Sinteza amidnog derivata disupstituiranog ferocena i desmuramil-peptida

master's thesis

• Title (english): Synthesis of amide derivative of a disubstituted ferrocene and desmuramyl-peptide
• Author: Adela Šambar
• Mentor: Željka Car (mentor)
• Committee member: Željka Car (predsjednik povjerenstva)
• Committee member: Marina Cindrić (član povjerenstva)
• Committee member: Iva Juranović Cindrić (član povjerenstva)
• Committee member: Vesna Petrović Peroković (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2023-09-29, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

U sklopu ovog diplomskog rada razvijen je sintetski put priprave amidnog derivata disupstituiranog ferocena i desmuramil-peptida (DMP). Ciljni spoj 10 je sintetiziran vezanjem također pripravljenih strukturnih motiva: O-benzilnog derivata disupstituirane ferocenkarboksilne kiseline 4 te tert-butilnog derivata DMP 8. Amidna veza između te dvije podjedinice ostvarena je pomoću pouzdane EDC/HOBt metode koja se često koristi u tu svrhu u peptidnoj kemiji. Spoj 4 je pripravljen prevođenjem polazne 1'-metoksikarbonilferocen-1-karboksilne kiseline u kiselinski klorid 1, zatim redukcijom spoja 1 s natrijevim borhidridom do alkohola 2, uvođenjem benzilne zaštite te saponifikacijom metilnog estera. Derivat DMP 8 je sintetiziran iz tert-butil- i Boc-zaštićene D-glutaminske kiseline koja je prvo pretvorena u izoglutaminski derivat 5 i amidnom vezom vezana na zaštićeni i aktivirani derivat L-alanina (Fmoc-L-Ala-OPfp) uz DIPEA kao bazu. Zatim je Fmoc skupina uklonjena s N-kraja spoja 7 uz oktan-1-tiol i DBU. Sintetski put priprave spoja 10 završava korakom uklanjanja benzilne zaštite sa spoja 9 hidrogenolizom. Provedena je strukturna karakterizacija svih sintetiziranih spojeva (1H i DEPTQ NMR spektroskopija, spektrometrija masa LC-MS). Ovako optimizirana metoda poslužit će za sintezu ostalih sličnih spojeva ove serije u budućim istraživanjima čiji je konačni cilj ispitivanje njihove adjuvantske aktivnosti.

Abstract (english)

In this Thesis the synthetic route for the preparation of amide derivative of disubstituted ferrocene and desmuramyl peptide (DMP) was optimized. The target compound 10 was prepared by combining following, also prepared structural motifs: O-benzyl derivative of disubstituted ferrocene carboxylic acid 4 and tert-butyl DMP derivative 8. Amide bond between those two units was formed by reliable EDC/HOBt method which is often used in peptide chemistry for this purpose. Compound 4 was synthesized by converting 1'-methoxycarbonyl ferrocene-1-carboxylic acid to acyl chloride 1, reduction of 1 with sodium borohydride to alcohol 2, incorporation of benzyl protection and methyl ester saponification. DMP derivative 8 was prepared from tert-butyl and Boc protected D-glutamic acid which was converted to isoglutamine 5 first and then connected to protected and activated L-alanine (Fmoc-L-AlaOPfp) by an amide bond with DIPEA as a base. Fmoc group was removed from
N-terminus of 7 by 1-octanethiol and DBU. The synthetic route to target molecule 10 ends with benzyl protection removal from 9 by hydrogenolysis. Structural characterization of all compounds was performed by 1H and DEPTQ NMR spectroscopy as well as mass spectrometry (LC-MS). Optimized synthetic route presented here will serve for the preparation of similar compounds of this series for the final purpose of evaluating their adjuvant activity.

• Keywords: adjuvant; amid; desmuramil-peptid; ferocen
• Keywords (english): adjuvant; amide; desmuramyl peptide; ferrocene
• Language: croatian
• URN:NBN: urn:nbn:hr:217:007230
• Project: Number: IP-2020-02-9162; Title: Ferocenski analozi biomolekula: strukturna karakterizacija i biološka evaluacija; Title: Ferrocene analogues of biomolecules: structural characterization and biological evaluation; Acronym: FER-AN-BIOMOL; Leader: Lidija Barišić; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Study programme: Title: Graduate university studies in chemistry; specializations in: Research programme; Course: Research programme; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra kemije (magistar/magistra kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2025-09-29
• Created on: 2023-10-16 12:40:13