Enantioselective Catalysis with Cyclopropenimines

环丙烯亚胺的对映选择性催化

• 批准号: 8974844
• 负责人: Tristan H Lambert
• 金额: $ 29.61万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-15 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974844
• 关键词: Acidity; Address; Aerobic; Alkylation; Amines; Architecture; Area; Benzene; Biomedical Research; Catalysis; Catechols; Chromans; Complex; Development; Diamines; Effectiveness; Flavanones; Glycine; Glycols; Grant; Health; Hydroquinones; Imidazole; Investigation; Lead; Molecular; Nitrogen; Organic Synthesis; Outcome; Oxides; Phenols; Preparation; Prevalence; Production; Protons; Pyrazoles; Quinones; Reaction; Research; Series; Structure; System; Variant; Work; alkalinity; aqueous; base; catalyst; drug discovery; invention; programs; scaffold

DESCRIPTION (provided by applicant): Access to enantioenriched molecules is crucial to modern biomedical research. Many of the most important reactions in organic synthesis rely on proton transfer as a key mechanistic step. As such, chiral Bronsted base catalysis has emerged as a promising strategy for the production of valuable molecular building blocks in enantioenriched form. This area of catalysis has been impeded, however, by the relatively limited basicity of established catalyst platforms, which has significantly curtailed the widespread application of these approaches. Thus, there exists a clear impetus for the invention of new catalysts with increased potency and effectiveness, which could provide a general solution to the challenge of enantioselective Bronsted base catalysis. Toward this end, we have developed a fundamentally new class of highly reactive and enantioselective chiral Bronsted base catalyst, based on 2,3-bis(dialkylamino)cyclopropenimines. Notably, cyclopropenimines possess significantly higher basicity than established catalytic platforms. Based on our early demonstrations, we envision that cyclopropenimines may emerge as the definitive platform for enantioselective Bronsted base catalysis. Cyclopropenimines offer unique advantages of: (1) high basicity and reactivity; (2) ease of preparation; (3) compatibility with aqueous and aerobic conditions; (4) catalyst modularity; and (5) amenability to scale. In each of the projects targeted herein, we aim to apply cyclopropenimine 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 glycine Mannich and α-thio Mannich reactions; α-arylations with quinones and benzene oxides; Michael additions with low acidity nucleophiles, including diazoesters; allylic alkylations; and enantioselective conjugate additions of phenols, amines, and nitrogen heterocycles. The development of these proposed transformations and the further establishment of the new cyclopropenimine catalyst platform will represent significant advances for the field of organic synthesis.

描述(由申请人提供)：获得富含对映体的分子对现代生物医学研究至关重要。有机合成中许多最重要的反应都依赖于质子转移作为关键的机理步骤。因此，手性Bronsted碱催化已成为一种很有前途的策略，可用于生产有价值的富含对映体的分子构筑块。然而，现有催化剂平台的碱性相对有限，这大大限制了这些方法的广泛应用，阻碍了这一催化领域的发展。因此，具有更高效率和效率的新型催化剂的发明具有明显的推动力，可以为对映选择性Bronsted碱催化的挑战提供一般的解决方案。为此，我们开发了一类全新的基于2，3-双(二烷氨基)环丙烯亚胺的高活性和对映体选择性的手性Bronsted碱催化剂。值得注意的是，环丙烯亚胺具有比已建立的催化平台显著更高的碱性。基于我们早期的论证，我们设想环丙烯亚胺可能成为不对称Bronsted碱催化的最终平台。环丙烯亚胺具有以下独特的优点：(1)高碱度和反应性；(2)易于制备；(3)与水和好氧条件相容；(4)催化剂模块化；(5)可缩放性。在每个目标项目中 在这里，我们的目标是应用环丙烯亚胺催化来解决有机合成中的一个突出挑战。这笔赠款中针对的不对称转化要么是目前未知的，要么是受到底物范围的重大限制。在我们旨在做出的具体反应中 在这笔赠款的背景下开发的有：不对称甘氨酸曼尼希反应和α-硫代曼尼希反应；与苯醌和苯氧化物的α芳基化反应；与包括重氮酸酯在内的低酸度亲核试剂的迈克尔加成反应；烯丙基烷基化反应；以及酚、胺和氮杂环的不对称选择性共轭加成反应。这些拟议转化的发展和新的环丙烯亚胺催化剂平台的进一步建立将是有机合成领域的重大进展。