Cascade Reactions for Biologically Active Natural Products

高三尖杉酯碱(HHT)是一种临床上使用的蛋白质翻译抑制剂，用于治疗慢性粒细胞白血病。除了FDA批准的白血病药物作用外，HHT还显示出治疗其他血液系统恶性肿瘤和肿瘤的令人兴奋的前景。最后，它是一个完美的分子，可以用来作为研究蛋白质翻译抑制的探针。 HHT目前是由天然产物三尖杉碱通过半合成方法制备的。三尖杉碱是从中国种植的亚洲李红豆杉中提取的。特别是HHT的费用，以及其他白血病治疗，被一个由100名领先的癌症专家组成的小组描述为“天文数字”和“对患者有害的”。这种成本在一定程度上是由于供应瓶颈，反映了其基于树的采购。该项目将彻底消除这一供应问题，并为我们和其他研究小组的研究提供三尖杉碱和HHT。 在整个历史上，天然产品一直是大多数药物的来源，今天仍然如此。化学合成领域直接促进了天然产物作为药物的应用。芳香环和杂芳环是生物活性化合物中不可缺少的模体。因此，允许构建含有取代芳环的分子结构的化学反应对人类健康特别有价值。以三尖杉生物碱为代表的多环含氮分子作为生物活性分子和药物也是至关重要的。然而，多环含氮分子，如生物碱，是出了名的难以制备，通常需要艰苦的化学合成才能制备。我们将开发两个新的级联反应来有效地制备：1.取代芳烃，2.复杂的多环生物碱。这项研究的创新之处在于战略性地使用级联反应来组装以前需要多个步骤才能制备的结构。这一战略的一个显著特点是其内在的效率。此外，我们还将在天然产物和天然产物类似物的合成中展示这些周环级联反应。更广泛地说，这一策略将立即应用于制备生物活性分子，如HHT；生物系统的化学探针，以及相关分子。

Homoharringtonine (HHT) is a clinically used protein translation inhibitor that is used to treat chronic myeloid leukemia. In addition to its FDA-approved role as a leukemia drug, HHT shows exciting promise for the treatment of other hematologic malignancies and tumors. Finally, it is a perfect molecule to use as a probe to investigate protein translation inhibition. HHT is currently prepared through semi-synthesis from naturally derived cephalotaxine. Cephalotaxine is obtained from Asian plum yew trees grown in China. The cost of HHT in particular, along with other leukemia treatments, has been described as “astronomical” and “harmful to patients” by a group of 100 leading cancer specialists. This cost results in part from a supply bottleneck reflecting its tree-based sourcing. This project will completely eliminate this supply problem, and provide cephalotaxine and HHT for our studies and those by other research groups. Natural products have been the source of the majority of drugs throughout history, and still are today. The field of chemical synthesis directly contributes to the application of natural products as medicines. Aromatic and heteroaromatic rings are indispensible motifs in biologically active compounds. Thus, chemical reactions that allow for the construction of molecular architectures containing substituted aromatic rings are particularly valuable to human health. Polycyclic nitrogenous molecules, exemplified by the Cephalotaxus alkaloids in this proposal, are also critically important as biologically active molecules and pharmaceuticals. However, polycyclic nitrogenous molecules, such as alkaloids, are notoriously difficult to prepare, often requiring arduous chemical syntheses for preparation. We will develop two new cascade reactions that efficiently prepare: 1. Substituted arenes, and 2. Complex polycyclic alkaloids. The innovativeness of this research is the strategic use of cascade reactions to assemble structures that previously required multiple steps to prepare. A distinguishing feature of this strategy is its inherent efficiency. Additionally, we will showcase these pericyclic cascades in syntheses of natural products and natural product analogs. More widely, this strategy will find immediate application in the preparation of biologically active molecules, such as HHT; chemical probes for biological systems, and related molecules.