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: 7939682
• 负责人: Liming Zhang
• 金额: $ 27.01万
• 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/7939682
• 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.

说明书(申请人提供)：N-杂环是包括药用实体在内的生物活性结构的基本成分。新型高效合成精制N-杂环化合物的开发将极大地促进药物研发和学术研究。由于Au盐/络合物在活化炔/烯/烯方面的特殊能力，Au的催化最近引起了极大的关注。铂催化剂，主要是PtCl2，也表现出类似的反应活性。已经开发了各种高效的合成方法，特别是在合成各种环大小和具有一系列结构特征的碳环方面。然而，金/铂催化的N-杂环化合物的制备一直比较滞后，主要局限于简单的N-杂环化合物(如吡啶、吡咯、恶唑、吡咯啉和吲哚)。这项建议的目标是开发高效的精制N-杂环的合成方法，并将其应用于生物碱及其类似物的合成。具体地说，有两个目标：a.开发Au/Pt催化合成复杂的N-杂环化合物。通过Au/Pt催化剂对炔烃/烯的初始活化，可以通过两种一般策略生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活性中间体，并且可以在Au/Pt催化剂参与或不进一步参与的情况下进行进一步的反应，从而导致结构复杂性增强；这些中间体包括亚甲基亚胺、硝酮、亚胺、含全碳金属的1，3-偶极和1，4-偶极；b)使用相对复杂但容易获得的底物，例如烯丙基内酰胺/舒坦和N-(2-烷基苯基)舒坦。将设计一系列单分子、双分子和三组分的反应，从而有效地合成各种N-杂环，包括吡咯并[2，1-a]异吲哚、吲哚嗪、吡咯利嗪、1，2-杂环/碳环稠合吲哚、吡咯烷酮、四环吲哚和苯并氮酮/苯并偶氮酮。此外，还将研究利用手性Au/Pt络合物对映体选择性地合成这些复杂的N-杂环化合物。B.7-甲氧基氮杂环丙烷及其类似物的合成采用模块化方法，实现了7-甲氧基氮杂环丙烷及其类似物的高效、对映选择性合成。以前开发的在金/铂催化下高效形成1，2-环戊酮-稠合吲哚的方法将被用作构建丝裂糖骨架的关键转化。利用这种方法，将制备各种氮杂环氧丙烷类似物，用于生物学研究。 与公众健康相关：该项目将开发高效和通用的合成方法，以促进药物发现的研发，并降低制药的制造成本。所提出的氮杂环氧丙烷类似物的合成将为癌症治疗提供新的先导结构。