Enantiodivergent Synthesis of (+) and (-) Pancratistatin

项目描述（申请人提供）：本项目的最终目标是为癌症的治疗提供新的治疗药物。从扁豆鳞茎中提取的生物碱(+)-扁豆素显示出有希望的抗肿瘤和抗病毒活性，目前正在由美国国家癌症研究所进行临床前评估。然而，由于从隔离中获得的材料数量有限，这些研究已被搁置。生物碱有限的可用性也阻碍了阐明其作用机制和结构-活性研究的努力，这对于鉴定更有效和/或毒性更低的类似物至关重要。因此，开发一种能够克量制备(+)-胰虫素的有效化学途径将极大地促进该化合物及其类似物的进一步生物学和医学评价，因此它一直是科学界长期追求的目标。本应用程序主要研究了d -木糖对映发散性合成(+)-潘克拉司汀和(-)-潘克拉司汀的方法。后一种化合物还没有以对映体纯形式合成，尽管最近的数据显示在对映体中有类似活性的可能性。除了三个步骤外，两种潘克拉他汀对映体的合成是基于相同的途径。关键的转化是闭合环的复合过程，这代表了一种组装多功能化环C的新策略。所提出的合成方案的灵活性将允许对合成进行彻底优化，以寻求高效率和实用性。

DESCRIPTION (provided by applicant): This project is aimed at the ultimate goal of providing new therapeutic agents for the treatment of cancer. The alkaloid (+)-pancratistatin, extracted from Pancratium littorale bulbs, displays promising antineoplastic and antiviral activity and is currently undergoing preclinical evaluation by the US National Cancer Institute. However, the studies have been put on hold due to the limited quantity of material available from isolation. The alkaloid's limited availability has also plagued efforts towards the elucidation of its mechanism of action as well as structure - activity studies, which could be crucial for the identification of more potent and/or less toxic analogs. Therefore, the development of an efficient chemical route enabling gram-quantity preparation of (+)-pancratistatin will tremendously facilitate further biological and medicinal evaluation of this compound and its analogs, hence it has been a long-sought objective of the scientific community. The work proposed in this application focuses on a practical enantiodivergent synthesis of (+)-pancratistatin and enantiomeric (-)-pancratistatin from D-xylose. The latter compound has not been synthesized in enantiomerically pure form, in spite of recent data revealing the possibility of similar activity in the enantiomeric pancratistatin series. With the exception of three steps, the proposed syntheses of the two pancratistatin enantiomers are based on the same pathway. The key transformation is a ring-closing metathesis process, which represents a novel strategy for assembling the multi-functionalized ring C of the pancratistatin skeleton. The flexibility of the proposed synthetic scheme will allow for thorough optimization of the synthesis in search for high efficiency and practicality.