Development of synthetic methods for the preparation of triazole derivatives of mannosylated desmuramyl dipeptide

U sklopu diplomskog rada ispitana je mogućnost strukturnog modificiranja desmuramil-dipeptida uvođenjem manozne i triazolne podjedinice supstituirane adamantanom. Kao polazni dipeptid pripravljen je Boc-L-alanil-D-glutaminska kiselina 6 (Boc-L-Ala-D-Glu(OBn)-OH). Adamantilom supstituirana triazolna podjedinica uvedena je na dipeptid azid-alkin cikloadicijom (klik-reakcija). Terminalna alkinska komponenta za klik-reakciju pripravljena je propargiliranjem α-karboksilne skupine glutaminske kiseline dipeptida 6 s propargilaminom pri čemu je dobiven propargilirani dipeptid 8, dok je 1-azidoadamantan (11) pripravljen iz adamantan-1-ola. Klik-reakcijom spojeva 8 i 11 dobiven je adamantilom modificiran dipeptid 12. Benzilima zaštićena manozna podjednica 4 sintetizirana je u nekoliko koraka iz polaznog metil-α-D-manopiranozida i vezana preko glikolne poveznice na terminalnu amino-skupinu alanina spoja 8, s kojeg je prethodno uklonjena Boc zaštita, dajući zaštićeni manozilirani propargilirani dipeptid 10. Klik-reakcijom spojeva 10 i 11 pripravljena je zaštićena ciljna molekula 13. Konačni cilj diplomskog rada jest optimizirati ključne korake u sintezi (priprava dipeptida, propargiliranje, klik-reakcija, vezanje manozne podjedinice) u smislu priprave izomerno čistih spojeva što će se primijeniti za pripravu različitih triazolnih derivata manoziliranog desmuramil-dipeptida u svrhu priprave novih adjuvanata.Structural modification of desmuramyl dipeptide by incorporation of mannose and adamantyl triazole subunit was investigated in this diploma thesis. Dipeptide Boc-L-alanyl-D-glutamic acid 6 (Boc-L-Ala-D-Glu(OBn)-OH) was prepared first. Adamantyl triazole subunit was incorporated to peptide structure by azide-alkyne cycloaddition (the click-reaction). Terminal alkyne part for the click reaction was prepared by propargylation of α-carboxyl group of glutamic acid on dipeptide 6 using propargyl amine. Thus, propargylated dipeptide 8 was obtained. Azide component, 1-azidoadamantane (11), was prepared from adamantan-1-ol. Click-reaction of compounds 8 and 11 resulted in adamantyl dipeptide conjugate 12. Benzylated mannose unit 4 was prepared in few steps from methyl-α-D-mannopyranoside. It was connected to terminal amino group of alanine in 8 through glycolic acid which gave benzylated mannosylated propargyl dipeptide 10. Boc protection was removed from compound 8 prior to that step. Click-reaction of 10 and 11 gave target compound 13. The aim of this thesis was to optimize the key synthetic steps (preparation of dipeptide, propargylation, click-reaction, incorporation of mannose unit) in order to obtain pure isomers. This optimized steps will be applied in the preparation of various triazole derivatives of mannosylated desmuramyl dipeptide as potential new adjuvants