Enantioselective Prins-type cyclizations via small molecule H-bonding catalysis

通过小分子氢键催化的对映选择性 Prins 型环化

• 批准号: 8983257
• 负责人: Shauna M Paradine
• 金额: $ 5.07万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-03 至 2018-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8983257
• 关键词: Achievement; Acids; Active Sites; Aldehydes; Architecture; Binding; Biological; Biological Factors; Catalysis; Cations; Chemical Structure; Chemicals; Complex; Computer Analysis; Cyclization; Development; Ensure; Enzymes; Future; Health; Human; Hydrogen Bonding; Ions; Kinetics; Lead; Libraries; Methodology; Methods; Modeling; Nature; Nitrogen; Organic Synthesis; Outcome; Oxygen; Pharmacologic Substance; Physical condensation; Preparation; Reaction; Research; Research Proposals; Structure; Structure-Activity Relationship; Substrate Interaction; Testing; Thiourea; Transition Elements; Treatment Efficacy; Variant; base; catalyst; computer studies; drug discovery; functional group; human disease; improved; insight; novel; nucleophilic addition; public health relevance; research study; scaffold; small molecule; three dimensional structure

 DESCRIPTION (provided by applicant): Stereochemically complex sp3-rich molecules represent privileged chemical scaffolds for the treatment of a broad range of human diseases, often with potent and specific biological activities. However, because these types of molecules are often challenging to prepare and modify, they have been underutilized in compound libraries for drug discovery. Therefore, the development of novel synthetic methods to access these structures in a general, efficient, and stereocontrolled manner is essential. The central hypothesis of this research proposal is that hydrogen bond donor catalysis using small molecule chiral thioureas is a general strategy for the preparation of highly enantioenriched molecules, which avoids potentially toxic transition metals and Lewis acids and obviates the requirement for functionality in the substrate that is capable of covalently interacting with a chiral catalyst. Instead, these catalysts mimic the active site of enzymes by utilizing hydrogen bonding and other non-covalent interactions to effect highly efficient and selective transformations without requiring the larger enzyme architecture. Specifically, this hypothesis will be tested in the development of the first highly enantioselective Prins-type cyclization reactions. These reactions, which involve the acid-catalyzed condensation of linear alkenols (or alkenylamines) and aldehydes followed by cyclization of an oxocarbenium/iminium intermediate, are a highly versatile synthetic strategy for the preparation of biologically prevalent oxygen- and nitrogen-containing aliphatic heterocycles, but have not been successfully rendered enantioselective using traditional asymmetric approaches. The proposed research will employ a cooperative catalysis approach by exploring chiral thiourea catalysts with functionality that is able to engage in cation-π interactions with the oxocarbenium/iminium intermediate in concert with Brønsted acid co-catalysts whose conjugate bases effectively bind to the thiourea to generate a tightly bound chiral ion pair that exerts significant control over the stereochemical outcome of the cyclization. With the establishment of a successful enantioselective method for the Prins and aza-Prins variants, this proposal will aim to 1) apply enantioselective Prins-type cyclizations to the synthesis of bioactive molecules, and 2) study the reaction mechanism and model catalyst-substrate interactions to elucidate the origin of enantioinduction. In particular, the synthetic ai of the proposed research will focus on introducing pharmacophoric moieties and maximizing the generality and structural diversity of the enantioselective transformations. The successful achievement of these specific aims would represent a significant practical and conceptual advance, solving an important synthetic problem and contributing to the utility and fundamental understanding of hydrogen bond donor catalysts. Moreover, this enabling synthetic method will allow biologically active aliphatic heterocycle-containing molecules to be prepared and modified efficiently for the development of diverse sp3-rich compound libraries in order to study and improve existing therapies and to discover new therapies for the treatment of human diseases.

 描述（适用提供）：立体化学上复杂的SP3分子代表特权化学支架，用于治疗广泛的人类疾病，通常具有潜在和特定的生物学活性。但是，由于这些类型的分子通常会挑战准备和修饰，因此它们在化合物库中被未被充分利用以进行药物发现。因此，开发新型合成方法以一般，高效和立体控制的方式访问这些结构是必不可少的。这项研究提出的中心假设是，使用小分子性手性硫脲氢键供体催化是制备高度映射分子的一般策略，避免了潜在的有毒过渡金属和刘易斯酸的潜在毒性过渡金属，并消除了与奇特型互动相互作用的功能的需求。取而代之的是，这些催化剂通过利用氢键和其他非共价相互作用来模仿酶的活性位点，以有效高效和选择性转化，而无需更大的酶结构。具体而言，该假设将在第一个高度对映选择性Prins型环化反应的开发中进行检验。这些反应涉及线性烷酚（或烷基胺）和醛的酸催化的凝结，然后是在生物学上具有高度通用的氧化氧气和氮气，但要制备的氧化型合成策略，是一种高度用途的合成策略使用传统的不对称方法对映选择性。拟议的研究将采用一种合作催化方法，通过探索能够参与的功能性的手性硫库催化剂。 在阳离子-π相互作用中与氧化甲苯/亚米岛的相互作用与BrønstedAcid共催化剂一致中间，其共轭碱基有效地结合了硫库，从而产生紧密结合的手性离子对，从而对环化学的定位效果产生重大控制。通过为Prins和Aza-Prins变体建立成功的对映选择性方法，该提案的目的是1）对映选择性Prins-type循环进行生物活性分子的合成，以及2）研究反应机械学和模型催化型 - 潜水型相互作用，以阐明启动的原点。特别是，拟议的研究的合成AI将重点放在引入药物宏观的部分，并最大程度地提高对映选择性转换的一般性和结构多样性。这些特定目标的成功实现将代表一个重要的实践和概念进步，解决了一个重要的合成问题，并为氢键供体催化剂的实用性和基本理解做出了贡献。此外，这种启用合成方法将允许生物活性脂肪族杂环分子进行准备并有效地修饰，以开发潜水员SP3富的化合物库，以研究和改善现有的治疗疗法并发现新的治疗人类疾病的疗法。