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.

项目总结/摘要 本研究的目的是开发新的合成方法，用于对映选择性地合成生物活性物质 分子。研究集中在利用一类新的阻转异构手性联芳基配体正在开发中， 我们的实验室初步工作已经发现，咪唑基联芳基P，N-配体擅长促进 对映选择性铜催化的碳-碳键形成反应。我们的目标是利用 这些配体和现有联芳基配体之间的行为差异，使得新的反应技术 在发现化学中的应用。在此应用中的研究集中在获得一个机械的 了解负责新的和独特的反应性赋予这种新的结构基础， 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。 在这个目标中，我们描述了化学，将推动过去的手性碳环和单杂原子领域 杂环至具有>1个杂原子的杂环。通过初步结果，我们证明除了 吡啶，但更重要的是吡嗪、哒嗪和嘧啶。后面这些例子是前所未有的 在文献中，这些催化对映选择性脱芳构化反应的成功是在这里开发的 提供快速获取复杂的天然产物，如斯韦他霉素B、石房蛤毒素和巴茨利定B，以及 另外的手性含氮结构单元。第二个目标是催化对映选择性 加成反应的C=N键独立的氮取代。在催化对映选择性方法中， 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- 取代是可能的。这一突破允许从双保护的胺（例如N，N-二苄基）移动到双保护的胺（例如N，N-二苄基）。 引入合成所需的基团。在这里，我们利用这一点， kopsanone和其它手性杂环如吗啉。此外，通过初步结果，我们还 证明了尽管存在E/Z-异构体问题，但在高ee下加成亚胺和硝酮是可能的。广泛 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 学术界和工业界的从业人员，特别是制药和生物技术部门。