Enantioselective Catalysis with Chiral Cyclopropenimines

手性环丙烯亚胺的对映选择性催化

• 批准号: 9277067
• 负责人: Tristan H Lambert
• 金额: $ 8万
• 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/9277067
• 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）：获得对映体富集的分子对于现代生物医学研究至关重要。有机合成中的许多最重要的反应都依赖于质子转移作为关键的机械步骤，因此，手性布朗斯台德碱催化已成为一种有前景的策略。然而，现有催化剂平台的碱度相对有限，这极大地阻碍了以对映体富集形式生产有价值的分子结构单元。因此，有明显的动力来发明具有更高效力和效率的新型催化剂，这可以为对映选择性布朗斯台德碱催化的挑战提供通用解决方案。基于 2,3-双（二烷基氨基）环丙烯亚胺的全新一类高反应性和对映选择性手性布朗斯台德碱催化剂值得注意的是，环丙烯亚胺具有根据我们的早期演示，我们预计环丙烯亚胺可能成为对映选择性布朗斯台德碱催化的最终平台，具有以下独特优势：（1）高碱性和反应性；（2）易于制备。 (3) 与水和有氧条件的兼容性；(4) 催化剂模块化；以及 (5) 每个目标项目的适应性。 在此，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。本次资助所针对的不对称转化要么是目前未知的，要么是我们目标的特定反应受到显着限制。 在该资助范围内开发的有：对映选择性甘氨酸曼尼希和α-硫代曼尼希反应；与醌和氧化苯的α-芳基化；与低酸性亲核试剂的迈克尔加成，包括烯丙基烷基化；以及苯酚、胺的对映选择性共轭加成；和氮杂环的发展以及新的转化的进一步建立。环丙烯宁催化剂平台将代表有机合成领域的重大进步。