Concise Asymmetric Total Synthesis of (+)-Peganumine A

在德国，癌症仍然是仅次于循环系统疾病的主要死亡原因之一。因此，开发癌症防治新药仍然是一项非常重要的任务。最近，从骆驼蓬种子中分离得到了一种具有良好抗癌应用潜力的β-咔啉生物碱(+)-peganumine A。其新颖的多环支架对合成提出了巨大的挑战，并为发展新的和广泛应用的化学提供了重要的机会。在生物合成考虑的启发下，计划使用容易获得的原料进行不对称全合成。这一简明合成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。利用高效的策略，包括催化不对称Pictet-Spengler反应、手性助剂和催化不对称Michael加成反应，将探索和开发有效的策略来生成具有立体化学控制的两个连续的四元取代碳中心。在这些研究中获得的(+)-peganumine A的合成样品和先进的合成中间体将通过麻省理工学院科赫综合癌症研究所的Movassaghi小组建立的合作关系进行详细的抗癌活性评估。

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.