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）是一种结构独特的化合物 一种不断增长的生物遗传学相关天然产物 从海绵中提取 已证明Madangamine A具有活性 针对几种不同类型的癌细胞系， 微克/毫升范围。 顺式多烯在功能上存在于1 似乎会抑制一个控制和系统的修改其 通过降解的方法。 此外，绝对 配置1尚未被阐明。 因此， 1的对映体控制的全合成，其足够灵活以允许 的类似物的简易合成提出。 拟议的路线 以非对映选择性Diels-Alder反应开始，接着是 碘内酯化以生成环己烷环。 三环核心 然后将使用烯胺环化与N- 酰亚胺。 每一个较大的环将形成一个 使用系链/环化策略的收敛方式， 易于适应不同系链长度的结合， 功能. 因此，生产1的类似物以 研究其结构/活性关系并提高其药用价值 价值将得到促进。