Enantioselective Bronsted Acid Catalysis with Chiral Cyclopentadienes

项目摘要。获得富含对映体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 Brnsted酸催化已成为生产有价值的分子的一种高效策略 富含对映体的积木。然而，这一催化领域一直由非常有限的 许多催化剂系统是费力、耗时和昂贵的，这是一个非常重要的事实 阻碍了新反应的发现、开发和应用。因此，存在着明显的推动力， 发明了具有更高的效力和有效性的新的对映体选择性的布鲁斯特酸催化剂， 准备简单，易于修改。此外，有一种强烈的预期是，从根本上不同 催化剂结构将提供正交的反应模式，从而使新方法的发明成为可能。 为此，我们开发了一类全新的高活性和对映体选择性化合物。 Brnsted酸催化剂，基于五羧基环戊二烯(PCCP)。值得注意的是，PCCP是正式的 酸度超过许多已建立的催化平台的碳酸。五羧基环戊二烯 提供许多令人信服的优势，包括：(1)高酸度和高反应性；(2)极易 制备；(3)催化剂模数；以及(4)可缩放性。根据我们的初步调查，我们 设想五氯环己烷可能成为对映体选择性Brnsted酸催化的最终平台。在每一个中 在这里的目标项目中，我们的目标是应用PCCP催化来解决有机中的一个突出挑战 综合。此授权中针对的非对称转换当前未知或正在遭受 底物范围的显著限制。在我们打算在以下背景下发展的具体反应中 这项资助是：与烷基亚胺的对映选择性Mukaiyama Mannich反应；亲核加成 二氢吡咯酮；氧碳正离子的烯醇加成反应；Gassman-Michael反应；苯甲醇 取代；二氢苯并呋喃缩醛取代；氧烯丙基阳离子取代；以及Gassman Diels- 阿尔德反应。这些拟议转型的发展和进一步建立 PCCP催化剂平台将代表着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.