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

基本信息

批准号：
7923311
负责人：
Michael Kevin Brown
金额：
$ 4.34万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2011-06-30
项目状态：
已结题

项目摘要

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来制备具有药物重要的天然产物和相关的类似物。通过发展新的复杂性建筑反应有效地访问这些天然产品至关重要。最近孤立的天然产物霍普醇具有独特而复杂的碳骨架，对许多癌细胞系具有有效的细胞毒性活性。该建议概述了一种新型的合成策略，可有效访问对映体的纯啤酒醇。总合成将通过开发和使用创新的1,2芳基迁移来强调，以提供高度替代的对映体纯苯并呋喃的支架。此外，该总合成将为新的和复杂的设置中先前开发的方法提供测试地面。更具体地说，1,1-二氯苯乙烯衍生物的顺序PD催化芳基化将立体选择性地提供复杂的TrisubStestated烯烃。此外，将证明将高度功能化的三侧取代的烯烃催化对映选择性环氧化具有基于风酮的催化剂。这些复杂性建筑反应的开发和利用将使对映体纯粹的希望醇以有效的方式制备。对靶标的生物学活性的最初兴趣和化学合成的上覆的原因植根于评估啤酒醇以及针对癌细胞系的结构类似物。 Hopeanol的总合成将为基础提供有关模拟合成的进一步研究。该建议将扩大我们对反应机制和合成设计的理解，并最终促进人类健康。在许多情况下，公共卫生相关性，将足够数量的分子与自然来源隔离来治疗重要疾病是不可能的任务。因此，从廉价的起始材料中以具有成本效益且有效的时间进行合成天然产品的合成制备至关重要。该提案的目标是有效准备有效的抗肿瘤天然产品啤酒醇。