Sinteza fluoriranih derivatov homoserina z Mitsunobu reakcijo

Rot, Karin (avtor), Iskra, Jernej (mentor)

Fluor je najbolj elektronegativen atom, njegovo jedro pa ima spin ½, zato ga lahko uporabljamo v magnetnih resonančnih tehnikah (NMR, MRS, MRI). Fluorirane organske spojine niso prisotne v večini bioloških sistemov, zato je fluor primerno diagnostično orodje v medicini. Fluorirane α-aminokisline predstavljajo odlične sonde za vključitev v proteine in peptide. Pri tem je zaželjeno, da ima aminokislina več kot tri kemijsko ekvivalentne fluorove atome, saj to pripomore k občutljivosti. Z Mitsunobu reakcijo je mogoče uvesti motive, ki imajo do 9 ekvivalentnih fluorovih atomov. V sklopu diplomske naloge sem pripravila ustrezno zaščiten L-homoserin, s katerim sem nato izvedla Mitsunobu reakcijo ob prisotnosti perfluoro-terc-butanola (PFTB), ki ima 9 ekvivalentih fluorovih atomov. Mitsunobu reakcija je metoda za dehidrativno spajanje primarnih ali sekundardnih alkoholov s pronukleofili. Kot pronukleofil lahko uporabimo tudi fluorirane alkohole z dovolj nizkim pKa, med katere spada perfluoro-terc-butanol. Z optimizacijo reakcijskih pogojev sem dobila perfluoriran derivat zaščitenega L-homoserina s 67 % izkoristkom. Glavni cilj diplomskega dela je bil priprava N-Fmoc zaščitenega gradnika, ki se uporablja v sintezi peptidov na trdnem nosilcu (SPPS). V ta namen sem fluoriranemu derivatu zaščitenega L-homoserina izmenjala zaščitne skupine, pri čemer sem dobila N-Fmoc-O-(perfluoro-terc-butil)-L-homoserinat s 77 % izkoristkom. Izveden postopek izmenjave zaščitnih skupin, ki sem ga uporabila v diplomski nalogi, je kazal na izboljšano efektivnost reakcije glede na predhodno predstavljene metode v literaturi. Celokupni izkoristek sinteze, od zaščite L- homoserina do izmenjave zaščitnih skupin, je znašal 26 %, medtem ko je v prej predstavljenem postopku sinteze v literaturi znašal le 4 %.

• Jezik: Slovenski jezik
• Ključne besede: Fluorirane aminokisline, L-homoserin, Mitsunobu reakcija, perfluoro-terc-butanol
• Vrsta gradiva: Diplomsko delo/naloga
• Tipologija: 2.11 - Diplomsko delo
• Organizacija: FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Leto izida: 2025
• PID: 20.500.12556/RUL-171953
• COBISS.SI-ID: 253495299
• Datum objave v RUL: 04.09.2025

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Synthesis of fluorinated homoserine derivatives via Mitsunobu reaction

Izvleček

Fluorine is the most electronegative atom and its nucleus has a spin of ½, which allows its use in magnetic resonance techniques (NMR, MRS, MRI). Fluorinated organic compounds are not present in most biological systems, making fluorine a useful diagnostic tool in medicine. Fluorinated α-amino acids make excellent probes for incorporation into proteins and peptides. It is important that the amino acid probe contains more than three chemically equivalent fluorine atoms, as this significantly enhances its sensitivity. The Mitsunobu reaction can be leveraged to introduce moieties containing up to nine equivalent fluorine atoms. As part of my thesis, I prepared appropriately protected L-homoserine, which was subjected to the Mitsunobu reaction in the presence of perfluoro-tert-butanol (PFTB), which contains nine equivalent fluorine atoms. The Mitsunobu reaction is a method for the dehydrative coupling of primary or secondary alcohols with pronucleophiles. Fluorinated alcohols with sufficiently low pKa values, such as PFTB, can be used as pronucleophiles. By optimizing the reaction conditions, I obtained the perfluorinated derivative of protected L-homoserine in 67 % yield. The main goal of the thesis was the preparation of an N-Fmoc-protected building block which could be used further in solid-phase peptide synthesis (SPPS). For this reason, I exchanged the protective groups of the fluorinated derivative of protected L-homoserine, affording N-Fmoc-O-(perfluoro-tert-butyl)-L-homoserinate in 77 % yield. The deprotection procedure I used in my thesis showed improved reaction efficiency compared to previously reported methods in the literature. The overall yield of the synthesis – from introduction of protecting groups to L-homoserine, to exchange of protective groups – was 26 %. This showed an improvement over a previous literature reported synthesis of only 4 % yield.

• Ključne besede: Fluorinated aminoacids, L-homoserine, Mitsunobu reaction, perfluoro-tert-butanol