji z benzaldehidom. Razen v primeru uporabe benzaldehidov z elektron-privlačnimi substituentami, kjer pa je potrebno vrstni red zamenjati. Poleg tega smo raziskali optimizacijo pogojev sinteze in detajlno analizo razporeditve produktov kislinsko katalizirane ciklizacije DHP in benzaldehida. Optimalna količina kisline, pri kateri je nesimetrični spiro TO nastal s 30 % izkoristkom je bila 0,1 ekv. pri temperaturi 0 °C. Ugotovili smo, da ima substituent na aromatskem obroču močan vpliv na izkoristek reakcije z linearno povezavo med izkoristki in pKa ter substitucijskimi konstantami iz Hammettove korelacije z dobro korelacijo (R2 je 0,992 za pKa oz. 0,996 za σ+). Pokazalo se je, da mora vlogo dihidroperoksida v reakciji ciklizacije prevzeti karbonilna spojina takrat, kadar je pK(BH+) benzaldehida nižji od −8,13. Raziskali smo občutljivost pripravljenih tetraoksanov na kislinsko in bazično hidrolizo ter ugotovili, da so tetraoksani z elektron privlačnimi substituenti na fenilnem obroču na kislinski razpad odporni, elektron donorske skupine na aromatu pa v kislem promovirajo Dakinovo oksidacijo do fenolov in ketonov. Elektronski učinek substituenta na bazični razpad ni imel vpliva in je v obeh primerih nastal 4-metilcikloheksanon in derivat benzojske kisline. Ugotovili smo, da dodatek koncentriranega vodikovega peroksida v reakcijo ciklizacije DHP in benzaldehida poveča izkoristek iz 26 % na 53 % pri dodanem štirikratnem ekvivalentu vodikovega peroksida. V sklopu strukturne študije gem-dihidroperoksidov smo pripravili nove tri nove DHP z strukturno določenimi funkcionalnimi skupinami, ki omogočajo tvorbo vodikovih vezi s hidroperoksidno skupino. Okarakterzirali smo do sedaj še neznane interakcije med hidroperoksidno skupino in nitro, hidroksi ter karboksilno skupino. Ugotovili smo, da je hidroperoksidna skupina dober akceptor in donor vodikovih vezi. Hidroksilna skupina je delovala le kot akceptor vodikovih vezi z dvema hidroperoksidnima skupinama sosednje molekule asimetrične enote. Karboksilna skupina je delovala kot akceptor in donor vodikovih vezi in se je v asimetrični enoti povezovala še z dvema sosednjima molekulama, medtem ko je nitro skupina le akceptor vodikovih vezi. Z in silico študijo smo raziskali in ovrednotili spiro fenil substituirane TO kot potencialne biološko aktivne spojine za bakterijo M. tuberculosis. Molekule so bile sestavljene iz vezavnega dela in toksičnega dela med seboj povezana s povezovalcem. Molekule smo sidrali na izbrano tarčo citidin kinazo Rv1712 za katero smo s poravnavo aminokislinskega zaporedja ugotovili, da v človeškem genomu nima analoga (enakost aminokislinskega zaporedja je 21,5 % in podobnost 36,4 %). V aktivno mesto smo najprej ločeno sidrali 15 izomerov citidin-5' monofosfata in fenil substituiranih tetraoksanov z različnimi skupinami na aromatskem obroču. Iz najboljših zadetkov smo pripravili himerne molekule ter z analizo vezavnih interakcij protein-ligand ugotovili, da bi bili tetraoksani lahko primerne biološko aktivne molekule, saj je izračunana konstanta vezanja najboljšega kandidata K7 v vezavni žep Rv1712 9,8 μM. Borovi peroksidi so zaradi nestabilnosti redka in precej slabo raziskana skupina spojin. Ugotovili smo, da lahko z uporabo bor-vsebujočih barvil BODIPY pripravimo stabilne borove perokside z zmernimi do dobrimi izkoristki in s tem povežemo senzorske lastnosti BODIPY barvil z redoks lastnostmi peroksidne skupine. Razvili smo metodo za sintezo peroksi-BODIPY derivatov s TMSOTf posredovano aktivacijo centra BF. Ugotovili smo, da uporaba metoksi derivatov BODIPY (BFOMe) poveča izkoristek. Pripravili smo analoge s tBuOO−, oktilOO− ter hidroperoksidno skupino vezano na borov atom v BODIPY. Pripravili smo tudi dva primera do sedaj še nepoznanih borovih diperoksidov s strukturnim elementom B(OOR)2. Di terc-butil- BODIPY smo pripravili z 31 % izkoristkom, spiro tetraoksan-BODIPY derivat pa z 10 % izkoristkom. Spojine smo okorakterizirali s ciklično voltametrijo, določili njihove spektroskopske lastnosti in jim strukturo določili tudi z rentgensko kristalografijo. The aim of this work is to introduce some new synthetic routes and insights into spiro phenyl- substituted 1,2,4,5-tetraoxanes, insights from extending the chemistry of organic peroxides to the BODIPY scaffold and crystallographic studies of interactions of dihydroperoxide groups. In silico studies of spiro phenyl-substituted tetraoxanes provided new bases for potential biologically active compounds against tuberculosis. We inestigated peroxidation of benzaldehyde derivatives to dihydroperoxides (DHP) with hydrogen peroxide and their transformation into potentially biologically active aryl- substituted 1,2,4,5-tetraoxanes (TO). A new synthetic route for the acid-catalyzed peroxidation of deactivated benzaldehydes with electron-withdrawing groups has been developed that enabled preparation of DHP from benzaldehydes with nitro, trifluoromethyl and cyano groups at p- and m-positions. Large access of hydrogen peroxide is required for peroxidation, as well as elevated temperature and long reaction times. DHPs were prepared with 2−56 % conversions, while hydroperoxy alcohols and polymeric peroxy compounds were formed as byproducts. The products were not isolated due to their instability, but were used directly in a cyclization reaction with 4-methylcyclohexanone to give non-symmetric phenyl- substituted TO with 19−32 % yields. The results suggest that the peroxidation and the order of cyclization reaction strongly affect the yield of TO. When benzaldehydes with electron donating groups are used it is preffered that the DHP is prepared from a carbonyl compound to have better yield of TOs, and vice versa for benzaldehydes with electron withdrawing groups. Optimum conditions for the cyclization reaction between DHP and benzaldehyde were determined to be 0.1 equivalents of acid catalyst and 0 °C, with non-symmetric TO formed in 30 % yield. The substituent on the benzaldehyde also strongly influences the yield of TO and linear corelations with pKa and σ+ were observed (R2 for pKa= 0,992 and 0,996 for σ+). We have shown that when pKa(BH+) of the substituted benzaldehyde is lower than −8.13, the benzaldehyde needs to take the role of DHP in the cyclization reaction. The hydrolysis sensitivity study on phenyl substituted tetraoxanes shows that TO with electron-withdrawing groups is resistant to acid hydrolysis while electron-donating groups promote Dakin oxidation to phenols and ketones. The electronic effects of substituents did not affect hydrolysis under basic conditions, with lactone and benzoic acid being the major products of the decomposition of both, TO with electron-withdrawing and electron-accepting groups. We also found that the addition of hydrogen peroxide to the cyclization reaction of DHP and benzaldehyde increased the yield of TO from 26 to 53 %. Within the structural study, three new DHP derivatives with structurally defined side groups were prepared and their hydrogen bonding ability with the hydroperoxide group was characterized. The interactions of the hydroperoxide group with hydroxyl, carboxyl and nitro groups were investigated by X-ray crystallography. The results show that the hydroperoxide group is an excellent acceptor and donor of hydrogen bonds. The hydroxyl group played only a role of acceptor, the carboxylic group played both an acceptor and donor role and nitro group was only an acceptor. In an in silico study, we evaluated spiro phenyl-substituted TO as potential biologically active compounds for M tuberculosis. The molecules were composed of »toxic« and »binding« parts joined with a linker. Rv1712, a small cytidine-5'-kinase for which there are no analogs in the human genome, was identified as a suitable target. Initially, docking of 15 isomers of cytidine- 5'-monophosphate and 15 analogs of TO with different side groups was performed. The best hits from both groups were then assembled into chimeric molecules and protein-ligand interaction analysis was performed. The results showed that such molecules have potential as biologically active compounds, with binding constant of 9.8 μM for the best hit. Boron peroxides are rare due to their inherent instability and their chemistry is poorly studied. Our results suggest that we can prepare stabile boron peroxides based on BODIPY dyes in good yields. This chemistry enables us to link the photochemical properties of BODIPY dyes with the redox potential of the peroxide moiety. A method has been developed for the preparation of peroxy-BODIPY derivatives with TMSOTf-mediated activation of the BF center. The use of methoxy BODIPY derivatives significantly increases the yields. Analogs containing tBuOO−, octylOO− and hydroperoxide groups were prepared. Moreover, we prepared the first diperoxo-boron species with B(OOtBu)2 structural motif in 31 % yield and its cyclic tetraoxane analog in 10 % yield. All the newly prepared mono- and diperoxy-BODIPY derivatives were characterized by cyclic voltammetry, their spectroscopic parameters were measured and their structure and bonding were confirmed and analyzed by single crystal X-ray diffraction. - - true false false Slovenski jezik Angleški jezik Doktorsko delo/naloga 2021-07-09 17:30:00 2021-07-09 17:30:01 2022-09-07 04:14:47 0000-00-00 00:00:00 2021 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 5704 74684163 Princic_Grisa_grigorij_-_Sinteza_in_optimizacija_aromatsko_substituiranih_nesimetricnih_1,2,4,5-.pdf Princic_Grisa_grigorij_-_Sinteza_in_optimizacija_aromatsko_substituiranih_nesimetricnih_1,2,4,5-.pdf 1 40F6E66B598968ED36AD1DB308C0E587 8339be9b1582b9f314dd4e8ebe2e1eea36db210f4367443badd880a9224c25d7 63f0006c-e0ca-11eb-a523-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=145098 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0