Development and application of cyclic hydrazides as organocatalysts

在过去的5年里，我们实验室的研究已经确定了环肼是Cope重排的有效有机催化剂，并将其扩展到Diels-Alder环加成和Michael加成取代α， β -不饱和醛。在这项拨款申请中，我们将把这些催化剂的使用扩展到新的反应中，并将其应用于天然产物的合成。多烯环化。基于我们的Cope重排机制，我们假设应该有可能捕获一个带有烯烃和富电子芳烃的阳离子中间体，以模拟类固醇和其他萜烯的生物合成反应。我们将开发通过弱C-H-O氢键起作用的对映选择性肼催化剂，并将其应用于几种萜烯天然产物的合成。克莱森重排。Claisen重排是有机合成中一种非常有用的反应，与Cope重排密切相关。我们将把我们的有机催化概念扩展到芳香Claisen重排，这是该反应的一个更常见的变体，并利用该反应制备在几种生物学相关分子类中发现的铬胺结构。Oxy-Cope /迈克尔反应。氧-Cope是Cope重排的另一种变体，在全合成中有重要的应用。我们将开发一个级联反应，将氧- cope与Michael反应连接起来，产生环戊烷，如果在环状底物上进行，可能会同时产生环扩张。fusicoccin A是一种糖基化萜烯，因其促进轴突生长而受到关注，使其及其类似物被用于治疗神经损伤。我们将开发丝孢霉素a的全合成方法，利用两个连续的氧- cope /Michael反应在扩环模式下制备该天然产物的核心5-8-5环体系。将氨催化与光氧化还原化学相结合。我们首次将光氧化还原化学与光氧化还原化学结合起来，假设光氧化还原离子的形成激活了光氧化还原催化剂的还原活性。我们将通过[2+2]环加成来研究这个概念

Research in our laboratory in the past 5 years has identified cyclic hydrazides as effective organocatalysts for the Cope rearrangement and these were extended to the Diels-Alder cycloaddition and Michael additions of alpha-substituted alpha,beta-unsaturated aldehydes. In this grant application, we will extend the use of these catalysts to new reactions and apply them to the synthesis of natural products. Polyene cyclizations. Based on the mechanism of our Cope rearrangement, we postulate that it should be possible to trap a cationic intermediate with alkenes and electron rich aromatics to mimic the reaction by which steroids and other terpenes are biosynthesized. We will develop enantioselective hydrazide catalysts which function through weak C-H-O hydrogen bonds and apply them to the synthesis of several terpene natural products.Claisen rearrangement. The Claisen rearrangement is a highly useful reaction in organic synthesis that is closely related to the Cope rearrangement. We will extend our organocatalysis concept to the aromatic Claisen rearrangement, one of the more common variants of this reaction, and use the reaction to prepare chromane structures found in several biologically relevant molecule classes.Oxy-Cope/Michael reaction. The oxy-Cope is another variant of the Cope rearrangement which has seen significant application in total synthesis. We will develop a cascade reaction which links the oxy-Cope with a Michael reaction to produce cyclopentanes and, if conducted on cyclic substrates, may be used to effect a simultaneous ring-expansion.Application of oxy-Cope/Michael to the synthesis of fusicoccin A. Fusicoccin A is a glycosylated terpene that is of interest for its promotion of axonal growth, making it and its analogs of interest for treatment of nerve damage. We will develop a total synthesis of fusicoccin A which leverages two sequential oxy-Cope/Michael reactions in ring-expansion mode to prepare the 5-8-5 ring system at the core of this natural product.Merging iminium catalysis with photoredox chemistry. We postulate that the formation of iminium ions should activate enals towards reduction by photoredox catalysts, for the first time merging iminium catalysis with photoredox chemistry. We will investigate this concept through a [2+2] cycloaddition