基于羰基-亚胺和羰基-羰基交叉二聚的oxy-azonia-Cope以及oxy-oxonia-Cope重排：反应设计、机理和合成应用

Various [3,3]-sigma rearrangement reactions constitute an invaluable class of methodologies for the atom-economical formation of carbon-carbon bond, and have found many applications as the key step in the total synthesis of natural products. Quite recently, in an attempt to synthesize a potential oxaspiro odorant by Prins reaction, we disclosed that beta,gamma-unsaturated ketones and alkoxy oximes or imines undergo nucleophilic addition to produce zwitterion intermediates, which subsequently afford homoallylic esters or amides by oxy-azonia and oxy-oxonia-Cope [3,3]-sigma rearrangement. Further, the concept was evolved to intramolecular version, leading to homoallylic macrolide or microlactams. Using this convergent and atom-economical [n+4] ring enlargement strategy, the total synthesis of alkaloid motuporamine G was completed and the structure was verified. In the present study, novel substrates including 4-oxo-alkynes, imines derived from aldehyde/keto carboxylic acids or esters, and beta,gmma,delta,epslong-unsaturated carbonyl compounds will be investigated. The substituent effects are to be analyzed by considering the effect on reactants, products, and the TS. The alkaloids motuporamines A, B, and C, which were isolated as an inseparable mixture from Xestospongia exigua collected in Papua New Guinea, represent a new family of cytotoxic sponge alkaloids containing a spermidine-like substructure. On the basis of the reaction scope study, the chemical synthesis will be explored. Meanwhile, chiral version of these valuable transformations by using chiral Lewis acids will be approached. Representative reactions will also be investigated computationally using density functional theory. This work is of primary importance to broaden the synthetic application of these novel oxy-oxonia-Cope and oxy-azonia-Cope rearrangements, and to obtain deeper insight in the nature of these reactions.

[3,3]-sigma重排反应是一种高效的C-C键构建策略。在最近的研究中，我们发现beta,gamma-不饱和醛、酮等的羰基在Lewis酸作用下，可以被另一分子羰基氧或者亚胺氮亲核进攻，构成一个新颖的两性离子[3,3]-sigma重排体系，即oxy-2-oxonia-Cope以及oxy-2-azonia-Cope重排。重排后形成高烯丙酯以及高烯丙基酰胺类化合物。本课题中我们将系统地考察底物结构对此重排的影响，探讨[5,5]-sigma重排反应的可行性，研究在手性Lewis酸催化下的不对称重排，并建立基于这种重排合成氨基酸的新方法，完成若干Motuporamines生物碱等具有重要生理活性的海洋天然产物的合成，发展新的扩环反应策略。我们还将结合实验，采用理论计算方法，揭示重排底物中取代基种类、取代位置对反应的影响规律。该项研究工作是一项具有重要的学术意义和突出的应用价值的课题。

各种[3 ,3] -σ重排反应已经成为原子经济性构建碳-碳键的重要方法。作为关键的步骤，这种策略在具有重要生理活性的天然产物合成中得到广泛的应用。在本课题中，我们主要围绕一系列不饱和酮与醛/酮、亚胺、肟醚等的反应而展开。这类反应都是从Lewis酸对羰基的活化开始，通过羰基或者亚胺对活化的羰基进行亲核加成，产生离子两性离子中间体，随后经过oxonia-Cope [3,3 ]-σ重排等转变，形成高烯丙基酯或酰胺等。所发展的oxonia-Cope重排以及azonia-Cope重排等策略也可扩展到分子内反应。本项研究所取得主要结果如下: (1)通过Lewis酸的作用，建立了由亚氨基乙醛酸乙酯和各种 β,γ-不饱和酮合成烯丙基α-氨基酸衍生物的方法，该方法无需缩合剂，所得产物为重要的合成中间体。(2) 在Lewis酸存在下，TMS取代的 β,γ-不饱和酮和醛（亚胺）进行亲核加成首先生成两性离子中间体，并由此建立了通过oxy-2-oxonia (azonia-)-Cope重排合成高烯丙基酯（酰胺）的方法。以含TMS的2-烯基环酮为底物，可以实现n + 4扩环，并利用这一策略合成10~16元环内酯。基于此策略，合成了(R)-phoracantholide和rac-(Z)-recifeiolide等天然产物。(3) 发展了新颖的Diels-Alder及重排的系列反应，为不同官能化的双环[2.2.1]庚烷的合成提供了新的途径。产物多具有新型花香和木本气息，有潜在的香料应用价值。这项研究还纠正了文献中对双环[2.2.1]庚酮相对构型判断的错误。(4) 发展了一种通用的、无金属催化和常压下的domino-Claisen–Cope重排反应。通过这种反应方式，从易得的alpah-betta-不饱和醛或缩醛和烯丙基醇出发，可以合成具有柑橘、玫瑰气味的潜香分子。(5) 使用B3LYP密度泛函理论方法及极化连续介质模型(PCM)模拟溶液体系，对在Lewis酸催化下的 β,γ-不饱和酮与亚胺之间的形成高烯丙基酰胺和内酰胺类化合物的oxy-2-azonia-Cope重排反应机制进行了理论研究。该研究表明，在四氯化锡催化下，反应经由串联的亲核性的二聚/ oxy-2-azonia-Cope 重排较另一可能的二聚/Prins环化途径更加有利。作为有用的策略，可应用于大环内酰胺类的合成。

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