Enantiodivergent Synthesis of (+) and (-) Pancratistatin

( ) 和 (-) Pancratistatin 的对映异构合成

• 批准号: 6593475
• 负责人: ALEXANDER KORNIENKO
• 金额: $ 14.47万
• 依托单位: NEW MEXICO INST OF MINING & TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-09 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6593475
• 关键词: alkaloids; antineoplastic antibiotics; chemical addition; chemical structure function; cyclization; drug design /synthesis /production; stereochemistry; xylose

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. The proposed synthesis of the two pancratistatin enantiomers follows two diverging synthetic pathways leading to each target enantiomer. The key step in both pathways is a ring-closing metathesis process, which represents a novel strategy for assembling the multi-functionalized ring C of pancratistatin skeleton. The flexibility of the proposed synthetic scheme will allow for thorough optimization of the synthesis in search for high efficiency and practicality. Additionally, the fact that L-xylose is commercially available as well will make it possible to reach (+)-pancratistatin via either of the two pathways.

描述（由申请人提供）：该项目的最终目标是提供治疗癌症的新治疗剂。从 Pancratium littorale 球茎中提取的生物碱 (+)-pancratistatin 具有良好的抗肿瘤和抗病毒活性，目前正在接受美国国家癌症研究所的临床前评估。然而，由于隔离可用的材料数量有限，这些研究已被搁置。生物碱的有限可用性也困扰着阐明其作用机制以及结构-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可能至关重要。因此，开发一种能够克级制备(+)-pancratistatin的有效化学路线将极大地促进对该化合物及其类似物的进一步生物学和医学评价，因此一直是科学界长期追求的目标。本申请提出的工作重点是从 D-木糖实际对映异构合成 (+)-pancratistatin 和对映体 (-)-pancratistatin。尽管最近的数据表明对映体 pancratistatin 系列可能具有类似的活性，但后一种化合物尚未以对映体纯形式合成。两种pancratistatin对映体的拟议合成遵循两条不同的合成途径，产生每种目标对映体。这两条途径的关键步骤是闭环复分解过程，它代表了组装 pancratistatin 骨架的多功能化 C 环的新策略。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。此外，L-木糖也可在市场上买到，这一事实将使得通过这两种途径之一到达 (+)-pancratistatin 成为可能。