Enantioselective Total Synthesis of (+)-Halichlorine

( )-卤氯的对映选择性全合成

• 批准号: 6742018
• 负责人: RODRIGO B ANDRADE
• 金额: $ 4.73万
• 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/6742018
• 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）：提出了一种高效、对映选择性合成（+）-卤氯的策略，卤氯是一种海洋天然产物，可抑制VCAM-1（血管细胞粘附分子-1），IC 50为7 μ g/mL。由于其在炎症调节中的关键作用，VCAM-1已成为药物发现的潜在靶点。这种蛋白质的抑制剂可能对动脉硬化、哮喘和癌症的治疗产生深远的影响。迄今为止，只有一种卤氯的全合成方法。拟议的计划概述了一种新的合成路线卤，可以修改访问pinnaic酸，一个相关的生物碱和有效的抑制剂胞质磷脂酶A2的前体。该计划利用交叉复分解方法来构建迄今为止尚未用于生物碱合成的关键烯键。这是一个独特的机会，研究交叉复分解的范围在全合成。一个分子内的岸野崎反应也提出了作为一个替代的大环化步骤。分子模拟表明，反应将以高度的非对映选择性发生，有利于所需的立体异构体。合成将提供足够数量的卤氯，以评估其作为治疗上述疾病的候选药物的潜力。