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.

项目摘要/摘要 该提议的这一目标是开发新的合成方法，用于对映选择性合成生物活性 分子。研究集中于利用新的阿托帕异构手性双子体配体正在开发 我们的实验室。初步工作发现，基于咪唑的biariall P，N-Ligands excel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 这些配体和现有的双子体配体之间的行为差​​异，以使新的反应技术成为 发现化学的应用。该应用中的研究重点是获得机械 理解负责这种新的新反应性的结构基础 配体脚手架。我们的第一个目的概述了开发氮杂环的新的亲爱的反应的计划。 在此目的中，我们描述了将田野推向手性碳纤维和单杂质的化学反应 杂环到杂环> 1个杂原子。通过初步结果，我们证明了 吡啶，但更重要的是吡嗪，吡啶嗪和嘧啶。这些后一个例子是前所未有的 在文献和这些催化对映选择性的亲爱的反应的成功中 为了快速获取复杂的天然产品，例如svetamycin B，saxitoxin和batzellidine B以及 其他含氮的基础。第二个目标集中于催化对映选择性 与氮取代无关的C = N键的加法反应。在催化对映选择过程中， 伊米尼离子通常需要2种相同的n降低来避免E/Z问题。我们发现 使用Stackphos催化对映选择性藻类化提升了这一要求，并使用了两个不同的n- 取代基是可能的。这一突破使从受BIS保护的胺（例如N，N-二苯基）转移到 合成所需的组。在这里，我们将此资本化以获得权宜的综合 山雀和其他手性杂环，例如吗啡。此外，通过初步结果，我们也 尽管存在E/Z异构体问题，但可以证明，在高EE中增加了亚胺和氮。广泛的 初步结果支持这些目标，我们预测这里开发的化学反应将产生广泛的影响 在学术界和工业环境中，特别是制药和生物技术领域的从业者。