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

Au/Pt 催化合成精细 N-杂环化合物：方法开发

• 批准号: 8324555
• 负责人: Liming Zhang
• 金额: $ 26.47万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324555
• 关键词: Alcohols; Alkaloids; Alkenes; Alkynes; Attention; Biological; Biological Factors; Carbon; Catalysis; Chemistry; Complex; DNA Sequence Rearrangement; Development; Distal; Goals; Gold; Health Personnel; Imines; Indoles; Indolizines; Industry; Laboratory Research; Lactams; Lead; Metals; Methodology; Methods; Organic Chemistry; Oxazoles; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacy (field); Preparation; Publications; Pyrroles; Pyrrolidinones; Reaction; Research; Salts; Scheme; Skeleton; Structure; System; analog; aziridinomitosene; base; cancer therapy; carbonyl group; catalyst; cost; cyclopentanone; design; drug discovery; indoline; mitosene; nanoparticle; nitrone; novel; propadiene; protonation; public health relevance; pyridine; pyrroline; research and development; small molecule libraries; ylide

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.

描述（由申请人提供）：N-杂环是包括药物实体在内的生物活性结构的重要组成部分。开发新型高效合成精细N-杂环化合物将极大地促进药物研发和学术研究。由于金盐/络合物在活化炔烃/丙二烯/烯烃方面具有特殊的能力，金催化最近引起了极大的关注。 Pt 催化剂（主要是 PtCl2）表现出类似的反应活性。人们已经开发了各种高效的合成方法，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催化的N-杂环的制备却相当落后，并且大多局限于简单的N-杂环（例如吡啶、吡咯、恶唑、吡咯啉和吲哚）。该提案的目标是开发精细N-杂环的有效合成方法，并将其应用于生物碱及其类似物的合成。具体来说，有两个目标： A. 开发复杂的 N-杂环的 Au/Pt 催化合成。通过使用 Au/Pt 催化剂对炔烃/丙二烯进行初始活化，可以通过两种通用策略形成更具挑战性和更有价值的精细 N-杂环：a) 从相对简单的底物可以生成反应性中间体，并且可以在有/没有进一步的 Au 的情况下进行进一步的反应/Pt催化剂的参与导致结构复杂性增强；这些中间体包括偶氮甲碱叶立德、硝酮、偶氮甲碱亚胺、含全碳金属的1,3-偶极子和1,4-偶极子； b)使用相对复杂但容易获得的底物，例如烯炔内酰胺/磺内酰胺和N-(2-炔基苯基)磺内酰胺。将设计一系列单分子、双分子和三组分反应，从而有效合成各种N-杂环，包括吡咯并[2,1-a]异吲哚、中氮茚、吡咯嗪、1,2-杂环/碳环稠合吲哚、吡咯烷酮、四环二氢吲哚和苯并氮杂酮/苯并氮杂辛酮。此外，还将研究使用手性 Au/Pt 配合物对映选择性合成这些复杂的 N-杂环。 B. 7-甲氧基吖丙啶基核糖烯及其类似物的合成通过模块化方法提出了7-甲氧基氮丙啶基核糖烯的高效、对映选择性合成。先前开发的 Au/Pt 催化有效形成 1,2-环戊酮稠合吲哚将被用作构建有丝分裂烯骨架的关键转化。使用这种方法，将制备各种氮丙啶核类似物用于生物学研究。 公共健康相关性：该项目将开发高效且通用的合成方法，以促进药物发现的研发并降低药品的制造成本。氮丙啶基核糖烯类似物的拟议合成将为癌症治疗提供新的先导结构。