Au/Pt Catalysis in the Synthesis of Elaborate N-Heterocycles: Methodology Develop

描述（由申请人提供）：n -杂环化合物是包括药物实体在内的生物活性结构的基本成分。新型高效合成n -杂环化合物的开发将极大地促进药物研发和学术研究。近年来，由于金盐/配合物在活化炔/烯/烯烃方面的特殊能力，金催化引起了人们的极大关注。Pt催化剂，主要是PtCl2，也表现出类似的反应活性。各种高效的合成方法已经被开发出来，特别是在合成各种环尺寸和具有一系列结构特征的碳环方面。然而，Au/ pt催化制备n -杂环的研究相对滞后，且大多局限于简单的n -杂环（如吡啶、吡咯、恶唑、吡咯和吲哚）。本课题的目标是开发复杂N-杂环化合物的高效合成方法，并将其应用于生物碱及其类似物的合成。具体来说，有两个目的：A.发展Au/ pt催化合成n -杂环的复杂性。通过Au/Pt催化剂对炔/烯烯的初始活化，可以通过两种一般策略形成更具挑战性和更有价值的复杂N-杂环：a)从相对简单的底物生成反应中间体，并可以在Au/Pt催化剂参与或不参与的情况下进行进一步反应，从而提高结构的复杂性；这些中间体包括亚甲亚胺酰基、亚硝基、亚胺亚胺、含1,3偶极子和1,4偶极子的全碳金属；b)使用相对复杂但容易获得的底物，例如，炔基内酰胺/舒坦和N-（2-炔基苯基）舒坦。一系列单分子、双分子和三组分反应将被设计，从而允许有效合成各种n -杂环，包括吡咯[2,1- A]异吲哚、吲哚嗪、吡咯利嗪、1,2-杂环/碳环融合的吲哚、吡咯烷酮、四环吲哚和苯并氮杂酮/苯并氮杂醌。此外，还将研究手性Au/Pt配合物对映选择性合成这些N-杂环复合物。B. 7-甲氧基叠氮基咪托烯及其类似物的合成提出了一种高效、对映选择性的7-甲氧基叠氮基咪托烯的合成方法。先前开发的Au/ pt催化的1,2-环戊酮融合吲哚的高效形成将被用作构建线粒体骨架的关键转化。利用这种方法，可以制备各种各样的叠氮二咪糖类似物用于生物学研究。

DESCRIPTION (provided by applicant): N-Heterocycles are essential components of bioactive structures including pharmaceutical entities. Development of novel and efficient synthesis elaborate N-heterocycles will substantially facilitate drug research and development and academic research. Au catalysis has attracted tremendous attention lately due to the exceptional capacities of Au salts/complexes in activating alkynes/allenes/alkenes. Pt catalysts, mostly PtCl2, have shown similar reactivities. Various highly efficient synthetic methods have been developed, especially in the synthesis of carbocycles of various ring sizes and with an array of structural features. However, Au/Pt-catalyzed preparations of N-heterocycles have been rather lagged behind and are mostly limited to simple N-heterocycles (e.g., pyridines, pyrroles, oxazoles, pyrroline and indoles). The goals of this proposal are to develop efficient synthetic methods for elaborate N- heterocycles and to apply them in synthesis of alkaloids and their analogs. Specifically, there are two aims: A. Development of Au/Pt-catalyzed synthesis of N-heterocycles of complexity. Via initial activation of alkynes/allenes with Au/Pt catalysts, more challenging and valuable elaborate N- heterocycles could be formed via two general strategies: a) from relatively simple substrates reactive intermediates can be generated and can undergo further reactions with/without further Au/Pt catalyst participation and lead to enhanced structural complexity; these intermediates include azomethine ylides, nitrones, azomethine imines, all-carbon metal-containing 1,3-dipoles and 1,4-dipoles; b) using relatively complex but readily available substrates, e.g., enynyl lactam/sultam and N-(2-alkynylphenyl)sultam. A range of unimolecular, bimolecular and three-component reactions will be designed and thus allow efficient synthesis of various N-heterocycles, including pyrrolo[2,1-a]isoindoles, indolizines, pyrrolizines, 1,2-heterocycle/carbocycle-fused indoles, pyrrolidinones, tetracyclic indolines, and benzoazepinones/benzoazocinones. Moreover, enantioselective synthesis of these complex N- heterocycles using chiral Au/Pt complexes will also be studied. B. Synthesis of 7-methoxyaziridinomitosene and its analogs A highly efficient, enantioselective synthesis of 7-methoxylaziridinomitosene is proposed via a modular approach. A previously developed Au/Pt-catalyzed efficient formation of 1,2-cyclopentanone-fused indoles will be used as a key transformation for constructing the mitosene skeleton. Using this approach, various aziridinomitosene analogs will be prepared for biological studies. PUBLIC HEALTH RELEVANCE: This project would develop efficient and versatile synthetic methods to facilitate R&D in drug discovery and lower down manufacturing costs of pharmaceutics. The proposed syntheses of aziridinomitosene analogs will provide new lead structures for cancer treatment.