Enantioselective Annulation Reactions

对映选择性成环反应

基本信息

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
项目类别：
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

项目摘要

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）：该项目的目标是开发新的合成方法来简洁合成手性杂环和碳环化合物。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，但它们的有效构建和绝对立体化学控制的方法仍然是限制步骤。我们开发了由 N-杂环卡宾 (NHC) 介导的新化学转化，使以前未被认识的合成对映体富集形式的内酰胺、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，并且可以应用于广泛的取代模式的合成。所有这些过程都是通过α-官能化醛（例如烯醛和α-卤代醛）催化生成活性物质来进行的。具体目标： (1) 开发通过手性 NHC 催化烯醛环化对映选择性合成双取代 γ-内酯、γ-内酰胺和环戊烯的简明单步方法。 (2) 显着扩展我们最近开发的 NHC 催化的逆电子需求 Diels-Alder 反应的范围和应用，该反应可以从简单的起始材料提供多种手性杂环。 (3) 通过化学和非对映选择性转化证明手性成环产物的合成效用，包括 (-)-chebulic 酸和神经保护剂 (-)-clausenamide 的简明不对称合成。意义。拟议的研究将为具有经过验证的治疗潜力的各种高度取代的结构提供独特的简洁和实用的入门。这项工作还将为手性小分子的合成提供机械上的新颖方法，并提供现有化学方法不易实现的独特、有效的合成策略。公共健康相关性：小有机分子构成了绝大多数经过验证的治疗剂和新候选药物。最近在靶点识别和筛选方面的努力已经超过了合成生物学相关杂环和碳环结构的化学方法，这些结构是基于小分子的药物发现和开发的进一步创新所需的。我们的研究提供了新颖、机制独特且高效的方法，用于从简单的起始材料合成这些结构，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。