Enantioselective synthesis of hetisine

描述(由申请人提供)：己二烷型生物碱(包括从乌头属、飞燕草属、唐松属、Consolida和Spirea属植物中分离出来的100多种化合物)已被证明具有抗心律失常的特性。到目前为止，还没有合成任何己烷生物碱。目前对新型抗心律失常药物的需求，加上这些化合物已知的抗心律失常特性，使这类分子成为一个有价值的目标。本文提出了Hetisine的对映选择性合成方法。这一合成将为开发基于己烷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自己来说是重要的。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产生有价值的结构-活性关系数据。 这一合成的关键步骤将是一个不寻常的Aza-Cope-Mannich转变，在该转变中，构象和空间限制通过通常不受欢迎的船型过渡态来驱动反应。建立以这种方式通过结构限制控制产品形成的能力将增强这一已被证实的反应的范围和一般性。

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.