Radical Ring Expansion Reactions on Solid support

该项目的目标是开发一种用于组合化学的新型无迹连接子。在建立了包括合成头孢菌素D在内的一些基础化学之后，我们将寻求合成一个小的肽类抑制剂文库，以针对各种酶靶点进行筛选，例如ras-法尼基转移酶(与癌症有关)、组织蛋白酶D(肿瘤转移)、血管紧张素转换酶(高血压)、中性内肽酶(充血性心力衰竭)和凝血酶(止血和凝血)。合成中的关键事件将是固体载体上的自由基扩环反应，同时从树脂中释放所需的缓蚀剂。自由基反应已成为溶液相化学中强有力的选择，但对固体载体上的自由基反应知之甚少。我们的项目将在这一领域提供有用的见解。幸运的是，自由基切割步骤中可能发生的副反应不应损害所需抑制剂的纯度，从而保证在生物筛选中取得有意义的结果。

The goal of this project is to develop a novel traceless linker for use in combinatorial chemistry. Afer establishing some basic chemistry including the synthesis of cephalosporolide D, we will seek to synthesize a small library of peptidomimetic inhibitors that will be screened against a variety of enzyme targets, such as ras-farnesyl transferase (involved in cancer), cathepsin D (tumor metastasis), angiotensin converting enzyme (hypertension), neutral endopeptidase (congestive heart failure) and thrombin (hemostasis and blood clotting). The key event in the synthesis will be a radical ring-expansion reaction on solid support that simultaneously releases the desired inhibitors from the resin. Radical reactions have emerged as powerful options in solution-phase chemistry, but comparatively little is known about radical reactions on solid support. Our project will provide useful insights in this area. Fortunately, possible side reactions in the radical cleavage step should not compromise the purity of the desired inhibitors, thus guaranteeing meaningful results in the biological screening.