利用含硼酯異腈化合物合成ugi四組成反應衍生物(I) 合成含硼酯之甲基醯胺異腈衍生物(II) 合成含硼之甲基醯胺四氮唑衍生物(III)

Synthesis of Ugi-4CR Analogs using Isocyanoboronate Ester Building Blocks(I) Synthesis of Amidomethyl Isocyano Boronate Ester Analogs(II) Synthesis of Boron-containing Amidomethyl Tetrazole Analogs(III)

李佳容(CHIA-JUNG LI)

指導教授 ： 潘伯申

淡江大學/理學院/化學學系碩士班/碩士(2015年)

https://doi.org/10.6846/TKU.2015.00521

摘要

利用含硼酯異腈化合物合成ugi四組成反應衍生物(I):
在傳統的藥物開發中，含硼分子顯少被列入考慮，近幾年在藥物合成上，不再侷限於一般天然物中含有的元素。硼，亦被使用在藥物合成中，近來研究發現含硼藥物分子對其所作用之生化目標具有高度選擇性與高度活性等優點，使許多研究單位逐漸積極投入含硼藥物之開發。
本研究講述兩種合成含硼甲基醯胺化合物之合成方法( Scheme 1 )，並討論兩種方法之優缺比較，將上述的含硼甲基醯胺化合物成功合成出含硼酯異腈化合物 ( Scheme 2 )。並間接利用含硼異腈化合物進行Ugi-4CR反應( Scheme 3 )，嘗試成功合成出含單硼原子化合物。
合成含硼酯之甲基醯胺異腈衍生物(II):
本研究目的在於開發適用於硼中子捕獲治療的藥物，鑒於硼中子捕獲治療的重要性並結合Ugi reaction的廣泛應用性，且成功合成出含硼之化合物 ( Scheme 4 )，期望能對癌症治療有進一步的發展。而後將所得之化合物進行一系列的藥物化學結構，找出作為後續藥物開發的領導藥物。此外，甲基醯胺官能基亦能轉成異腈結構( Scheme 5 )，提高分子多樣性及生物多樣性。
合成含硼之甲基醯胺四氮唑衍生物 (III):
雜環化合物是一類具有藥理活性的小分子化合物，例如四氮唑衍生物可做為抗腫瘤、抗過敏活性，亦可減緩肝臟代謝率，進而增加生物利用度，根據上述所合成出的含硼酯之甲基醯胺異腈，可藉由TMS-N3轉換成含硼之甲基醯胺四氮唑衍生物( Scheme 6 )，提供一個新的含硼分子合成路徑，並且增加了異腈化合物的廣用性。

關鍵字

含硼酯異腈化合物 ； 含硼之甲基醯胺四氮唑衍生物 ； 含硼酯之甲基醯胺異腈衍生物

並列摘要

The boron analogs are less considered as pharmaceutical agents. However, the approval of Bortezomib ( velcadeTM ) has encouraged medicinal chemists to put an effort on discovering boron-containing drugs. In the first part of this thesis, I will talk about the synthesis of boron-containing formamide via two different synthetic strategies ( Scheme 1 ). Their advantages and disadvantages will be included as well. After successfully obtained the desired boron-containing formamides, these analogs were transformed to the corresponding isocyanides through dehydration process ( Scheme 2 ). With these boron-containing isocyanides in hand, the microwave-assisted Ugi-4CR was employed to construct series of amidomethyl isocyano boronate esters ( Scheme 3 ).
In the second part of my thesis, I successfully synthesized boron-containing formyl compounds via Ugi-
3CR ( Scheme 4 ), These compounds were then converted to the corresponding boron-containing amidomethyl isocyanides ( Scheme 5 ).Heterocycles are often appears in many biological active nature products, which possess interesting medicinal properties (i.e. such as spasmolytic, diuretic, anticoagulant, anticancer, and antianaphylactic activities.), hence, they are considered as an important class of functional group in medicinal chemistry. In the third part of my thesis, I will utilize the amidomethyl isocyano boronate ester analogs, which were synthesized from the previous chapter, to construct series of the corresponding tetrazoles. ( Scheme 6 ). These compounds were currently under biological evaluations, and the results will be reported in the future.

並列關鍵字

Boron-containing ； Ugi reaction ； isocyanide ； Terazole

參考文獻

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