Synthesis of new pyrrolidine derivatives via [3+2] cycloadditions of Michael acceptors

APSTRAKT: U okviru ove doktorske disertacije sprovedena je sinteza tri serije novih, strukturno sličnih derivata pirolidina. Sinteza je izvedena [3+2] cikloadicionim reakcijama, odnosno 1,3-dipolarnom cikloadicijom, uz poseban osvrt na diverzitet dipolarofila koji spadaju u red Michael-ovih (Majklovih) akceptora. Reakcija je izvođena pod blagim reakcionim uslovima, dok je prinose diktirala voluminoznost reaktanata. Sve dobijene proizvode je moguće podeliti u dve velike grupe: jednu u kojoj su derivati pirolidina koji u svom sastavu ne sadrže ferocensko jezgro i drugu gde su produkti sa ferocenom. Izvedena je spektroskopska karakterizacija svih proizvoda. Produkti bez ferocenske jedinice su poslužili za ispitivanje reakcionih uslova, mehanizma reakcije i izomerizacionog procesa, uz komentarisanje teorijski dobijenih vrednosti razlika u slobodnim energijama dijastereoizomernih proizvoda. Optimizacija reakcionih uslova je podrazumevala ispitivanje različitih baza, katalizatora i rastvarača, kao i vremena trajanja reakcije. Proizvodi koji sadrže ferocensku jedinicu su podvrgnuti daljem ispitivanju elektrohemijskih osobina, koristeći tehnike ciklične voltametrije i diferencijalne pulsne voltametrije. Osim osnovne procene elektrohemijskog potencijala proizvoda, ovim tehnikama je sprovedeno i preliminarno istraživanje biološke aktivnosti produkata na osnovu njihovog afiniteta prema molekulu DNK. Na osnovu parametara dobijenih voltametrijskim tehnikama, izračunate su konstante vezivanja i određen dominantni tip interakcija proizvoda i DNK. Izvršena je i molekularna doking analiza određenih proizvoda u molekul DNK, a kod ove serije proizvoda bilo je moguće strukturu i konformaciju odabranih jedinjenja potvrditi difrakcijom X-zraka na monokristalima.ABSTRACT: Within this doctoral dissertation, the synthesis of three series of new, structurally similar pyrrolidine derivatives has been achieved. The synthesis was performed via [3+2] cycloadditions (1,3-dipolar cycloaddition), with reference to the diversity of dipolarophiles which belong to the class of Michael acceptors. The reaction was conducted under mild conditions, while the yields were depended upon the volume of the reactants. All obtained products can be divided into two large groups: one in which pyrrolidine derivatives do not contain ferrocene core, and the other where products have ferrocene in their structure. Spectroscopic characterization of all products was performed. Products without ferrocene unit were used to examine the reaction conditions, reaction mechanism and isomerization process, with respect to the theoretically obtained values of differences in free energy of diastereoisomeric products. The optimization of the reaction conditions involved the investigation of different bases, catalysts and solvents, as well as the time required to conduct the reaction. Pyrrolidine derivatives containing a ferrocene unit were subjected to further investigation of electrochemical properties, using cyclic voltammetry and differential pulse voltammetry. In addition to the basic assessment of the electrochemical potential of products, these techniques were used to provide a preliminary study of the biological activity of products concerning their affinity for the DNA molecule. The binding constants and the dominant type of product-DNA interactions were determined using the parameters obtained by voltammetric techniques. The selected products were docked into DNA molecule and subjected to the single-crystal X-ray diffraction analysis