Enatioselective Total Synthesis of Potent Cytotoxic Natural Product Hopeanol

强效细胞毒性天然产物希望醇的对映选择性全合成

• 批准号: 7688100
• 负责人: Michael Kevin Brown
• 金额: $ 4.72万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688100
• 关键词: Alkenes; Antitumor Natural Products; Benzofurans; Biological; Biological Factors; Cancer cell line; Carbon; Complex; Development; Disease; Evaluation; Exhibits; Foundations; Goals; Health; Human; Ketones; Methods; Organic Chemistry; Plant Roots; Preparation; Process; Reaction; Skeleton; Source; Testing; Time; analog; base; catalyst; chemical synthesis; cost effective; cytotoxic; design; drug discovery; innovation; interest; migration; novel; public health relevance; scaffold

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.

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，因为有必要通过化学合成制备药用重要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物是至关重要的。最近分离出的天然产物藜芦醇，具有独特而复杂的碳骨架，对许多癌细胞系表现出强有力的细胞毒活性。该建议概述了一种新的合成策略，以有效地获得对映体纯的藜芦醇。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的苯并呋喃支架，将突出全合成。此外，这种全面综合将为以前在新的复杂环境中开发的方法提供一个试验场。更具体地，1，1-二氯苯乙烯衍生物的连续Pd催化的芳基化将立体选择性地提供复杂的三取代烯烃。此外，将展示用手性酮基催化剂催化高度官能化的三芳基取代烯烃的对映选择性环氧化。开发和利用这些复杂的构建反应将允许以有效的方式制备对映体纯的藜芦醇。对该靶标的最初兴趣是由于其生物活性而获得的，其化学合成的主要原因是基于对藜芦醇以及结构类似物对癌细胞系的评价。该方法为今后类似物的合成研究奠定了基础。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，从廉价的起始材料以成本有效和时间有效的方式合成制备天然产物是至关重要的。本课题的目的是高效制备具有抗肿瘤活性的天然产物藜芦醇。