- 學位論文
利用二碘化釤介導的環化和頻哪醇重排合成雙環[2.1.1]己烷衍生物作為鄰位取代的苯生物電子等排體
Synthesis of Bicyclo[2.1.1]hexane Derivatives as ortho-Substituted Benzene Bioisosteres via SmI2-mediated Cyclization and Pinacol Rearrangement
摘要
在藥物開發領域中，人們對於鄰位和間位取代的苯生物電子等排體的認識不斷增加，促進了其製備方法的發展。近年來提出幾種非共軛剛性碳氫化合物可作為苯生物電子等排體，其中發表較少的雙取代雙環[2.1.1]己烷具有相當高的潛力。因此我們提出了兩種可能的方法來獲得所需的5-取代雙環[2.1.1]己-1-醇和1-取代雙環[2.1.1]己-5-酮，分別是二碘化釤介導的環化和嚬哪醇重排反應。我們在二碘化釤介導的反應中得到不可預期的結果，而另一種重排方法已被證明可以成功建構雙環[2.1.1]己烷。該方法涉及連續的環丙烷化、嚬哪醇重排反應，將α-羥基矽基烯醇醚轉化為1-取代雙環[2.1.1]己-5-酮，此種雙環核心是製備鄰位取代苯生物電子等排體的關鍵中間體。為此，我們對雙環酮進行了多種官能基轉化，獲得多種1,5-雙取代的雙環[2.1.1]己烷衍生物。我們相信這些新方法可以有效解決合成鄰位取代苯生物電子等排體的障礙。
並列摘要
The increased recognition of ortho- and meta-substituted benzene bioisosteres in drug development has prompted the development of synthetic methods for their preparation. Several non-conjugated rigid hydrocarbons have been proposed as benzene bioisosteres, and among them, the less reported disubstituted bicyclo[2.1.1]hexanes (BCHs) have the potential to serve as bioisosteric frameworks. Herein, we propose two possible methods to obtain the desired 5-substituted bicyclo[2.1.1]hexan-1-ol and 1-substituted bicyclo[2.1.1]hexan-5-ones, namely SmI2-mediated cyclizations and pinacol rearrangement reactions. Despite encountering setbacks in the SmI2-mediated reaction, a simple and effective rearrangement approach was shown to deliver BCHs. This process involves the conversion of α-hydroxyl silyl enol ether to 1-substituted bicyclo[2.1.1]hexan-5-ones through a sequential cyclopropanation/pinacol rearrangement reaction. This bicyclic core was envisioned as a key intermediate for the preparation of ortho-substituted benzene bioisosteres. As such, several functional group interconversions were performed on the bicyclic ketone, resulting in various 1,5-disubstituted BCHs that could serve as ortho-substituted benzene bioisosteres. We believe these approaches offer a promising strategy to address the complex obstacles associated with the construction of bioisosteres resembling ortho-substituted benzenes.