TOTAL SYNTHESIS OF THE GPI-ANCHORING INHIBITOR YW3548

GPI锚定抑制剂YW3548的全合成

• 批准号: 6518894
• 负责人: TIMOTHY S SNOWDEN
• 金额: $ 3.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6518894
• 关键词: acyl group; bioengineering /biomedical engineering; carbanion; carbonyl compound; chemical binding; chemical reaction; chemical structure; chemical substitution; chemical synthesis; cyclic compound; glycosylphosphatidylinositols; lactones; phospholipid inhibitor; stereochemistry; terpenes

The proposed research is aimed at completing a convergent, stereoselective total synthesis of a recently characterized glycoslyphosphatidylinositol (GPI)-anchoring inhibitor YW3548. YW3548 consists of unusual tricarbocyclic sesterterpenoid delta-lactone framework and is a very potent inhibitor of GPI synthesis in eukaryotic cells. The proposed convergent synthesis will feature a sequential intermolecular carbonyl addition to a vinyl carbanion followed by an intramolecular nucleophile acyl substitution mediated by diiododsamarium to form the functionalized eight-membered carbocyclic ring B. This approach is unique in that it produces alkenyl, oxo and diol substituents, which will provide handles for synthetic elaboration of the generated eight-membered ring. The strategies for formation of the molecules involved in the sequenced reaction are described along with a route to the completion of YW3548.

该研究的目的是完成一个收敛的，立体选择性的全合成最近表征的糖磷脂酰肌醇（GPI）锚定抑制剂YW 3548。YW 3548由不寻常的三碳环二萜类δ-内酯骨架组成，是真核细胞中GPI合成的非常有效的抑制剂。建议的收敛合成将具有顺序的分子间羰基加成到乙烯基碳负离子，然后由二碘钐介导的分子内亲核酰基取代形成官能化的八元碳环B。这种方法是独特的，因为它产生烯基，氧代和二醇取代基，这将提供处理所产生的八元环的合成阐述。沿着完成YW 3548的路线描述了用于形成参与测序反应的分子的策略。