Enantioselective synthesis of hetisine

Hetisine的对映选择性合成

• 批准号: 6659784
• 负责人: MATTHIAS BREWER
• 金额: $ 4.16万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6659784
• 关键词: alkaloids; alkenes; antiarrhythmic agent; chemical synthesis; conformation; cyclization; drug design /synthesis /production; ketones; postdoctoral investigator; reduction; stereochemistry; stereoisomer

DESCRIPTION (provided by applicant): Hetisane-type alkaloids (which comprise a family of over 100 compounds isolated from plants of the genre Aconitum, Delphinium, Thalictrum, Consolida, and Spirea) have been shown to possess antiarrhythmic properties. To date, none of the hetisane alkaloids have been synthesized. The current need for novel antiarrhythmic agents, coupled with the known antiarrhythmic properties of these compounds makes this class of molecule a worthwhile target. Proposed here is the enantioselective synthesis of hetisine. This synthesis would lay the groundwork for developing novel structural variants based on the hetisane carbon skeleton. In this respect, the intermediates generated throughout this synthesis would be important unto themselves. Not only would they provide a basis for the synthesis of novel compounds, but they themselves could be used to generate valuable structure-activity relationship data. The key step in this synthesis will be an unusual aza-Cope-Mannich transformation in which conformational and steric restrictions drive the reaction through a normally unfavored boat transition state. Establishing the ability to control product formation through structural restrictions in this manner would enhance the scope and generality of this already proven reaction.

描述（由申请人提供）：已显示赫替烷型生物碱（其包括从菊科植物、飞燕草属植物、白菊属植物、康索利达属植物和绣线菊属植物中分离的超过100种化合物的家族）具有抗肿瘤特性。到目前为止，没有一个hetisane生物碱已被合成。目前对新型抗肿瘤药物的需求，加上这些化合物已知的抗肿瘤特性，使得这类分子成为值得研究的目标。本文提出了对映选择性合成海替辛的方法。这种合成将为开发基于hetisane碳骨架的新型结构变体奠定基础。在这方面，在整个合成过程中产生的中间体对它们本身是重要的。它们不仅为合成新化合物提供了基础，而且它们本身也可以用来生成有价值的结构-活性关系数据。 在这个合成的关键步骤将是一个不寻常的氮杂-科普-曼尼希转换，其中构象和空间限制驱动反应通过一个通常不受欢迎的船过渡态。以这种方式建立通过结构限制控制产物形成的能力将提高这种已经证明的反应的范围和一般性。