synthesis, structure and chemical transformations.

[ Z. Džambaski]

[13], 187 listova

Hemija-Organska hemija / Chemistry-Organic chemistry

Sulfoksidna funkcionalna grupa je česta u farmakološki značajnim jedinjenjima, a literaturni podaci ukazuju na to da uvođenje ove funkcionalne grupe u tiazolidinski prsten može da poveća biološku aktivnost molekula koji sadrže ovaj strukturni fragment. Iako je sinteza, hemijsko ponašanje i biološka aktivnost 4-oksotiazolidinskih S-oksida predmet interesovanja velikog broja hemičara, podaci o stereohemijskom nivou strukture često nedostaju ili su nedovoljno jasno predstavljeni. S tim u vezi, detaljno ispitivanje reakcije oksidacije sumpora kod 2-alkiliden-4-oksotiazolidina, kao i stereohemijska karakterizacija proizvoda od značaja su za utvrđivanje stepena i uzroka diastereoselektivnosti pri oksidaciji različitih cikličnih i acikličnih organskih sulfida koji poseduju stereogeni centar u susedstvu atoma sumpora. U skladu sa postavljenim ciljevima, nakon optimizacije reakcionih uslova sintetizovana je serija 4-oksotiazolidinskih S-oksida oksidacijom atoma sumpora kod 2- alkiliden-4-oksotiazolidina koji se razlikuju po supstituentima vezanim za egzocikličnu dvostruku vezu, atom azota i C(5) položaj prstena. Oksidacijom pomoću m-CPBA 5- supstituisani 4-oksotiazolidinski sulfoksidi dobijeni su kao smese dva diastereomera uz umerenu diastereoselektivnost koja varira od 57-74% diastereomernog viška. Relativna konfiguracija 5-supstituisanih sulfoksida određena je korelacijom eksperimentalno i teorijski dobijenih NMR podataka. Strukture polaznih 2-alkiliden-4- oksotiazolidina i sintetizovanih tiazolidinonskih S-oksida optimizovane su na DFT nivou, korišćenjem B3LYP funkcije i 6-31G* baznog seta, u gasnoj fazi. NMR hemijska pomeranja izračunata su primenom GIAO metode, na istom nivou teorije, u gasnoj fazi i u prisustvu rastvarača. Na osnovu eksperimentalnih i računski dobijenih rezultata utvđeno je da je proces oksidacije 5-supstituisanih 2-alkiliden-4-oksotiazolidina kinetički kontrolisan, pri čemu lakšim prilaskom reagensa (m-CPBA) sa sterno manje zaštićene strane u većoj količini nastaje manje stabilan anti-izomer. U toku obrade reakcione smese dolazi do uravnotežavanja pa se kao krajni proizvod dobijaju smese obogaćene termodinamički favorizovanim sin-izomerom. Veća stabilnost sin-izomera posledica je intramolekulskog C(5')H···OS 1,5-vodoničnog vezivanja i jače σC(5)-H → σ*S-O hiperkonjugacione interakcije nasuprot slabijoj σC(5)-C(5') → σ*S-O interakciji kod antiizomera...

The sulfoxide functional group is common in pharmaceutically important compounds and many sulfoxides are known to have high biological activity. Sulfur oxidation of 4- oxothiazolidine may result in more potent compounds. Although synthesis, chemical behavior, and biological activity of 4-oxothiazolidine S-oxides have been frequently investigated, no information concerning their diastereomeric purity or stereochemical structure has been given usually. Having this in mind, detailed investigation of 2-alkylidene- 4-oxothiazolidine oxidation reaction and stereochemical characterization of sulfoxide products should be of interest for further investigations of sulfur oxidation in acyclic and cyclic sulfides having stereogenic center adjacent to sulfur atom. In accordance with the aims of this thesis, after initial screening of different oxidizing agents, a series of 5-substituted and 5-unsubstituted 2-alkylidene-4-oxothiazolidine S-oxides were synthesized by the sulfur-oxidation of the parent sulfides with m-CPBA. The products were obtained in good yields, 51-95%, and with moderate diastereoselectivity in case of 5- substituted derivatives (de 54-74%). The relative configuration of 5-substituted sulfoxides was determined by means of NMR spectroscopy and DFT theoretical calculations. The structures of starting 2-alkylidene- 4-oxothiazolidines and sulfoxides were optimized in the gas phase at the B3LYP/6-31G∗ level. NMR chemical shifts were calculated by using the GIAO method, at the same level of theory in the gas phase and with inclusion of solvent. On the basis of experimental and computational results it was found that the stereochemistry of the oxidation step was kinetically controlled by the reagent (m-CPBA) approach from the sterically less hindered side. Less stable anti-isomer was initially formed, but it underwent epimerization to the mixture enriched in the more stable syn-isomer, during the work-up process. The higher stability of syn-isomers was ascribed to the stronger hyperconjugative σC(5)−H → σ∗ S−O interaction versus the weaker σ C(5)-C(5') → σ∗ S−O delocalization in their anti-counterparts and to the existence of intramolecular 1,5-C(5')H⋅⋅⋅O hydrogen bonds. Specific reactivity of β-keto sulfoxide and vinyl sulfoxide fragments present in 2- alkylidene-4-oxothiazolidine S-oxides offer a possibility for further regioselective functionalization of the studied thiazolidinone derivatives. Another important issue of this...

2-alkiliden-4-oksotiazolidinski S-oksidi, stereohemija sulfoksida Pummerer-ova reakcija, hlorsulfonijum-jon, DFT izračunavanja, regioselektvnost, diastereoselektivnost, CH···O vodonična veza

2-alkylidene-4-oxothiazolidine S-oxides, sulfoxide stereochemistry, Pummerer reaction, chlorosulfonium ion, DFT calculations, regioselectivity, diastereoselectivity, CH···O hydrogen bond

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