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.

项目总结