藉由 Bruylants 反應合成一系列的 6-alkyluridine 衍生物

Synthesis of 6-Alkyluridine Derivatives via Bruylants Reaction

楊雅媖(Ya-Ying Yang)

指導教授 ： 簡敦誠

國立臺灣師範大學/理學院/化學系/碩士(2012年)

摘要

本論文主旨為合成 6-alkyluridine 衍生物，作為具潛力的 orotidine 5’-monophosphate decarboxylase (ODCase) 酵素抑制劑。 6-Alkyluridines 為重要的 uridine 類似物，特別的是其構型為 syn conformation ，不同於 uridine 的 anti conformation 。 Uridine 衍生物的構型與其生物活性有密切的關係，因此 6-alkyluridine 成為探討這類生物標的物的有效探針。
在我們的研究中，嘗試利用 ethyl magnesium bromide 對 6-cyano-1,3-dimethyliracil 進行加成反應來得到 6-propinoyl-1.3-dimethyluracil ，反應結果卻意外得到直接取代的化合物 6-ethyl-1,3-dimethyliracil 。此取代反應使我們獲得不同以往文獻方法，來合成 6-alkyluridine 衍生物。
以 6-Cyano-1,3-dimethyluracil 作為反應模型，與具有 sp3 混成的格林納試劑進行取代反應，可有效率地得到 6-alkyl-1,3-dimethyluracil 產物，此外加入路易士酸 ZnCl2 可幫助提高反應的效率。此方法應用於具適當保護的 6-cyanouridine上，然後藉由與格林納試劑進行取代反應並移除保護基後，得到一系列的 6-alkyluridine 的衍生物。
我們發展一個新穎且有效率的合成方法，利用 6-cyanouridine 來得到一系列的 6-alkyluridine 衍生物。我們期望將此方法應用在合成一系列六位具取代的 uridine 上。

關鍵字

格林納試劑 ； 6-alkyluridine

並列摘要

The focus of this thesis is the synthesis of 6-alkyuridine derivatives as po-tential inhibitors for orotidine 5’-monophosphate decarboxylase (ODCase). 6-Alkyluridines are an important class of uridine analogs that has a syn confor-mation, in contrast to the anti conformation of uridine. The conformation of uridine derivatives play an important role in the biological system, and therefore, 6-alkyluridines have become effective probes to study the interaction between the small molecules and the biological targets.
In our attempt to synthesize 6-propinoyl 1.3-dimethyluracil, the reaction of 6-cyano-1,3-dimethyluracil with ethyl magnesium bromide did not afford the desired addition product but resulted in an unexpected substitution product, 6-ethyl-1,3-dimethyluracil. The substitution reaction provided an alternative and effective route for the synthesis of 6-alkyluridine derivatives. Subsequently, 6-cyano-1,3-dimethyluracil was chosen as the reaction model to investigate the substitution reaction with Grignard reagents. In addition, the ZnCl2 as a Lewis acid was added to enhance the reaction efficiency. Our studies have shown that 6-cyano-1,3-dimethyluracil can undergo the substitution with sp3 Grignard rea-gents effectively to introduce the alkyl substituents. Therefore, the methodology was applied to an appropriately protected 6-cyanouridine and, after the deprotection, a series of 6-alkyluridine derivatives were synthesized accordingly.
We have developed a novel and efficient protocol for the synthesis of the 6-alkyluridine derivatives from the corresponding 6-cyanouridines. We antici-pated that this approach will be feasible for the preparation a wide variety of 6-substituted uridine.

並列關鍵字

Grignard reagent ； 6-alkyluridine

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