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认环肼是COPE重排的有效有机催化剂，并扩展到α-取代α，β-不饱和醛的Diels-Alder环加成和Michael加成反应。在这项拨款申请中，我们将把这些催化剂的用途扩展到新的反应，并将它们应用于天然产物的合成。多烯环化反应。根据我们的Cope重排机理，我们假设应该有可能用烯烃和富含电子的芳香族化合物捕获阳离子中间体来模拟类固醇和其他萜类的生物合成反应。我们将开发通过弱C-H-O氢键起作用的不对称肼催化剂，并将其应用于几种萜类天然产物的合成。克莱森重排。Claisen重排反应在有机合成中是一个非常有用的反应，它与Cope重排反应密切相关。我们将把我们的有机催化概念扩展到芳香族Claisen重排反应，这是该反应更常见的变体之一，并利用该反应制备在几个生物相关分子类中发现的色胺结构。Oxy-Cope/Michael反应。COX-COPE是COPE重排的另一种变体，在全合成中有重要的应用。我们将开发一种级联反应，将氧杂与Michael反应连接起来，生成环戊烷，如果在环状底物上进行，可能用于同时扩环。氧合/Michael在合成褐霉素A中的应用。褐霉素A是一种糖基化的萜类化合物，可促进轴突生长，使其及其类似物用于治疗神经损伤。我们将开发一种全合成褐霉素A的方法，它利用两个顺序的氧-钴/迈克尔反应在扩环模式下制备这一天然产物的核心5-8-5环系。将亚胺催化与光氧化还原化学相结合。我们推测，亚胺离子的形成应该会激活enals走向光氧化还原催化剂的还原，这是首次将亚胺催化与光氧化还原化学相结合。我们将通过[2+2]环加成来研究这一概念

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