Syntheses of GPI-Anchoring Inhibitors YW3548 and YW 3699

GPI 锚定抑制剂 YW3548 和 YW 3699 的合成

• 批准号: 6710307
• 负责人: DAMTEW DEMEKE
• 金额: $ 3.83万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-28 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6710307
• 关键词: binding proteins; carbopolycyclic compound; chemical synthesis; glycosylphosphatidylinositols; inhibitor /antagonist; postdoctoral investigator; stereochemistry

DESCRIPTION: (provided by applicant) Proposed are the total syntheses of the natural products Y W3548 and Y W3699, potent inhibitors of cellular glycophosphatidylinositol (GPI)-anchoring. GPI-anchoring is a biochemical process for covalently attaching proteins onto cell surfaces, whose species-specific inhibition is sought as a means for developing anti-parasitic drugs. We propose herein divergent syntheses of these natural products that highlight a novel application of the Ni(ll)/Cr(ll)-mediated coupling reaction with enolizable and highly electrophilic vicinal tricarbonyl substrates. This application will permit the concise assembly of the tetracyclic skeletons of YW3548 and YW3699, by the stereospecific intramolecular coupling of the respective vinyl iodide and vicinal tricarbonyl functionalities to form their central oxocene rings. The brevity of the proposed syntheses depends on the procurement of most stereocenters with the advantageous employment of thermodynamic and kinetic conditions. In this manner, all but one (Cl of YW3548) stereogenic center of natural products are derived from the amplification of one stereocenter present in (+)-carvone. The realization of the proposed syntheses would promote the elucidation of GPI-biosynthesis that is necessary for the design of new anti-parasitic drugs to combat the observed drug resistance among virulent parasites.

描述：（由申请人提供）建议的是全合成的 天然产物Y W3548和Y W3699，有效的细胞增殖抑制剂， 糖磷脂酰肌醇（GPI）锚定。GPI锚定是一种生物化学 将蛋白质共价连接到细胞表面上的方法， 寻求物种特异性抑制作为开发抗寄生虫药物的手段 毒品我们在此提出了这些天然产物的不同合成方法， 突出了Ni（II）/Cr（II）介导的偶联反应的新应用 与可烯醇化和高度亲电的邻位三羰基底物。这 应用将允许四环骨架的简洁组装， YW 3548和YW 3699，通过立体特异性的分子内偶联， 相应的乙烯基碘和邻位三羰基官能团，以形成它们的 中央氧茂环。建议的合成的简洁性取决于 采购大多数立体中心， 热力学和动力学条件。以这种方式，除了一个之外的所有（C1， YW 3548）立体异构中心的天然产物是从 扩增存在于（+）-香芹酮中的一个立构中心。实现 所提出的合成将促进GPI-生物合成的阐明， 是必要的设计新的抗寄生虫药物，以打击观察到的 有毒寄生虫的抗药性。

项目成果

Asymmetric Ni(II)/Cr(II)-mediated coupling reaction: stoichiometric process.

不对称 Ni(II)/Cr(II) 介导的偶联反应：化学计量过程。

• DOI: 10.1021/ol0269805
• 发表时间: 2002
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Wan,Zhao-Kui;Choi,Hyeong-Wook;Kang,Fu-An;Nakajima,Katsumasa;Demeke,Damtew;Kishi,Yoshito
• 通讯作者: Kishi,Yoshito