Building Molecular Complexity through Alkyne Transformations

描述(由申请人提供)：制药发展的一个主要限制因素是化学空间的覆盖范围较差。分子多样性和广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会提供更高的效力或选择性，但由于艰巨的合成挑战，治疗开发变得难以解决。这项应用的总体目标是设计和执行高效的合成路线，以获得一系列具有令人印象深刻的生物特性的天然产品。这一目标是由基于炔烃活化的新转化的创新推动的。该提案概述了同时实现的三个具体目标。每个目标都集中在一个或多个生物活性天然产物的全合成上，其中将进行关键转化，以快速建立嵌入目标的复杂分子结构(S)。目的1描绘了一条有效的合成阿罗他酮A的途径，这是一种与cAMP信号有关的分子，具有治疗癌症和神经退行性疾病的潜力。这一计划依赖于硅基迁移的应用来构建三环核心。目的2描述了PI3Kα抑制剂利福平和抗菌剂西霉素A的新方法。通向这些目标的两条路线都以金属催化的多环化事件为特色，以建立其复杂的环系统。最后，目标3概述了针对钩吻生物碱的统一合成策略。其中几个化合物具有耐人寻味的生物活性(包括抗A431人表皮样癌)，它们的致密结构在合成上是一个巨大的挑战。在这里，获得核心的关键串联转换包括从单一的、容易获得的立体生成碳形成两个C-C键和多个立体中心。将这些目的统一起来的是炔烃活化在新的化学转化中的应用。这些反应的重点是有效地构建分子的复杂性，以多个成键事件的形式和选择性地产生立体生成碳中心的形式。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一个极好的结构。此外，靶向分子的生物学相关性突出了我们的反应发展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具有可衡量的意义，无论是在我们具体追求的目标上，还是在已建立的广泛适用的方法上。

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.