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 需要有效构建手性构件的方法的需求已大大增加 在过去的20年中，由于实施了有关 创建新的立体构造药物。 β-酮酯的氢化转化是 在行业中广泛建立和广泛使用，每年提供100吨以上的材料， 与γ的不对称和化学选择性转化，δ-不饱和β-酮酸盐保留 由于其潜水功能和非常规的电子偏见，因此没有遭到疏忽。这 提案旨在发展实用的催化反应，以利用 绑扎的铜种类有选择地使三个可能的亲电位点之一官能化 这些分子化学和立体选择性。这些方法将提供高度访问 富含对映的次级和第三级烯丙基醇，其中包含两个连续的 立体中心和羧酸盐部分，并将扩大β-二骨的合成效用 通过利用其潜在的亲电性向其他核阳具的化合物。与 我们对访问结构复杂且与生物学相关的天然产品的兴趣，我们是 提出一种可调节和收敛的方法，该方法将提供对不自然变体的访问 Veratrum生物碱Jervine。我们的策略涉及映选择性共轭添加 复杂的立体片段，立体化化性生物碱三轮车。