Syntheses of GPI-Anchoring Inhibitors YW3548 and YW 3699

描述：(由申请人提供)建议的是 天然产物Y W3548和Y W3699，有效的细胞抑制物 糖磷脂酰肌醇(GPI)-锚定。GPI锚定是一种生化 将蛋白质共价附着到细胞表面的过程，其 寻求特定物种的抑制作为开发抗寄生虫的手段 毒品。我们在这里提出了这些天然产物的不同合成方法 突出Ni(11)/Cr(11)介导的偶联反应的一个新应用 具有可烯醇化和高度亲电的邻位三羰基底物。这 应用程序将允许简明地组装四环骨架 YW3548和YW3699，通过立体特异的分子内偶联 各自的乙烯基碘和邻位三羰基官能团形成它们的 中央二新世环。建议合成的简洁性取决于 采购大多数立体声中心，并有利地雇用 热力学和动力学条件。以这种方式，除一个(CL)外，所有的(CL YW3548)天然产物的立体中心源自 在(+)-香芹酮中存在一个立体中心的放大。的实现。 建议的合成将促进GPI生物合成的阐明 有必要设计新的抗寄生虫药物来对抗观察到的 强毒寄生虫中的抗药性。

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.