Enantioselective Total Synthesis of (+)-Halichlorine

( )-卤氯的对映选择性全合成

• 批准号: 6847444
• 负责人: RODRIGO B ANDRADE
• 金额: $ 4.99万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847444
• 关键词: alkaloids; alkenes; antiinflammatory agents; arteriosclerosis; asthma; biological products; biotechnology; biotherapeutic agent; chemical bond; chemical reaction; drug design /synthesis /production; drug discovery /isolation; inflammation; molecular dynamics; neoplasm /cancer; phospholipase inhibitor; postdoctoral investigator; stereoisomer; vascular cell adhesion molecule

DESCRIPTION (provided by applicant): A strategy for the efficient, enantioselective synthesis of (+)-halichlorine, a marine natural product which inhibits VCAM-1 (vascular cell adhesion molecule-1) with an IC50 of 7 ¿g/mL, is proposed. Due to its critical role in the regulation of inflammation, VCAM-1 has emerged as a potential target for drug discovery. Inhibitors of this protein could have a profound impact on the treatment of arteriosclerosis, asthma, and cancer. To date there only exists one total synthesis of halichlorine. The proposed plan outlines a novel synthetic route to halichlorine which can be modified to access precursors of pinnaic acid, a related alkaloid and potent inhibitor of cytosolic phospholipase A2. The plan utilizes cress-metathesis methodology for the construction of key olefinic bonds which heretofore has not been used in alkaloid synthesis. This represents a unique opportunity to study the scope of cross-metathesis in total synthesis. An intramolecular Kishi-Nozaki reaction is also proposed as an alternative macrocyclization step. Molecular modeling suggests the reaction will take place with a high degree of diastereoselectivity in favor of the desired stereoisomer. The synthesis will furnish sufficient quantities of halichlorine to assess its potential as a candidate for the treatment of the above conditions.

描述（由申请人提供）：效率的策略，（+）nhibiosexective合成（nhib）vcam-1（血管细胞粘附分子1），IC50为7€ G/ML由于在调节炎症中的关键作用，VCAM-1已成为发现该蛋白质的潜在靶标。总合成halichloine的平面o访问Pinnaic Acid的前体，一种相关的生物碱和有效的抑制剂，可用于蛋白磷酸化的phossolic phossolipase A2研究总合成的跨度范围。作为上述条件的裤子的候选人。