Catalytic Asymmetric Route to Enantioenriched Cyclic Allenes and a Nickel-catalyzed Dynamic Kinetic Resolution of Cyclic Allenes

生成对映体富集的环状八烯的催化不对称路线以及环状八烯的镍催化动态动力学拆分

• 批准号: 10218217
• 负责人: Rachel Knapp
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218217
• 关键词: Address; Alkylation; Area; Carbon; Catalysis; Chemicals; Chemistry; Complex; Development; Disease; Goals; Health; Heterocyclic Compounds; Human; Investigation; Kinetics; Lead; Methodology; Methods; Molecular; Nickel; Organic Synthesis; Palladium; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Process; Research; Resolution; Route; Transition Elements; adduct; cycloaddition; drug discovery; propadiene; scaffold; small molecule; stereochemistry

Highly functionalized heterocycles are important motifs in pharmaceuticals. Although there have been many noteworthy advances in synthetic organic methodologies, the efficient synthesis of enantioenriched heterocycles remains an ongoing challenge in the field. The primary goal of this proposal is to access enantioenriched compounds utilizing heterocyclic allene intermediates. Cyclic allenes have been avoided historically due to their high reactivity. However, the proposed research seeks to harness cyclic allenes for the efficient construction of complex scaffolds. Moreover, the inherent chirality of cyclic allenes opens opportunities to access enantioenriched adducts. The manipulation of heterocyclic allenes in a controlled manner would offer new tactics for the synthesis of enantioenriched, complex heterocycles. This proposal includes two strategies that utilize heterocyclic allenes to generate enantioenriched products. In Aim 1, an asymmetric, catalytic synthesis of oxacyclic allene precursors will be optimized to ultimately enable facile access to enantioenriched oxacyclic allenes. An investigation into the ability to transfer stereochemical information from the allene precursor all the way to enantioenriched cycloadducts will be described. The studies in Aim 2 will allow access to enantioenriched heterocycles via a transition metal- catalyzed dynamic kinetic resolution of heterocyclic allenes. Optimization of the transformation and exploration of the substrate scope is described. These studies would ultimately demonstrate the utility of strained cyclic allenes in asymmetric synthesis.

高度官能化的杂环是药物中的重要基序。虽然已经有 许多值得注意的进展，在合成有机方法，高效合成对映体富集 杂环化合物仍然是该领域中的持续挑战。该提案的主要目标是获得 利用杂环丙二烯中间体的对映体富集的化合物。环状联烯已经被避免 历史上由于其高反应性。然而，所提出的研究试图利用环状联烯用于 复杂支架的高效构建。此外，环状联烯的固有手性为 以获得对映体富集的加合物。以可控的方式操纵杂环丙二烯将提供 合成对映体富集的复杂杂环化合物的新策略。 该方案包括两种策略，即利用杂环丙二烯生成对映体富集的 产品.在目标1中，将优化氧杂环丙二烯前体的不对称催化合成， 最终能够容易地获得对映体富集的氧杂环联烯。一项关于转移能力的调查 从丙二烯前体一直到对映体富集的环加合物的立体化学信息将是 介绍了目标2中的研究将允许通过过渡金属- 杂环联烯的催化动态动力学拆分。优化改造探索 描述了衬底范围。这些研究将最终证明应变循环的效用。 不对称合成中的联烯