Total synthesis of bioactive natural products

摘要 建议的研究计划结合了三个研究主题：1）方法的开发和应用 对于使用容易获得的手性氨基锂作为可回收的立体定向的有效不对称合成， 试剂，2）复杂生物活性分子的全合成，和3）研究环亚胺（CI）的作用 通过定义它们与烟碱乙酰胆碱的相互作用， 受体（nAChRs）。复杂的天然产物，特别是Cl毒素的全合成，已经作为一种有效的方法。 为我们不同的研究兴趣提供统一的平台。在前两个领域，我们将扩展手性的效用 锂试剂用于与单阴离子和双阴离子中间体的不对称烷基化反应。这 方法学形成了针对对映选择性制备的合成策略的基础， 倍癌霉素生物碱和吗啡及相关生物碱的最短合成顺序。在 第三个领域，我们在CI毒素的可扩展合成方面拥有专业知识，以生产亚型选择性探针， 用于nAChRs研究的放射性示踪剂。CI毒素是一组新兴的海洋毒素，具有全球性分布 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 使用电生理学、放射性配体置换和放射性配体置换， 其他功能研究。使用放射性标记的全合成产生的CI毒素，我们将在体内研究 以鸡胚为模型，研究了这些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，合成CI毒素将作为独特的工具，有望丰富我们对此的知识。 离子型受体的重要类别，包括，从长远来看，额外的洞察代谢周转， nAChR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.