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（由适用提供）：提出了一种抑制VCAM-1（血管细胞粘合分子1）的海洋天然产物的高效，对映选择性合成的策略。由于其在调节感染中的关键作用，VCAM-1已成为药物发现的潜在靶标。该蛋白质的抑制剂可能会对动脉硬化，哮喘和癌症的治疗产生深远的影响。迄今为止，只有一种总合成halichlorine。提出的计划概述了一种新的合成途径，可以将其修改为访问Pinnaic Acid的前体，PINNAIC ACIC，一种相关的生物碱和胞质磷脂酶A2的潜在抑制剂。该计划利用了音乐 - - 教方法来构建关键的烯烃键，迄今未用于生物碱合成。这代表了研究总合成中跨度发生范围的独特机会。分子内基希 - 诺萨基反应也被提出为替代大环化步骤。分子建模表明，该反应将具有高度的非对映选择性，有利于所需的立体异构体。该合成将提供足够数量的卤化氯，以评估其作为治疗上述疾病的候选者的潜力。