Enantioselective Annulation Reactions

对映选择性成环反应

• 批准号: 7679509
• 负责人: Jeffrey William Bode
• 金额: $ 30.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679509
• 关键词: Acids; Aldehydes; Alder plant; Alkenes; Binding; Chemicals; Cyclopentane; Cyclopentenes; Development; Diels Alder reaction; Electrons; Evaluation; Funding; Generations; Goals; Imines; Lactams; Lactones; Mediating; Methods; Neurodegenerative Disorders; Neuroprotective Agents; Oxidation-Reduction; Pathway interactions; Pattern; Pharmacologic Substance; Preparation; Procedures; Process; Reaction; Reporting; Research; Screening procedure; Structure; Therapeutic Agents; Variant; Work; adduct; analog; base; cancer therapy; carbene; catalyst; clausenamide; design; drug candidate; drug discovery; enolate; human disease; improved; innovation; insight; novel; novel strategies; programs; public health relevance; small molecule; stereochemistry

DESCRIPTION (provided by applicant): The goal of this project is to develop new synthetic methods for the concise synthesis of chiral heterocyclic and carbocyclic compounds. These structures constitute the structural core of a growing number of pharmaceuticals and biologically active molecules but methods for their efficient construction and control of absolute stereochemistry remain limiting steps. We have developed new chemical transformations mediated by N-heterocyclic carbenes (NHCs) that make possible previously unrecognized strategies for the synthesis of lactams, lactones, and cyclopentanes in enantioenriched form. Importantly, these processes precede under mild reaction conditions and can be applied to the synthesis of a broad range of substitution patterns. All of these processes proceed by the catalytic generation of reactive species from alpha-functionalized aldehydes such as enals and alpha-haloaldehydes. Specific Aims: (1) To develop concise, single-step methods for the enantioselective synthesis of disubstituted gamma-lactones, gamma-lactams, and cyclopentenes by chiral NHC-catalyzed annulations of enals. (2) To significantly expand the scope and applications of our recently developed NHC- catalyzed inverse electron demand Diels-Alder reactions that afford diverse, chiral heterocycles from simple starting materials. (3) To demonstrate the synthetic utility of chiral annulation products through chemo- and diastereoselective transformations including the concise asymmetric syntheses of (-)-chebulic acid and the neuroprotective agent (-)-clausenamide. Significance. The proposed research will provide a uniquely concise and practical entry to a wide variety of highly substituted structures with proven therapuetic potential. This work will also contribute mechanistically novel approaches to the synthesis of chiral small molecules and provide a unique, efficient synthetic strategy not readily implemented with exisiting chemical methods. PUBLIC HEALTH RELEVANCE: Small organic molecules constitute the vast majority of proven therapeutic agents and new drug candidates. Recent efforts in target identification and screening have outpaced chemical methods for the synthesis of the biologically relevant heterocyclic and carbocyclic structures needed for further innovation in small molecule-based drug discovery and development. Our research offers novel, mechanistically unique, and highly efficient methods for the synthesis of these structures from simple starting materials and will contribute to ongoing efforts aimed at the discovery, understanding, and manufacture of new treatments for human diseases.

描述（由申请人提供）：该项目的目的是开发新的合成方法，以简化手性杂环和碳环循环化合物的合成。这些结构构成了越来越多的药物和生物活性分子的结构核心，但是它们有效地结构和控制绝对立体化学的方法仍然是限制步骤。我们开发了由N-杂环碳烯（NHC）介导的新化学转化，这些化学转化使得以前的lactams，Lactones和cyclopentanes以甲基化形式的合成以前无法识别的策略。重要的是，这些过程在轻度反应条件下，可以应用于多种替代模式的综合。所有这些过程是通过α功能化醛（例如烯醇和α-甲醛）的催化产生反应性物种进行的。具体目的：（1）通过手性NHC催化的烯烯化的烯烯化，开发出简洁的单步方法，用于对对映射的伽马 - 内酯，γ-内酰胺和环戊烯的合成。 （2）显着扩大了我们最近开发的NHC-催化逆电子需求Diels-Alder反应的范围和应用，这些反应提供了来自简单的起始材料的多种性手性杂环。 （3）通过化学和非对映选择性转化（包括（ - ） - chebulic Acid和神经保护剂（ - ） - 氯森酰胺，通过化学和非对映选择性转化证明了手性环的合成效用。意义。拟议的研究将为具有良好替代的高度替代结构提供独特的简洁和实用的进入，具有良好的治疗潜力。这项工作还将为手性小分子的合成而有助于机械新颖的方法，并提供一种独特的，有效的合成策略，而不容易使用化学方法来实施。公共卫生相关性：小型有机分子构成了绝大多数经过验证的治疗剂和新药候选者。目标识别和筛查的最新努力已经超过了化学方法，用于合成与基于小分子的药物发现和发育中进一步创新所需的生物学相关杂环和碳环循环结构。我们的研究为从简单的起始材料中综合这些结构提供了新颖，机械上独特且高效的方法，并将有助于旨在旨在发现，理解和制造新的人类疾病治疗方法的持续努力。