Enantioselective Catalysis with Cyclopropenimines

环丙烯亚胺的对映选择性催化

• 批准号: 8595321
• 负责人: Tristan H Lambert
• 金额: $ 29.35万
• 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/8595321
• 关键词: Acidity; Address; Aerobic; Alkylation; Amines; Architecture; Area; Benzene; Biomedical Research; Catalysis; Catechols; Chromans; Complex; Development; Diamines; Effectiveness; Flavanones; Glycine; Glycols; Grant; Hydroquinones; Imidazole-Pyrazole; Investigation; Lead; Molecular; Nitrogen; Organic Synthesis; Outcome; Oxides; Phenols; Preparation; Prevalence; Production; Protons; Quinones; Reaction; Research; Series; Solutions; Structure; System; Variant; Work; alkalinity; aqueous; base; catalyst; drug discovery; programs; public health relevance; 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 ?-thio Mannich reactions; ?-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途的策略，用于生产有价值的分子结构单元的对映体富集的形式。然而，这一领域的催化受到了已建立的催化剂平台的相对有限的碱性的阻碍，这显著地限制了这些方法的广泛应用。因此，存在发明具有增加的效力和有效性的新催化剂的明显动力，其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。为此，我们已经开发了一种全新的高反应性和对映选择性的手性布朗斯台德碱催化剂，基于2，3-双（二烷基氨基）环丙烯亚胺。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。基于我们早期的演示，我们设想环丙烯亚胺可能会成为对映选择性布朗斯台德碱催化的最终平台。环丙烯亚胺提供以下独特优点：（1）高碱性和反应性;（2）易于制备;（3）与水性和有氧条件相容;（4）催化剂模块性;和（5）可规模化。在每一个目标项目中， 本文中，我们旨在应用环丙烯亚胺催化来解决有机合成中突出挑战。在这个补助金目标的不对称转换是目前未知的或遭受基板范围的重大限制。在我们的具体反应中， 开发的背景下，这一授权是：对映选择性甘氨酸曼尼希和？-硫代Mannich反应;与醌和苯氧化物的芳基化;与低酸度亲核试剂（包括重氮酯）的迈克尔加成;烯丙基烷基化;以及酚、胺和氮杂环的对映选择性共轭加成。这些提出的转变的发展和新的环丙烯亚胺催化剂平台的进一步建立将代表有机合成领域的重大进展。