Natural product Synthesis by Rh Catalyzed {2+2+2} Cycloadditions

描述(申请人提供)：该项目在合成有机方法学方面的广泛的、长期的目标是开发一种快速、高效和对映体选择性的方法来组装含有天然产物的生物相关的吲哚利定和喹诺利定。具体地说，建议的研究目的是将铑催化的烯基异氰酸酯与外源炔烃的[2+2+2]环加成反应扩展到包括官能化的高活性环炔。我们计划将新扩展的方法学应用于合成复杂的天然产物：乌头碱和达西卡布明。这些金刚烷生物碱已被用作民间药物，用于治疗包括梅毒和疟疾在内的许多疾病。此外，阿科斯明已被证明通过增加胰岛素分泌而有效地治疗大鼠糖尿病。我们选择追求这些生物碱的合成有两个原因。首先，双金刚烷骨架构成了独特的合成挑战，其次，将我们的方法学应用于这些化合物的合成将突出其实用性，同时将其范围扩大到其当前状态之外。总之，这些化合物的合成将有利于开发能够有效治疗糖尿病、梅毒和疟疾的新药。

DESCRIPTION (provided by applicant): The broad, long-term objective of this project in synthetic organic methodology is to develop a rapid, efficient, and enantioselective means of assembling biologically relevant indolizidine and quinolizidine containing natural products. Specifically the proposed research aims to extend the rhodium catalyzed [2+2+2] cycloaddition of alkenyl isocyanates with exogenous alkynes to include functionalized, highly reactive cycloalkynes. We plan to apply the newly expanded methodology to the synthesis of complex natural products: acosmine and dasycarpumine. These diazadamantane alkaloids have been used as folk medicines for the treatment of a number of ailments including syphilis and malaria. Additionally, acosmine has been shown to be effective in the treatment of diabetes in rats by increasing insulin secretion. The reasons we have chosen to pursue the synthesis of these alkaloids are twofold. First, the diazadamantane skeleton poses unique synthetic challenges, and second, the application of our methodology to the synthesis of these compounds would highlight its utility while expanding its scope beyond its current state. Ir all, the synthesis of these compounds wou|d be of benefit to the development of new drugs that could be effective in the treatment of diabetes, syphilis, and malaria.