Concise Asymmetric Total Synthesis of (+)-Peganumine A

癌症仍然是德国的主要死因之一，仅次于循环系统疾病。因此，开发用于癌症预防和治疗的新药仍然是一项非常重要的任务。最近从骆驼蓬（Peganum harmala）种子中分离得到一种具有良好抗癌活性的β-咔啉生物碱（+）-骆驼蓬胺A（peganumine A）。它的新型多环支架提出了一个艰巨的合成挑战，并为开发新的和广泛适用的化学提供了重要的机会。受生物合成考虑的启发，计划采用容易获得的起始材料进行不对称全合成。在这个简洁的合成中的关键步骤被设想为不对称Pictet-Spengler反应或β-咔啉衍生物的选择性偶联。研究和开发的有效策略，用于生成必要的两个连续的季取代的碳中心的立体化学控制将探索使用有效的策略，包括催化不对称Pictet-Spengler反应，容易获得的手性助剂和催化不对称迈克尔加成反应。这些研究中获得的（+）-peganumine A和高级合成中间体的合成样品将通过麻省理工学院科赫综合癌症研究所Movassaghi小组的既定合作项目进行抗癌活性的详细评价。

Cancer is still one of the main causes of death in Germany, second only to diseases of the circulatory system. Thus the development of new drugs for cancer prevention and treatment is still a highly important task. Recently a complex beta-carboline alkaloid, (+)-peganumine A, with excellent potential application as an anticancer compound was isolated from the seeds of Peganum harmala. Its novel polycyclic scaffold presents a formidable synthetic challenge and offers significant opportunity for development of new and broadly applicable chemistry. Inspired by biosynthetic considerations an asymmetric total synthesis is planned that employs readily available starting materials. The key step in this concise synthesis is envisioned to be either an asymmetric Pictet-Spengler reaction or a selective coupling of beta-carboline derivatives. The investigation and development of efficient strategies for generation of the necessary two contiguous quaternary substituted carbon centers with stereochemical control will be explored using efficient strategies including catalytic asymmetric Pictet-Spengler reactions, readily available chiral auxiliaries and catalytic asymmetric Michael addition reactions. The synthetic samples of (+)-peganumine A and advanced synthetic intermediates accessed in these studies will be subject to detailed evaluation for anticancer activity through established collaborative engagements of the Movassaghi group at the MIT Koch Institute for Integrative Cancer Research.