Novel Bond-Forming Processes Based on Energetic Intermediates

介绍。本提案涉及新的有机转化的发明和发展，以及它们在构建生物感兴趣的复杂靶标中的应用。贯穿始终的一个共同主线是利用瞬态物种的独特反应性来开发新颖的、非直觉的键形成过程。为了实现这些目标，HQP将专注于机制研究，以了解反应性中间体的命运，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，以开发利用新方法能力的复杂目标路线。Metallocarbene化学。我们已经开发了一种绿色途径，通过铜催化从重氮叠氮化合物中获得活性c -酰基胺。唯一的副产品是两分子氮气。生成的亚胺亲电试剂可被亲核试剂有效捕获。用吲哚捕获有助于激活三酸铜预催化剂，形成具有催化活性的铜(I)和Brønsted酸，促进吲哚加成到酰基胺中。我们计划利用Brønsted酸催化的干预来实现外部手性酸的不对称催化。在一个相关的项目中，我们试图通过金属卡宾衍生的磺酰化物来开发一种中型氮杂环的一般途径。循环艾伦。在一个小环（8个成员或更少）内强加一个烯片段会对分子产生足够的键角应变，使其无法被分离。这些扭曲的烯的高反应性允许它们参与各种极其容易的周环或基基过程。我们希望优化反应性烯的新途径，包括允许对映选择性烯生成的方法。此外，将探索允许使用通常不反应的部分的分子内捕获过程，并将研究捕获产物对天然产物目标的应用。路易斯酸催化。我们最近发现了一种在硅烷存在下使用简单醛和酮进行吲哚衍生化的方法。该反应既需要三氯化铁的催化作用，也需要蓝光的催化作用。我们希望推广这一过程，同时探索其他地球上丰富的金属盐。同时，我们还将研究其他Lewis酸介导的键形成过程，包括高阶阳离子电环化，如“vinylogous Nazarov反应”和使用三烯酮生成环七烷类产物的Nazarov反应的6倍变体。这项研究需要一个强大的培训环境，使HQP接触化学和制药行业高需求的重要实验室技术和表征技能。

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.