Enantioselective Annulation Reactions

对映选择性成环反应

• 批准号: 7872765
• 负责人: Jeffrey William Bode
• 金额: $ 29.84万
• 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/7872765
• 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.

项目描述（由申请人提供）：本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，但用于它们的有效构建和绝对立体化学控制的方法仍然是限制性步骤。我们已经开发了新的化学转化介导的N-杂环卡宾（NHCs），使以前未被认识的策略，用于合成内酰胺，内酯，和环戊烷的对映体富集的形式。重要的是，这些过程在温和的反应条件下进行，并且可以应用于广泛的取代模式的合成。所有这些方法都是通过从α-官能化醛如烯醛和α-卤醛催化生成反应性物质来进行的。具体目标：（1）通过手性NHC催化烯醛的成环反应，发展了对映选择性合成双取代γ-内酯、γ-内酰胺和环戊烯的简明、一步法。(2)为了显著扩大我们最近开发的NHC催化的反电子需求Diels-Alder反应的范围和应用，该反应从简单的起始原料得到多样化的手性杂环。(3)通过化学和非对映选择性转化，包括（-）-诃子酸和神经保护剂（-）-黄皮酰胺的简明不对称合成，证明手性成环产物的合成效用。意义拟议的研究将提供一个独特的简洁和实用的入口，以各种各样的高度取代的结构与证实的治疗潜力。这项工作也将有助于机械新颖的方法来合成手性小分子，并提供了一个独特的，有效的合成策略不容易实现的化学方法。公共卫生相关性：有机小分子构成了绝大多数已证实的治疗剂和新药候选物。最近在靶点鉴定和筛选方面的努力已经超过了用于合成生物学相关的杂环和碳环结构的化学方法，所述生物学相关的杂环和碳环结构是在基于小分子的药物发现和开发中进一步创新所需要的。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，独特和高效的方法，并将有助于旨在发现，理解和制造人类疾病新疗法的持续努力。