Novel Bond-Forming Processes Based on Energetic Intermediates

基于含能中间体的新型成键工艺

• 批准号: RGPIN-2018-04366
• 负责人: West, Frederick
• 金额: $ 13.7万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748153
• 关键词: Novel; Bond; Forming; Processes; Based

Intro. This proposal concerns the invention and development of new organic transformations, and their application in the construction of complex targets of biological interest. A common thread throughout is harnessing the unique reactivity of transient species to permit the development of novel, non-intuitive bond-forming processes. To accomplish these goals, HQP will focus on mechanistic studies to understand the fate of reactive intermediates, molecular design and systematic study of conditions to optimize the desired pathways, and synthetic design to develop routes to complex targets that take advantage of the capabilities of new methodology.Metallocarbene Chemistry. We have developed a green route to reactive C-acylimines from diazo-azides via copper catalysis. The only by-products are two molecules of nitrogen gas. The resulting imine electrophiles are subject to efficient capture by pi-nucleophiles. Trapping with indole serves to activate the copper(II) triflate precatalyst, forming catalytically competent copper(I) and Brønsted acid to promote indole addition to the acylimine. We plan to exploit the intervention of Brønsted acid catalysis to achieve asymmetric catalysis using external chiral acids. In a related project, we seek to develop a general route to medium-sized azacycles via metallocarbene-derived sulfonium ylides.Cyclic Allenes. Imposition of an allene moiety within a small ring (8 members or less) places sufficient bond angle strain on the molecule that it cannot be isolated. The high reactivity of these distorted allenes permits their participation in a variety of extremely facile pericyclic or radical-based processes. We wish to optimize new routes to the reactive allenes, including methods that allow for enantioselective allene generation. In addition, intramolecular trapping processes that permit the use of ordinarily unreactive moieties will be explored, and the application of trapping products to natural product targets will be investigated.Lewis Acid Catalysis. We have recently discovered a process for indole derivatization employing simple aldehydes and ketones in the presence of silane. The reaction requires both catalytic ferric chloride and blue lightomission of either results in little or no conversion. We wish to generalize this process, while exploring other earth-abundant metal salts. At the same time, we will also examine other Lewis acid-mediated bond-forming processes, including higher-order cationic electrocyclizations, such as the “vinylogous Nazarov reaction” and a 6pi variant of the Nazarov reaction employing trienones to generate cycloheptanoid products.This research entails a strong training environment, exposing HQP to important laboratory techniques and characterization skills that are in high demand in the chemical and pharmaceutical industries.

介绍一下。这项建议涉及到新的有机转化的发明和发展，以及它们在构建具有生物学意义的复杂靶标方面的应用。贯穿始终的一个共同主线是利用瞬变物种的独特反应性来开发新的、非直觉的成键过程。为了实现这些目标，HQP将专注于机理研究以了解活性中间体的命运，分子设计和条件的系统研究以优化所需的途径，以及合成设计以利用新方法的能力开发通往复杂目标的路线。我们开发了一条由重氮叠氮化物通过铜催化合成活性C-酰亚胺的绿色路线。唯一的副产品是两个氮气分子。由此产生的亚胺亲电体容易被pi-亲核剂有效捕获。吲哚的捕获作用是激活三氟化铜(II)预催化剂，形成具有催化活性的铜(I)和Brnsted酸，以促进吲哚与酰亚胺的加成反应。我们计划利用Brnsted酸催化的介入来实现使用外部手性酸的不对称催化。在一个相关的项目中，我们试图开发一条通过金属卡宾衍生的硫化物叶立德来合成中型氮杂环的一般路线。在一个小环(8个成员或更少)内施加一个联烯部分会使分子受到足够的键角应变，使其无法分离。这些扭曲的联烯的高活性允许它们参与各种极其容易的周环或基于自由基的过程。我们希望优化活性联烯的新路线，包括允许生成对映体选择性联烯的方法。此外，还将探索允许使用通常非活性部分的分子内捕获过程，并将研究捕获产物在天然产品靶标中的应用。我们最近发现了一种在硅烷存在下使用简单的醛和酮进行吲哚衍生化的方法。该反应需要三氯化铁和蓝色光的催化作用，两者的转化率都很低或没有转化率。我们希望在探索其他富含地球的金属盐的同时，推广这一过程。同时，我们还将研究刘易斯酸介导的其他成键过程，包括更高级别的阳离子电环化，如“Vinylogous Nazarov反应”和纳扎罗夫反应的6pi变体，使用三烯酮生成环庚烷产品。这项研究需要强大的培训环境，使HQP接触到重要的实验室技术和表征技能，这些技术在化工和制药行业中需求很高。