Building Molecular Complexity through Alkyne Transformations

描述（由申请人提供）：药物开发的一个主要限制因素是化学空间覆盖率低。这种分子多样性和宽度的缺乏在很大程度上是由合成的权宜之计决定的。更复杂的化合物，可能提供更高的效力或选择性，由于令人生畏的合成挑战，对于治疗开发变得棘手。该应用程序的总体目标是设计和执行有效的合成路线，以获得具有令人印象深刻的生物特性的天然产物。这一目标是由基于炔活化的新转化的创新驱动的。该提案概述了三个并行实现的具体目标。每个目标都集中在一种或多种生物活性天然产物的全合成上，其中将开发一种关键的转化，以快速建立嵌入靶标内的复杂分子结构。目的1描绘了一种有效的途径alotaketal A，一个分子参与cAMP信号转导，保持潜在的治疗癌症和神经退行性疾病。该计划依赖于硅基团迁移的应用来构建三环核心。目的2描述了PI 3 K α抑制剂liphagal和抗菌剂xiamycin A的新方法。这两种途径的特点是这些目标的金属催化的多环化事件，以建立其复杂的环系统。最后，目标3概述了钩吻生物碱的统一合成策略。这些化合物中的一些具有有趣的生物活性（包括抗A431人表皮样癌），并且它们的致密结构代表了合成中的重大挑战。在这里，进入核心的关键串联转化涉及从单个容易进入的立体碳形成两个C-C键和多个立体中心。将这些目标统一起来的是炔活化在新型化学转化中的应用。这些反应的重点是有效地构建分子的复杂性，设想在多个键形成事件和立体碳中心的选择性生成的形式。我们对这些复杂天然产物的合成方法为这些转化的发明提供了极好的构建体。此外，靶向分子的生物学相关性突出了我们的反应开发在医学背景下的潜在影响。我们希望我们的研究将在未来的治疗发展中产生可衡量的影响，无论是在我们具体追求的目标还是在建立的广泛适用的方法中。

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.