TOTAL SYNTHESIS OF MADANGAMINE A

马达加明 A 的全合成

• 批准号: 2518842
• 负责人: SCOTT D EDMONDSON
• 金额: $ 2.44万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2518842
• 关键词: Diels Alder reaction; Porifera; alkaloids; analog; antineoplastics; biological products; chemical structure function; chemical synthesis; cyclization; drug design /synthesis /production; stereochemistry

The recently isolated alkaloid madangamine A (1) is a structurally unique member of a growing class of biogenetically related natural products obtained from marine sponges. Madangamine A has been shown to be active against several different types of cancer cell lines with ED50's in the microgram/milliliter range. The cis polyene functionally present in 1 would appear to inhibit a controlled and systematic modification of its structure through degradative methods. Moreover, the absolute configuration 1 has not yet been elucidated. Consequently, an enantiocontrolled total synthesis of 1 which is flexible enough to allow for the facile synthesis of analogs is proposed. The proposed route begins with a diastereoselective Diels-Alder reaction followed by an iodolactonization to generate the cyclohexane ring. The tricyclic core of 1 will then be assembled using an enamine cyclization with an N- acyliminium ion. Each of the larger rings will then be formed in a convergent manner using a tether/cyclization strategy which will be easily amenable to the incorporation of different tether lengths and functionality. Consequently, the production of analogs of 1 in order to study its structure/activity relationships and improve its medicinal value will be facilitated.

最近分离出的生物碱 Madangamine A (1) 是一种结构独特的 越来越多的生物遗传相关天然产品类别的成员 从海绵中获得。 Madangamine A 已被证明具有活性 对抗几种不同类型的癌细胞系，其 ED50 值在 微克/毫升范围。 顺式多烯功能性存在于 1 似乎会抑制对其进行受控和系统的修改 通过降解方法进行结构。 而且，绝对 配置1尚未阐明。 因此，一个 1 的对映体控制全合成足够灵活，可以 提出了类似物的简便合成。 拟定路线 以非对映选择性狄尔斯-阿尔德反应开始，然后是 碘内酯化生成环己烷环。 三环核心 然后使用烯胺环化与 N- 组装 1 酰亚胺离子。 然后，每个较大的环将形成一个 使用系链/环化策略的收敛方式，这将是 很容易适应不同长度的系绳的结合 功能。 因此，生产 1 的类似物 研究其结构/活性关系并改进其药用 价值将得到促进。