A novel synthetic route to adamantyltriazole derivative of mannosylated desmuramyl dipeptide

U sklopu diplomskog rada ispitana je mogućnosti priprave adamantil-triazolnog derivata desmuramildipeptida, L-Ala-D-isoGln, koji je dodatno modificiran uvoĎenjem manozne podjedinice vezane za dipeptid preko acetilne poveznice. Kao peptidni prekursor pripravljen je zaštićeni dipeptid Boc-L-Ala- D-Glu(OBn), a na istome je uspješno provedena reakcija amidacije s propargilaminom uz Nmetilmorfolin te n-butil-klorformijat kao kondenzacijski reagens. Metoda amidacije optimirana je i uspješno iskorištena i prilikom uvoĎenja adamantil-triazolne podjedinice u strukturu dipeptida. Adamantil-triazolna podjedinica pripravljena je „one-pot“ sintezom iz komercijalno dostupnog propargilamina i prethodno pripravljenog 1-azidoadamantana. Optimirana „one-pot“ sinteza uspješno je upotrijebljena u laboratoriju za pripravu novih 1,4-supstituiranih triazolnih derivata propargilamina. U klik-reakciji koja je dio „one-pot“ sinteze kao katalizator korišten je in situ generirani bakar(I). Prethodno pripravljena benzilima zaštićena manoza preko acetilne poveznice u reakciji kondenzacije povezana je s propargiliranim dipeptidom i adamantil-triazolnim derivatom desmuramil-dipeptida. Konačni cilj diplomskog rada je pripravljanje izomerno čistog manoziliranog adamantil-triazolnog derivata desmuramil-dipeptida kojem je po pripravi potrebno in vivo ispitati adjuvantsku aktivnost.In this diploma thesis, the possibilities of preparation of the adamantyltriazole derivative of desmuramyldipeptide, which was further modified by the introduction of a mannose subunit bound to the dipeptide via an acetyl linker, were investigated. The protected dipeptide Boc-L-Ala-D-Glu-(OBn) was prepared first as a peptide precursor and then modified successfully in the amidation reaction with propargylamine. In this reaction n-butyl chloroformate was used as the condensing reagent and Nmethylmorpholine as a base. The amidation method was optimized and successfully applied for the introduction of the adamantyltriazole subunit into the structure of the dipeptide. The adamantyltriazole subunit was prepared by one-pot synthesis from commercially available propargylamine and previously prepared azidoadamantane. Optimized one-pot synthesis has been successfully used in the laboratory for the preparation of new 1,4-substituted triazole propargylamine derivatives. As a part of the one-pot synthesis in situ-generated copper(I) was used as a catalyst. Previously prepared benzylprotected mannose in the penultimate step of the overall synthesis is connected to a propargylated dipeptide and an adamantyltriazole derivative of desmuramyldipeptide. The final goal of the diploma thesis is the preparation of an isomerically pure deprotected manosylated adamantyltriazole derivative of desmuramyldipeptide. Adjuvant activity will be tested in vivo on the prepared target molecule