Utilizing Non-Functionalized Terpenes to Develop Novel Strategies and Chemoselective Transformations

利用非功能化萜烯开发新策略和化学选择性转化

• 批准号: 9903397
• 负责人: Scott Alan Snyder
• 金额: $ 30.31万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903397
• 关键词: Acids; Affect; Alkaloids; Alkenes; Architecture; Biological; Breathing; Carbon; Chemicals; Chemistry; Collection; Complex; Creativeness; Critical Thinking; Cyclization; Development; Disease; Event; Family; Generations; Goals; Hydrogen; Industrialization; Laboratories; Methodology; Methods; Molecular; Molecular Structure; Natural Products; Nature; Nitrogen; Oxygen; Pathway interactions; Pattern; Plants; Polyenes; Process; Reaction; Reagent; Research; Route; Site; Specificity; Steroids; Structure; Terpenes; Testing; base; cost; design; flexibility; functional group; insight; member; novel strategies; operation; oxidation; polyphenol; premature; pressure; scaffold; success; tool

PROJECT SUMMARY/ABSTRACT As a class, terpene-based natural products have long led to critical scientific discoveries and advances. For instance, the particular connectivity of longifolene served as the inaugural ground upon which to establish the power of retrosynthetic analysis, while larger molecules such as steroids have been valuable tools to treat and understand disease as well as a scaffold upon which to develop powerful bond-forming reactions such as electrophile-induced polyene cyclizations and site-specific functionalizations. We believe that numerous opportunities remain for further development within the class, and here we seek specifically to probe the potential of structurally complex, but relatively non-functionalized, members to contribute to the development of new reactions, strategies, and tactics of broad applicability. Our goal is to develop the means to both tailor and deliver molecular structure with high specificity, mirroring chemistry that Nature can accomplish enzymatically as well as contributing new reactions and tools that have no biological counterpart. As delineated within the proposal, we seek to explore several avenues for possible advances. First, drawing from a previously accomplished total synthesis of a strained molecule known as presilphiperfolan-8-ol, we have designed an array of Pd-based Heck relay cascades, in a variety of different formats, to generate a key patterning of atoms that is seemingly conserved across several different molecular collections despite having distinct plant, and likely biogenetic, origins. Key goals for the present study are to affect such reactions in contexts where competing β-hydride elimination pathways could preclude success, and to probe the viability of Heck-type processes in highly hindered settings, such as ones that would utilize tetrasubstituted olefins as acceptors. Second, we seek to utilize C-PdII intermediates in unprecedented trappings with intermolecular oxygen and nitrogen nucleophiles to access highly regio- and enantioselectively functionalized gem-dimethyl moieties. Finally, careful consideration of both how to synthesize and use quaternary centers has afforded what we believe to be critical insights pertinent to synthetic design. This concept is illustrated by the proposed generation of two different families of natural products in syntheses which either would be the only available route to date or which are marked improvements on past efforts in terms of overall step economy.

项目总结/摘要 作为一个类别，基于铽的天然产品长期以来一直导致关键的科学发现和进步。 例如，长叶烯的特殊连接性是建立 逆转录合成分析的力量，而更大的分子，如类固醇一直是有价值的工具，以治疗 并了解疾病，以及一个支架，在其上发展强大的成键反应， 亲电诱导的多烯环化和位点特异性官能化。我们认为，许多 机会仍然是进一步发展的阶级，在这里，我们寻求专门探讨 结构复杂但相对非功能化的成员有助于发展 具有广泛适用性的新反应、战略和战术。我们的目标是开发既能量身定制， 提供具有高度特异性的分子结构，反映了自然界可以通过酶实现的化学反应 以及贡献新的反应和工具，没有生物学对应物。 正如提案中所述，我们寻求探索几种可能取得进展的途径。第一、 从先前完成的称为presilphiferfolan-8-ol的应变分子的全合成中得出， 我们已经设计了一个基于Pd的Heck中继级联阵列，以各种不同的格式，以产生一个 原子的关键模式，似乎是保守的几个不同的分子集合， 具有独特的植物起源，可能是生物起源。本研究的主要目标是影响这种反应 在竞争性β-氢化物消除途径可能妨碍成功的情况下， Heck型工艺在高度受阻的环境中的应用，例如将利用四取代烯烃作为 受体。第二，我们寻求利用C-PdII中间体在前所未有的陷阱与分子间 氧和氮亲核试剂以获得高度区域选择性和对映选择性官能化的偕二甲基 部分。最后，仔细考虑如何合成和使用季中心， 我们认为是与合成设计相关的重要见解。这一概念由拟议的 在合成中产生两个不同家族的天然产物， 这是迄今为止的路线，或在整体步骤经济方面对过去的努力有显着改进。