|
|
Synthesis of fluorinated nucleosides
Nguyen, Van Hai ; Hocek, Michal (advisor) ; Baszczyňski, Ondřej (referee)
The key intermediate 6-amino-7-iodo-7-deazapurine 3'-deoxy-3'-fluororibonucleoside was synthesized using multistep sequence of several reactions, which started from the commercially available D-xylose and 6-chloro-7-deazapurine. The synthetic strategy was based on fluorination of sugar and glycosylation with corresponding nucleobase afterwards. The fluorination of 5-protected-1,2-isopropylidine xylose with different protecting groups at position 5 always led to elimination. It was later discovered that isopropylidine forces the conformation, which is unfavorable for substitution. During the extensive optimization it was also found out that DAST appears to be an optimal fluorinating agent. Fluorination was performed on 2,3-unprotected xylose, which was subsequently used for glycosylation. After several unsuccessful attempts on "protection group free" glycosylation, Vorbrüggen glycosylation was successful and gave desired 3'-fluoro nucleoside in good yield. However, benzoyl group had to be introduced into position 2'. The protected nucleoside was then aminated and simultaneously deproctected with solution of aqueous NH3 and 1,4-dioxane. The obtained key intermediate was used for synthesis of a small series of desired 6-amino-7-hetaryl nucleoside using Pd-catalyzed Suzuki reaction under aqueous...
|
|
|
Synthesis of nucleoside analogs based on derivatives of 2-deoxy-2-fluoro- and 3-deoxy-3-fluoro-D-ribose and pyrazines
Smolka, Ondřej ; Jindřich, Jindřich (advisor) ; Smrček, Stanislav (referee)
This thesis deals with the synthesis of prodrugs based on analogs of nucleoside phosphonates derived from 6-fluoro-3-hydroxypyrazine-2-carboxamide (T-705) and 3- hydroxypyrazine-2-carboxamide (T-1105). T-705 and T-1105 act as inhibitors of an influenza RNA polymerase. Both compounds mimic naturally occurring nucleobases, so their fluorinated nucleoside phosphonates could also be biologically active. Derivatives of 2-deoxy-2-fluoro-D-ribose (2-FdR) were prepared in this work. Because of complications during the syntthesis of 3-deoxy-3-fluoro-D-ribose (3-FdR) derivatives, 5- deoxy-5-fluoro-D-xylose (5-FdX) derivatives were prepared instead. Deoxyfluorination was done after incorporation of suitable protecting groups followed by selective deprotection and phosphonate binding. Furthermore nucleosides were synthetised using silyl-Hilbert-Johnson method and their bis-POM derivattives were also prepared. Key words: favipiravir (T-705), T-1105, prodrugs, phosphonates, fluorinated nucleosides
|
|
|
Synthesis of fluorinated nucleosides
Nguyen, Van Hai ; Hocek, Michal (advisor) ; Baszczyňski, Ondřej (referee)
The key intermediate 6-amino-7-iodo-7-deazapurine 3'-deoxy-3'-fluororibonucleoside was synthesized using multistep sequence of several reactions, which started from the commercially available D-xylose and 6-chloro-7-deazapurine. The synthetic strategy was based on fluorination of sugar and glycosylation with corresponding nucleobase afterwards. The fluorination of 5-protected-1,2-isopropylidine xylose with different protecting groups at position 5 always led to elimination. It was later discovered that isopropylidine forces the conformation, which is unfavorable for substitution. During the extensive optimization it was also found out that DAST appears to be an optimal fluorinating agent. Fluorination was performed on 2,3-unprotected xylose, which was subsequently used for glycosylation. After several unsuccessful attempts on "protection group free" glycosylation, Vorbrüggen glycosylation was successful and gave desired 3'-fluoro nucleoside in good yield. However, benzoyl group had to be introduced into position 2'. The protected nucleoside was then aminated and simultaneously deproctected with solution of aqueous NH3 and 1,4-dioxane. The obtained key intermediate was used for synthesis of a small series of desired 6-amino-7-hetaryl nucleoside using Pd-catalyzed Suzuki reaction under aqueous...
|
|
|
Preparation of fluorinated carbocyclic derivatives of nucleosides as potential viral replication inhibitors
Štefek, Milan ; Nencka, Radim (advisor) ; Šimák, Ondřej (referee)
This master thesis is dedicated to the preparation of fluorinated derivatives of carbocyclic nucleosides, that may serve as flaviviral replication inhibitors. Preparation of both monofluorinated as well as gem-difluorinated analogs of ribo and 2'-deoxyribonucleoside was attempted. While a suitable and reliable route for the preparation of monofluorinated compounds way found, synthesis of gem-difluorinated turned out to be rather challenging. Although most of the presented work dealt with compounds bearing adenine as a nucleobase, the universal applicability of the developed procedures, demonstrated on the preparation of a guanosine-type molecule, suggests that after slight optimization larger series of this type of compounds could be prepared.
|
guest ::
