Enantioselective Total Synthesis of (+)-Halichlorine

描述（由申请人提供）：提出了一种高效，对映选择性合成(+)-氯盐的策略，氯盐是一种抑制VCAM-1（血管细胞粘附分子-1）的海洋天然产物，IC50为7¿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、哮喘和癌症的治疗有深远的影响。迄今为止，只存在一种全氯合成方法。提出的计划概述了一种新的合成途径，可以修饰获得蒎酸的前体，一种相关的生物碱和胞质磷脂酶A2的有效抑制剂。该计划利用交叉复分解方法来构建关键的烯烃键，迄今为止尚未在生物碱合成中使用。这为研究全合成中交叉复分解的范围提供了独特的机会。分子内的Kishi-Nozaki反应也被提出作为一种替代的大环化步骤。分子模拟表明，该反应将以有利于所需立体异构体的高度非对映选择性进行。该合成将提供足够数量的氯，以评估其作为治疗上述条件的候选物的潜力。

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.