Concise Asymmetric Total Synthesis of (+)-Peganumine A

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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.