Enantiodivergent Synthesis of (+) and (-) Pancratistatin

( ) 和 (-) Pancratistatin 的对映异构合成

• 批准号: 6896624
• 负责人: ALEXANDER KORNIENKO
• 金额: $ 19.56万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896624
• 关键词: alkaloids; antineoplastic antibiotics; biological products; chemical addition; chemical structure function; cyclization; drug design /synthesis /production; isoquinolines; 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. 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.

项目描述（申请人提供）：本项目的最终目标是为癌症治疗提供新的治疗药物。从Pancratium littorale鳞茎中提取的生物碱（+）-panvastatin显示出有希望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，由于可从隔离中获得的材料数量有限，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至关重要。因此，开发一种有效的化学途径，能够克量制备（+）-潘曲他汀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寻求的目标。本申请中提出的工作集中于从D-木糖合成（+）-潘司他汀和对映体（-）-潘司他汀的实际对映体发散合成。后一种化合物尚未以对映体纯的形式合成，尽管最近的数据揭示了在对映体的帕帕司他汀系列中具有类似活性的可能性。除了三个步骤之外，两种帕帕司他汀对映体的拟定合成基于相同的途径。关键的转化是闭环复分解过程，其代表了用于组装潘帕他汀骨架的多官能化环C的新策略。所提出的合成方案的灵活性将允许彻底优化的合成，以寻求高效率和实用性。

项目成果

An approach to pancratistatins via ring-closing metathesis: efficient synthesis of novel 1-aryl-1-deoxyconduritols F. cv.

• DOI: 10.1021/ol049942p
• 发表时间: 2004-01
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: O. N. Nadein;A. Kornienko

Enantiodivergent formal synthesis of (+)- and (-)-cyclophellitol from D-xylose based on the latent symmetry concept.

基于潜在对称性概念，从 D-木糖对映异构正式合成 ( )- 和 (-)-环苯乙醇。

• DOI: 10.1021/jo048459p
• 发表时间: 2005
• 期刊: The Journal of organic chemistry.
• 作者: Kireev,ArtemS;Breithaupt,AugustT;Collins,William;Nadein,OlegN;Kornienko,Alexander
• 通讯作者: Kornienko,Alexander