Development of Strategies for the Enantioselective Synthesis of Heterocycles and Acyclic Amines

杂环和无环胺对映选择性合成策略的发展

• 批准号: 10656344
• 负责人: AARON APONICK
• 金额: $ 29.23万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656344
• 关键词: 3-Dimensional; Academia; Acceleration; Aldehydes; Alkynes; Amines; Area; Behavior; Biology; Biotechnology; Carbon; Catalysis; Characteristics; Chemicals; Chemistry; Clinical; Collection; Complex; Copper; Coupling; Development; Elements; Goals; Health; Human; Imidazole; Imines; Industrialization; Ions; Isomerism; Laboratories; Lifting; Ligands; Literature; Methods; Natural Products; Nitrogen; Pharmacologic Substance; Phase; Piperazines; Positioning Attribute; Preparation; Process; Pyrazines; Pyridazines; Pyrimidine; Reaction; Research; Route; Sampling; Saxitoxin; Science; Structure; Synthesis Chemistry; Technology; Work; catalyst; chiral molecule; design; enantiomer; improved; morpholine; natural product inspired; nitrone; novel; novel strategies; novel therapeutics; pre-clinical; pyridine; quinoline; scaffold; screening; small molecule therapeutics; success; transmission process

Project Summary/Abstract This objective of this proposal is to develop new synthetic methods for the enantioselective synthesis of bioactive molecules. Studies are centered on utilizing a new class of atropisomeric chiral biaryl ligand being developed in our laboratory. Preliminary work has found that imidazole-based biaryl P,N-ligands excel at promoting enantioselective copper catalyzed carbon-carbon bond-forming reactions. Our goal is to capitalize on the differences in behavior between these ligands and existing biaryl ligands to enable new reaction technology for applications in discovery chemistry. The research in this application is focused on gaining a mechanistic understanding of the structural underpinnings responsible for new and unique reactivity imparted by this new ligand scaffold. Our first aim outlines plans to develop new dearomatization reactions of nitrogen heterocycles. In this aim we describe chemistry that will push the field past chiral carbocycles and single-heteroatom heterocycles to heterocycles with >1 heteroatom. Through preliminary results we demonstrate addition to pyridine, but more importantly pyrazine, pyridazine, and pyrimidine. These latter examples are unprecedented in the literature and the success of these catalytic enantioselective dearomatization reactions is developed here to provide rapid access to complex natural products like svetamycin B, saxitoxin, and batzellidine B as well as additional chiral nitrogen-containing building blocks. The second aim is focused on catalytic enantioselective addition reactions to C=N Bonds independent of nitrogen substitution. In catalytic enantioselective processes, it is common for iminium ions to require 2 identical N-substituents to avoid the E/Z issue. We have found that catalytic enantioselective alkynylation using StackPhos lifts this requirement and the use of two different N- substituents is possible. This breakthrough allows the move from bis-protected amines (e.g. N,N-dibenzyl) to the incorporation of groups needed for the synthesis. Here we capitalize on this for an expedient synthesis of kopsanone and other chiral heterocycles such as morpholines. In addition, through preliminary results, we also demonstrate that addition to imines and nitrones in high ee is possible, despite the E/Z-isomer issue. Extensive preliminary results support these aims and we predict that the chemistry developed here will be of broad impact to practitioners in academia and industrial settings, particularly the pharmaceutical and biotech sectors.

项目概要/摘要 该提案的目的是开发新的合成方法来对映选择性合成生物活性物质 分子。研究的重点是利用正在开发的一类新型阻转异构手性联芳基配体 我们的实验室。初步工作发现，基于咪唑的联芳基P,N-配体擅长促进 对映选择性铜催化碳-碳键形成反应。我们的目标是利用 这些配体与现有联芳基配体之间的行为差​​异使新的反应技术成为可能 在发现化学中的应用。本应用的研究重点是获得机械 了解这种新的赋予新的和独特的反应性的结构基础 配体支架。我们的第一个目标概述了开发新的氮杂环脱芳构化反应的计划。 在此目标中，我们描述的化学将推动该领域超越手性碳环和单杂原子 杂环至具有>1个杂原子的杂环。通过初步结果，我们证明了除 吡啶，但更重要的是吡嗪、哒嗪和嘧啶。后面这些例子是史无前例的 在文献中，这些催化对映选择性脱芳构化反应的成功在这里得到了发展 提供快速获取复杂天然产物的途径，如斯维他霉素 B、石房蛤毒素、batzellidine B 以及 额外的手性含氮结构单元。第二个目标集中于催化对映选择性 C=N 键的加成反应与氮取代无关。在催化对映选择性过程中， 亚胺离子通常需要 2 个相同的 N-取代基以避免 E/Z 问题。我们发现 使用 StackPhos 的催化对映选择性炔基化提高了这一要求，并且使用两种不同的 N- 取代基是可能的。这一突破使得从双保护胺（例如 N,N-二苄基）转向 掺入合成所需的基团。在这里，我们利用这一点进行方便的综合 高普撒酮和其他手性杂环化合物，例如吗啉。此外，通过初步结果，我们还 证明尽管存在 E/Z 异构体问题，但在高 ee 下添加亚胺和硝酮是可能的。广泛的 初步结果支持这些目标，我们预测这里开发的化学将产生广泛的影响 学术界和工业界，特别是制药和生物技术领域的从业者。