Total synthesis of bioactive natural products

摘要 拟议的研究方案结合了三个研究主题：1)方法的发展和应用 使用容易获得的手性锂酰胺作为可回收的立体定向有效的不对称合成 试剂，2)复杂生物活性分子的全合成，3)环亚胺(CI)的作用 毒素与烟碱型乙酰胆碱相互作用对胆碱能传递的多方面影响 受体(NAChRs)。复杂天然产物的全合成，特别是CI毒素，一直是 为我们多样化的研究兴趣提供统一的平台。在前两个领域中，我们将扩展手性的用途 锂试剂与单阴离子和双阴离子中间体的不对称烷基化反应。这 方法学构成了针对对映体选择性制备的合成策略的基础 多卡霉素生物碱和吗啡及相关生物碱以迄今为止最短的合成序列合成。在 第三个领域，我们引入了我们在可扩展合成CI毒素方面的专业知识，以生产亚型选择性探针和 用于nAChRs研究的放射性示踪剂。CI毒素是一类全球分布的新兴海洋毒素 以及不确定的人类健康风险。我们将对CI的相互作用进行全面的功能研究 利用电生理学、放射性配基置换和 其他功能研究。利用全合成产生的放射性标记CI毒素，我们将在体内研究 以鸡胚胎为模型的海洋毒素的生物分布及其发育生物学效应。 从这个意义上说，人工合成CI毒素将作为一种独特的工具，有望丰富我们对这方面的知识 一类重要的亲离子受体，从长期来看，包括对代谢周转和 NAChRs对神经退行性疾病的更广泛影响。

Abstract The proposed research program combines three research topics: 1) development and application of methods for efficient asymmetric synthesis using readily available chiral lithium amides as recoverable stereodirecting reagents, 2) total synthesis of complex bioactive molecules, and 3) investigating effects of Cyclic Imine (CI) toxins on various aspects cholinergic transmission by defining their interaction with nicotinic acetylcholine receptors (nAChRs). Total synthesis of complex natural products, in particular CI toxins, has served as a unifying platform for our diverse research interests. Within the first two areas, we will extend the utility of chiral lithium reagents for asymmetric alkylation reactions with momoanionic and dianionic intermediates. This methodology forms the basis of synthesis strategies directed at the enantioselective preparation of duocarmycin alkaloids and a morphine and related alkaloids by a shortest synthetic sequence to date. In the third area, we bring in our expertise in scalable synthesis of CI toxins to produce subtype-selective probes and radiotracers for the study of nAChRs. CI toxins are an emerging group of marine toxins with global distribution and uncertain human health risks. We will carry out comprehensive functional studies on the interaction of CI toxins with selected subtypes of individual nAChRs using electrophysiology, radioligand-displacement, and other functional studies. Using radiolabeled CI toxins produced by total synthesis, we will investigate in vivo biodistribution of these marine toxins and their effect of developmental biology using chick embryo as a model. In this sense, synthetic CI toxins will serve as unique tools that promise to enrich our knowledge of this important class of ionotropic receptors, including, in long term, additional insight into metabolic turnover and broader impact of nAChRs on neurodegenerative disorders.