Enantioselective Bronsted Acid Catalysis with Chiral Cyclopentadienes

项目摘要。获得对映体富集的分子对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的机械步骤。因此，手性 布朗斯台德酸催化已成为生产有价值的分子的高效策略。 对映体富集形式的结构单元。然而，这一催化领域一直由非常有限的 许多催化剂体系的制备是费力、耗时和昂贵的，这一事实极大地 阻碍了新反应的发现、开发和应用。因此，有一个明确的动力， 发明了具有增加的效力和有效性的新的对映选择性布朗斯台德酸催化剂， 准备简单，易于修改。此外，还有一种强烈的预期， 催化剂结构将提供正交反应性模式，从而能够发明新方法。 为此，我们开发了一类全新的高反应性和对映选择性的 基于五羧基环戊二烯（PCCP）的布朗斯台德酸催化剂。值得注意的是，PCCP正式 酸性超过许多已建立的催化平台的碳酸。五羧基环戊二烯 提供了许多令人信服的优点，包括：（1）高酸度和反应性;（2）非常容易 制备;（3）催化剂模块化;和（4）规模适应性。根据初步调查，我们 设想PCCP可能成为对映选择性布朗斯台德酸催化的决定性平台。在每个 在本文所针对的项目中，我们的目标是应用PCCP催化来解决有机化学领域的一个突出挑战。 合成.这项资助的非对称转换目标目前要么是未知的，要么是遭受 基板范围的显著限制。在我们的具体反应中， 这些授权是：与烷基亚胺的对映选择性Mukaiyama Mannich反应; 二氢吡咯酮;烯醇化加成; Gassman-Michael反应;苄醇 取代;二氢苯并呋喃缩醛取代;经由氧烯丙基阳离子的取代;和Gassman Diels- 桤木反应。发展这些拟议的改革和进一步建立 PCCP催化剂平台将代表有机合成领域的重大进展。

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.