Enantioselective Annulation Reactions

项目描述（申请人提供）：本项目的目标是开发新的合成方法，用于简洁地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控制绝对立体化学的方法仍然是有限的步骤。我们已经开发了由n -杂环碳烯（NHCs）介导的新的化学转化，使以前未被认识的合成内酰胺、内酯和环戊烷的对映体富集形式成为可能。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图。所有这些过程都是由α功能化醛（如烯醛和α卤醛）催化生成反应物质进行的。具体目标：(1)通过手性nhc催化的烯醛环，开发简洁、单步的对映选择性合成双取代-内酯、-内酰胺和环戊烯的方法。(2)为了显著扩大我们最近开发的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中获得多种手性杂环。(3)通过化学和非对映选择性转化，包括(-)-chebulic酸和(-)-clausenamide神经保护剂的简明不对称合成，证明手性环制品的合成用途。的意义。拟议的研究将提供一个独特的简洁和实用的入口，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、有效的合成策略，这种策略在现有的化学方法中是不容易实现的。公共卫生相关性：小有机分子构成了绝大多数已证实的治疗剂和新候选药物。最近在靶标鉴定和筛选方面的努力已经超过了化学方法来合成生物相关的杂环和碳环结构，这是小分子药物发现和开发中进一步创新所必需的。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、机制独特和高效的方法，并将有助于持续的努力，旨在发现、理解和制造新的治疗人类疾病的方法。

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.