利用向山試劑促進烯酮[2+2]環加成合成雙環[2.1.1]己烷衍生物

Abstract

當今，在藥物化學中，生物等排體的概念仍然是一個關鍵策略，能夠幫助研究人員優化藥物候選化合物的性質，提高其生物活性，同時減少不良反應。苯環經常作為藥物分子中的關鍵組成部分，因其穩定性和與特定生物靶點的互動能力，有助於增強藥物的效能。然而，使用苯環需要特別注意代謝變化可能導致的毒理學風險和代謝活化問題。過去的研究主要集中在對位以及單取代苯環的生物等排體，然而鄰位和間位取代的苯環的生物等排體卻缺乏相關的研究。在本研究中，我們決定將苯環替換為雙環[2.1.1]己烷作為鄰位取代苯環的生物等排體以解決苯環所導致的毒性問題。在本研究中，我們介紹了一種利用烯酮的分子內[2+2]環加成反應來合成1-雜原子取代的雙環[2.1.1]己-5-酮的方法。關鍵在於使用向山試劑（2-氯-N-甲基吡啶碘化物）能夠促進[2+2]環加成反應，並能以較高的產率合成雙環[2.1.1]己烷-5-酮，而這化合物已知是鄰位取代苯的生物等排體衍生物。為了證明這一點，我們利用這種方法成功製備並利用官能基轉換合成非類固醇抗炎藥芬氯芬酸的生物等位變體，顯示了這種雙環酮的合成實用性。

In contemporary medicinal chemistry, bioisosterism remains a critical approach, enabling researchers to refine drug candidates by enhancing efficacy and minimizing adverse effects. Benzene rings frequently play a pivotal role in drug molecules due to their stability and targeted biological interactions, thereby bolstering drug effectiveness. However, incorporating benzene rings necessitates caution due to potential metabolic alterations and subsequent toxicological risks from metabolic activation. To circumvent this issue, there is significant interest in the replacement of aromatic rings with constrained polycyclic hydrocarbons, such as bicyclo[2.1.1]hexanes. In this thesis, we introduce a synthetic strategy to 1-heteroatom-substituted bicyclo[2.1.1]hexan-5-ones via the intramolecular [2+2] cycloaddition of homoallyl ketenes. A key advancement involves the utilization of the Mukaiyama reagent (2-chloro-N-methyl-pyridinium iodide), which facilitates the ketene formation with high efficiency. These substrates can be potentially converted into 1,5-disubstituted bicyclo[2.1.1]hexanes, which are known to be ortho-substituted benzene bioisosteres. To demonstrate this, we prepared a bioisosteric variant of fenclofenac, a nonsteroidal anti-inflammatory drug.