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.

项目概要 对构建手性构件的有效方法的需求正在显着增加 过去 20 年来，由于有关监管准则的实施 β-酮酯的氢化转化是新的立体定义药物的创造。 成熟且主要用于工业，每年提供超过 100 吨材料， 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常规的电子偏差而未被充分开发。 该提案旨在开发实用的催化反应，利用 连接铜物种选择性地功能化三个可能的亲电位点之一 这些方法将提供对这些分子的化学选择性和立体选择性。 含有两个连续的对映体丰富的仲烯丙醇和叔烯丙醇 立体中心和羧酸酯部分，并将扩大 β-二羰基的合成用途 通过利用其对其他亲核试剂的潜在亲电性来合成化合物。 我们对获取结构复杂且生物学相关的天然产品感兴趣，我们 提出一种可调节和收敛的方法，该方法将提供对非自然变体的访问 我们的策略涉及藜芦生物碱 jervine 的非对映选择性缀合添加。 具有立体化学致密的生物碱三环的复杂类固醇片段。