透過連續分子內二碘化釤介導的還原偶聯和酸催化頻哪醇重排反應合成 1-取代雙環[2.1.1]己-2-酮

Abstract

“逃離平面”的概念已成為藥物化學中的一個關鍵焦點，旨在提高候選藥物進入市場的成功率。這涉及從傳統的平面芳香結構（如苯環）向探索三維結構的轉變。其中一類特定的結構是雙環[2.1.1]己烷，其中二取代的雙環[2.1.1]己烷有望成為鄰位和間位取代苯的生物等排體。這些雙環化合物提供了獨特的取代模式和幾何形狀，顯示出有望替代藥物分子中特定苯衍生物的潛力。 這篇論文提出一種合成策略，涉及分子內的二碘化釤介導的酮-酮頻哪醇偶聯反應和酸催化的頻哪醇重排反應，以將3-(2-氧-2-乙基)環丁酮轉化為1-取代雙環[2.1.1]己酮。我們相信，這些雙環酮可作為易於修飾的中間體，從而獲得鄰位取代芳烴的潛在生物等排體。

The concept of "escape from flatland" has become a pivotal focus in medicinal chemistry, aiming to enhance the success of drug candidates reaching the market. This involves a departure from traditional flat, planar aromatic structures, like benzene rings, towards the exploration of three-dimensional (3-D) architectures. One specific class of such structures is bicyclo[2.1.1]hexanes (BCHs), with disubstituted BCHs emerging as potential bioisosteres for ortho- and meta-substituted benzenes. These bicyclic compounds offer unique substitution patterns and geometries, making them promising candidates to replace specific benzene derivatives in drug molecules. This thesis describes a synthetic strategy involving an intramolecular SmI2-mediated ketone-ketone pinacol coupling and an acid-catalyzed pinacol rearrangement to convert 3-(2-oxo-2-ethyl)cylobutan-1-ones into 1-substituted bicyclo[2.1.1]hexan-2-ones. We believe that these bicyclic ketones could serve as easily modifiable intermediates to access potential bioisosteres to ortho-substituted arenes.