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

项目摘要 对构建手性构筑块的有效方法的需求已显著增加 在过去的20年里，由于实施了关于 创造新的固定定义的药物。而β-酮酸酯的氢化转化是 建立良好并在工业中广泛使用，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向，开发不足。这 一项提案旨在开发实用的催化反应，利用 连接的铜物种选择性地使三个可能的亲电位点之一官能化 这些分子具有化学和立体选择性。这些方法将提供访问高度 多种富含对映体的仲烯丙醇和叔烯丙醇，含有两个连续的 立体中心和羧酸部分，并将扩大β-二羰基的合成用途 通过利用化合物对其他亲核试剂的潜在亲电性。与保持一致 我们对获得结构复杂和生物相关的天然产品的兴趣，我们正在 提出一种可调和收敛的方法，该方法将提供对 藜芦碱。我们的策略涉及一种非对映选择性的共轭加法 具有立体化学密度的生物碱三环的复杂类固醇片段。

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.