Enantioselective Bronsted Acid Catalysis with Chiral Cyclopentadienes

手性环戊二烯对映选择性布朗台德酸催化

• 批准号: 9158042
• 负责人: Tristan H Lambert
• 金额: $ 30.8万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9158042
• 关键词: Acetals; Acidity; Acids; Address; Alcohols; Alder plant; Amines; Architecture; Area; Biomedical Research; Carbon; Catalysis; Cations; Complex; Computer Analysis; Cyclopentadienes; Development; Diels Alder reaction; Effectiveness; Ethers; Goals; Grant; Imines; Indoles; Investigation; Ions; Lead; Menthol; Methods; Minerals; Molecular; Organic Synthesis; Outcome; Pattern; Phosphoric Acids; Preparation; Prevalence; Procedures; Production; Protons; Reaction; Research; Series; Structure; Structure-Activity Relationship; System; Technology; Time; Variant; Work; base; catalyst; cycloaddition; drug discovery; enolate; expectation; invention; method development; nucleophilic addition; programs; protonation; scaffold; small molecule

Project Summary. Access to enantioenriched molecules is crucial to modern biomedical research. Many of the most important reactions in organic synthesis rely on protonation as a key mechanistic step. As such, chiral BrØnsted acid catalysis has emerged as a highly effective strategy for the production of valuable molecular building blocks in enantioenriched form. This area of catalysis has been dominated, however, by a very limited number of catalyst systems that are laborious, time-consuming, and expensive to prepare, a fact that greatly impedes new reaction discovery, development, and application. Thus, there exists a clear impetus for the invention of new enantioselective BrØnsted acid catalysts with increased potency and effectiveness that are trivial to prepare and easy to modify. In addition, there is a strong expectation that fundamentally different catalyst structures will offer orthogonal reactivity patterns and thus enable the invention of new methods. Toward this end, we have developed a fundamentally new class of highly reactive and enantioselective BrØnsted acid catalysts, based on pentacarboxycyclopentadienes (PCCPs). Notably, PCCPs are formally carbon acids with acidities that exceed many established catalytic platforms. Pentacarboxycyclopentadienes offer a number of compelling advantages including: (1) high acidity and reactivity; (2) extreme ease of preparation; (3) catalyst modularity; and (4) amenability to scale. Based on our initial investigations, we envision that PCCPs may emerge as a definitive platform for enantioselective BrØnsted acid catalysis. In each of the projects targeted herein, we aim to apply PCCP catalysis to address a prominent challenge in organic synthesis. The asymmetric transformations targeted in this grant are either currently unknown or suffer from significant limitations of substrate scope. Among the specific reactions that we aim to develop in the context of this grant are: enantioselective Mukaiyama Mannich reactions with alkyl imines; nucleophilic additions to dihydropyrrolones; enolate additions to oxocarbenium ions; Gassman-Michael reactions; benzylic alcohol substitutions; dihydrobenzofuran acetal substitutions; substitutions via oxyallyl cations; and Gassman Diels- Alder reactions. The development of these proposed transformations and the further establishment of the PCCP catalyst platform will represent significant advances for the field of organic synthesis.

项目摘要。获取对映体分子对于现代生物医学研究至关重要。许多 有机合成中最重要的反应依赖于质子化作为关键机械步骤。因此，手性 BrønstedAcid催化已成为产生有价值的分子的高效策略 以对映基形式的构建块。但是，该催化区域已被非常有限 实验室，耗时且准备昂贵的催化剂系统数量，这一事实极为 阻碍了新的反应发现，开发和应用。那存在明显的动力 发明新的对映选择性的Brønsted酸催化剂，其效力和有效性提高了 琐碎的准备和易于修改。此外，有一个强烈的期望从根本上不同 催化剂结构将提供正交的反应性模式，从而实现新方法的发明。 为此，我们开发了一类新的高度反应性和对映选择性类别 BrønstedAcid催化剂，基于Pentacarboxyclopentadienes（PCCP）。值得注意的是，PCCP正式 酸度超过许多已建立的催化平台的碳酸。五羧基环境 提供许多引人注目的优势，包括：（1）高酸度和反应性； （2）极端 准备; （3）催化剂模块化； （4）缩放性的适用性。根据我们的初步调查，我们 设想PCCP可以成为对映选择性BrønstedAcid催化剂的确定平台。每个 在本文针对的项目中，我们旨在应用PCCP催化以应对有机的巨大挑战 合成。本赠款中针对的不对称转换目前未知或遭受 底物范围的显着局限性。我们旨在在以下背景下发展的具体反应 这项赠款是：对映选择性的mukaiyama mannich用烷基胺反应；亲核的添加 二氢吡咯；氧化离子添加烯；加斯曼·迈克尔（Gassman-Michael）反应；苯并醇 取代；二氢苯并呋喃乙酰替代；通过含氧阳离子取代；和加斯曼的Diels- alder反应。这些提议的转变的发展以及进一步的建立 PCCP催化平台将代表有机合成领域的重大进步。