Building Molecular Complexity through Alkyne Transformations

通过炔烃转化构建分子复杂性

基本信息

批准号：
8930281
负责人：
ERIC M FERREIRA
金额：
$ 17.43万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): A primary constraint on pharmaceutical development is the poor coverage of chemical space. This lack of molecular diversity and breadth has been largely dictated by synthetic expediency. More complex compounds, which may offer increased potency or selectivity, become intractable for therapeutic development because of the daunting synthetic challenge. The overall objective of this application is to design and execute efficient synthetic routes to a host of natural products featuring an impressive array of biological properties. This objective is driven by the innovation of new transformations based on alkyne activation. The proposal outlines three specific aims to be pursued in parallel. Each aim is focused on the total synthesis of one or more bioactive natural product, where a key transformation will be developed that will rapidly establish the complex molecular architecture embedded within the target(s). Aim 1 delineates an efficient route to alotaketal A, a molecule implicated in cAMP signaling, holding potential for the treatment of cancer and neurodegenerative disease. This plan relies on the application of a silicon group migration to construct the tricyclic core. Aim 2 describes novel approaches to both liphagal, a PI3K α inhibitor, and xiamycin A, an antibacterial agent. Both routes to these targets feature a metal-catalyzed polycyclization event to establish their complex ring systems. Lastly, Aim 3 outlines a unified synthetic strategy toward the Gelsemium alkaloids. Several of these compound have intriguing bioactivity (including anti-A431 human epidermoid carcinoma), and their dense architectures represent significant challenges in synthesis. Here, the pivotal tandem transformation to access the core involves the formation of two C-C bonds and multiple stereocenters from a single, readily accessed stereogenic carbon. Unifying these aims is the application of alkyne activation in novel chemical transformations. The emphasis of these reactions is on the efficient construction of molecular complexity, envisioned in the form of multiple bond-forming events and selective generation of stereogenic carbon centers. Our synthetic approaches to these complex natural products provide an excellent construct for the invention of these transformations. Moreover, the biological relevance of the targeted molecules highlights the potential impact of our reaction development in medicinal contexts. We expect our studies will have measurable implications in future therapeutic development, both in the targets we specifically pursue and in the widely applicable methods that are established.

描述（通过应用程序提供）：药物开发的主要限制是化学空间的覆盖率不佳。缺乏分子多样性和广度的缺乏，主要取决于合成的权宜之计。由于艰巨的合成挑战，更复杂的化合物可能具有提高的效力或选择性，因此在治疗发展方面变得棘手。该应用程序的总体目标是设计和执行有效的合成路线，以具有令人印象深刻的生物学特性的许多天然产品。该目标是由基于酒精激活的新转化的创新驱动的。该提案概述了三个特定的目标，要同行追求。每个目标都集中在一种或多种生物活性天然产物的总合成上，在该产品中将开发关键转化，该产品将迅速建立嵌入目标中的复杂分子体系结构。 AIM 1描述了在营地信号传导中实现的分子的有效途径，具有治疗癌症和神经退行性疾病的潜力。该计划依靠硅组迁移的应用来构建三轮车核心。 AIM 2描述了Liphagal，PI3Kα抑制剂和甲霉素A（抗菌剂）的新方法。这些目标的两种路线均具有金属催化的多环化事件，以建立其复杂的环系统。最后，AIM 3概述了针对凝胶生物碱的统一合成策略。其中几种化合物具有有趣的生物活性（包括抗A431人表皮类癌），其密集建筑师代表了合成的重大挑战。在这里，访问核心的关键串联变换涉及从单个，容易访问的立体源碳形成两个C-C键和多个立体中心。统一这些目标是在新型化学转化中应用炔烃激活。这些反应的重点是分子复杂性的有效构建，以多种键形成事件的形式设想，并选择性地生成立体碳中心。我们对这些复杂天然产物的合成方法为这些转换的事件提供了出色的结构。此外，靶向分子的生物学相关性突出了我们在医疗环境中反应发展的潜在影响。我们预计我们的研究将对未来的治疗发展具有可衡量的含义，无论是在我们专门追求的目标和广泛适用的方法中。