Enatioselective Total Synthesis of Potent Cytotoxic Natural Product Hopeanol

描述(申请人提供)：合成有机化学是药物发现和开发过程的支柱之一，因为必须通过化学合成来制备具有重要药用价值的天然产物和相关类似物。通过开发新的、复杂的建筑反应来有效地获得这些天然产品是至关重要的。新近分离的天然产物厚朴酚具有独特而复杂的碳骨架，对许多癌细胞具有强大的细胞毒活性。这项建议概述了一种新的合成策略，以有效地获得对映体纯的何首乌。全合成将通过开发和使用创新的1，2-芳基迁移来提供高度取代的、对映体纯度高的苯并呋喃支架来强调。此外，这种全面的综合将为以前开发的方法在新的和复杂的环境中提供一个试验场。更具体地说，钯催化的1，1-二氯苯乙烯衍生物的连续芳基化反应将立体选择性地合成复杂的三取代烯烃。此外，还将展示手性酮基催化剂催化高官能化三芳基取代烯烃的对映选择性环氧化反应。开发和利用这些复杂的构建反应将允许以高效的方式制备对映体纯的何首乌。人们最初对该靶标的兴趣是因为它的生物活性，而其化学合成的根本原因是对异戊醇以及针对癌细胞的结构类似物的评估。荷叶醇的全合成将为类似物合成的进一步研究提供基础。这一建议将拓宽我们对反应机理和合成设计的理解，最终为人类健康做出贡献。与公共卫生相关在许多情况下，从自然来源中分离出足够数量的分子用于治疗重要疾病是一项不可能完成的任务。因此，从廉价的原料中以成本效益和时间效率的方式合成天然产物至关重要。这项建议的目标是高效地制备有效的抗肿瘤天然产物何首乌。

DESCRIPTION (provided by applicant): Synthetic organic chemistry is one of the pillars of the drug discovery and development process as it is necessary to prepare medicinally important natural products and related analogs through chemical synthesis. Efficient access to these natural products through development of new, complexity building reactions is of the utmost importance. The recently isolated natural product hopeanol, possessing a unique and complex carbon skeleton, exhibits potent cytotoxic activity against a number of cancer cell lines. This proposal outlines a novel synthetic strategy to efficiently access enantiomerically pure hopeanol. The total synthesis will be highlighted through the development and use of an innovative 1,2-aryl migration to afford highly substituted enantiomerically pure benzofuran scaffolds. In addition, this total synthesis will provide a testing ground for previously developed methods in new and complex settings. More specifically, sequential Pd-catalyzed arylation of 1,1-dichlorostyrene derivatives will stereoselectively afford complex trisubstituted olefins. Additionally, catalytic enantioselective epoxidation of highly functionalized triarylsubstituted olefins with chiral ketone-based catalysts will be demonstrated. Development and utilization of these complexity building reactions will allow enantiomerically pure hopeanol to be prepared in an efficient manner. Initial interest in the target was garnered for its biological activity and overlying reasons for its chemical synthesis are rooted in evaluation of hopeanol as well as structural analogs against cancer cell lines. The total synthesis of hopeanol will provide a foundation on which further studies regarding analogue synthesis will be based. This proposal will broaden our understanding of reaction mechanism and synthetic design and ultimately contribute to human health. PUBLIC HEALTH RELEVANCE In many cases, isolation of sufficient quantities of molecules from natural sources to be used for the treatment of important diseases is an impossible task. Therefore, synthetic preparation of natural products in a cost effective and time efficient manner from inexpensive starting materials is of the utmost importance. It is the goal of this proposal to efficiently prepare potent anti-tumor natural product hopeanol.