Enantioselective Annulation Reactions

对映选择性成环反应

• 批准号: 7526705
• 负责人: Jeffrey William Bode
• 金额: $ 28.76万
• 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/7526705
• 关键词: Acids; Aldehydes; Alder plant; Alkenes; Binding; Chemicals; Condition; Cyclopentane; Cyclopentenes; Development; Diels Alder reaction; Electrons; Evaluation; Facility Construction Funding Category; Funding; Generations; Goals; Imines; Lactams; Lactones; Mediating; Methods; Neurodegenerative Disorders; Neuroprotective Agents; Numbers; Oxidation-Reduction; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Procedures; Process; Public Health; Range; Reaction; Reporting; Research; Screening procedure; Structure; Therapeutic Agents; Variant; Work; adduct; analog; base; cancer therapy; carbene; catalyst; clausenamide; design; drug discovery; enolate; human disease; improved; innovation; insight; novel; novel strategies; programs; 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(申请人提供)：该项目的目标是开发新的合成方法，用于手性杂环和碳环化合物的简明合成。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，但有效构建和控制绝对立体化学的方法仍然是有限的。我们开发了由N-杂环卡宾(NHCS)介导的新的化学转化，这使得以前未知的合成内酰胺、内酯和环戊烷的策略成为可能。重要的是，这些过程在温和的反应条件下进行，可以应用于合成广泛的取代模式。所有这些过程都是由烯醛和α-卤代醛等α-官能化的醛催化生成活性物种进行的。具体目标：(1)开发简明、一步法，通过手性NHC催化的烯烃环化反应选择性地合成二取代的伽马-内酯、伽马-内酰胺和环戊烯。(2)为了显著扩展我们最近开发的NHC催化的反电子需求Diels-Alder反应的范围和应用，该反应可以从简单的起始原料生成各种手性杂环。(3)通过化学转化和非对映选择性转化，包括(-)-柴草酸和神经保护剂(-)-黄皮酰胺的简明不对称合成，展示了手性环化产物的合成用途。意义重大。拟议的研究将提供一个独特的简明和实用的入口，以广泛的各种高度取代的结构已证实的治疗潜力。这项工作还将为手性小分子的合成提供机械上的新方法，并提供一种独特的、有效的合成策略，这是现有化学方法所不能实现的。与公共卫生相关：小有机分子构成了绝大多数已证实的治疗剂和新药候选药物。最近在目标识别和筛选方面的努力已经超过了合成生物相关杂环和碳环结构的化学方法，这是进一步创新基于小分子的药物发现和开发所需的。我们的研究为从简单的起始材料合成这些结构提供了新颖的、机械上独特的和高效的方法，并将有助于正在进行的旨在发现、理解和制造治疗人类疾病的新方法的努力。