Enatioselective Total Synthesis of Potent Cytotoxic Natural Product Hopeanol

描述（由申请人提供）：合成有机化学是药物发现和开发过程的支柱之一，因为它是通过化学合成制备药用重要天然产物和相关类似物所必需的。通过开发新的、复杂的反应来有效地获得这些天然产物是至关重要的。最近分离的天然产物希望烷醇，具有独特而复杂的碳骨架，对许多癌细胞系显示出强大的细胞毒活性。本提案概述了一种新的合成策略，以有效地获得对映体纯希望醇。总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苯并呋喃支架。此外，这种全面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，顺序pd催化的1,1-二氯苯乙烯衍生物的芳基化将立体选择性地得到复杂的三取代烯烃。此外，手性酮基催化剂催化高功能化三芳基取代烯烃的对映选择性环氧化反应也将得到证实。这些复杂反应的开发和利用将使对映体纯希望醇的制备成为可能。最初对该靶标的兴趣是由于其生物活性，而其化学合成的主要原因是对希望烷醇的评估以及对癌细胞系的结构类似物。希望烷醇的全合成将为类似物合成的进一步研究奠定基础。这一建议将拓宽我们对反应机理和合成设计的理解，并最终为人类健康做出贡献。在许多情况下，从天然来源中分离出足够数量的分子以用于治疗重要疾病是一项不可能完成的任务。因此，利用廉价的原料以具有成本效益和时间效率的方式合成天然产物是至关重要的。本课题旨在高效制备强效抗肿瘤天然产物希望烷醇。

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.