Expanding the Synthetic Utility of β-Keto Esters in Enantioconvergent Addition Reactions and Progress Towards a Convergent, De Novo Synthesis of Jervine

扩展 β-酮酯在对映收敛加成反应中的合成效用以及 Jervine 收敛、从头合成的进展

• 批准号: 10225321
• 负责人: Pedro R De Jesús Cruz
• 金额: $ 3.75万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225321
• 关键词: Agrochemicals; Alcohols; Alkaloids; Alkylation; Area; Binding; Biological; Biological Process; Complex; Copper; Esters; Fellowship; Generations; Goals; Grant; Guidelines; Health Sciences; Hydrogen; Industry; Intention; Methods; Modernization; Motivation; Natural Products; Organic Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Proteins; Reaction; Research; Research Personnel; Route; SHH gene; Site; Steroids; Structure; Structure-Activity Relationship; Synthesis Chemistry; Teratogens; Therapeutic; Time; Variant; Veratrum; base; carboxylate; drug discovery; interest; novel; operation; response; small molecule; smoothened signaling pathway

Project Summary The need for efficient methods to construct chiral building blocks has been increasing significantly over the last 20 years because of the implementation of regulatory guidelines regarding the creation of new stereodefined drugs. While hydrogenative transformations of β-keto esters are well established and used extensively in industry to provide over 100 tons of material annually, asymmetric and chemoselective transformations with γ,δ-unsaturated β-ketoesters remain underexplored due to their diverse functionality and unconventional electronic biases. This proposal aims to develop practical catalytic reactions that take advantage of the high tunability of ligated copper species to selectively functionalize one of the three possible electrophilic sites in these molecules chemo- and stereoselectively. These methods will provide access to highly diversifiable enantioenriched secondary and tertiary allylic alcohols containing two contiguous stereocenter and a carboxylate moiety, and will expand the synthetic utility of β-dicarbonyl compounds by exploiting their potential electrophilicity towards other nucleophiles. Aligning with our interest in accessing structurally complex and biologically relevant natural products, we are proposing a tunable and convergent approach that will provide access to unnatural variants of the Veratrum alkaloid jervine. Our strategy involves a diastereoselective conjugate addition of a complex steroid fragment with a stereochemically dense alkaloidal tricycle.

项目摘要 对构建手性结构单元的有效方法的需求显著增加 在过去的20年里，由于实施了有关 创造新的定型药物。而β-酮酯的氢化转化是 在工业中得到广泛的建立和使用，每年提供超过100吨的材料， γ，δ-不饱和β-酮酯的不对称和化学选择性转化仍然存在 由于其多样化的功能和非传统的电子偏见，这 该提案旨在开发实用的催化反应，利用高可调性的 连接的铜物种选择性官能化的三个可能的亲电位点之一， 这些分子的化学和立体选择性。这些方法将提供访问高度 含有两个邻接的对映体富集的可多样化的仲和叔烯丙醇 立体中心和羧酸酯部分，并将扩大β-二羰基的合成用途 通过利用它们对其他亲核试剂的潜在亲电性来制备化合物。看齐 我们对获取结构复杂和生物相关的天然产品的兴趣，我们是 提出了一种可调和收敛的方法，将提供访问非自然的变体， 藜芦生物碱我们的策略涉及非对映选择性共轭加成， 复杂的类固醇片段，具有立体化学上致密的环状三轮结构。