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酰肼作为科普重排的有效有机催化剂，这些被扩展到α-取代的α，β-不饱和醛的Diels-Alder环加成和Michael加成。 在这项资助申请中，我们将把这些催化剂的用途扩展到新的反应中，并将其应用于天然产物的合成。 ** 多烯环化。基于我们的科普重排的机制，我们假设，它应该是可能的捕获一个阳离子中间体与烯烃和富电子芳烃模拟的反应，其中甾体和其他萜烯的生物合成。我们将开发通过弱C-H-O氢键发挥作用的对映选择性酰肼催化剂，并将其应用于多种萜烯天然产物的合成。*克莱森重排反应。克莱森重排反应是有机合成中一个非常有用的反应，它与科普重排反应密切相关。 我们将把我们的有机催化概念扩展到芳香克莱森重排，这是该反应的一种更常见的变体，并使用该反应制备在几种生物学相关分子类别中发现的色满结构。氧-科普-迈克尔反应。氧-科普是科普重排的另一种变体，其在全合成中具有重要的应用。 我们将开发一种级联反应，将氧-Cope与迈克尔反应连接起来以产生环戊烷，并且如果在环状底物上进行，则可以用于实现同时扩环。** Oxy-Cope/Michael催化剂在褐孢菌素A合成中的应用梭孢菌素A是一种糖基化的萜烯，其促进轴突生长是令人感兴趣的，使其及其类似物对于治疗神经损伤是令人感兴趣的。 我们将开发一种fusicoccin A的全合成方法，该方法利用两个连续的oxy-Cope/Michael反应在扩环模式下制备这种天然产物核心的5-8-5环系统。亚胺催化与光氧化还原化学的结合。我们假设，亚胺离子的形成应激活enals对减少光氧化还原催化剂，第一次合并亚胺催化与光氧化还原化学。 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