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（由申请人提供）：立体化学复杂的富含 sp3 的分子代表了用于治疗多种人类疾病的特殊化学支架，通常具有有效且特定的生物活性，然而，因为这些类型的分子通常难以制备和修饰。 ，它们在药物发现的化合物库中尚未得到充分利用，因此，开发以通用、有效和立体控制的方式获取这些结构的新合成方法至关重要。该研究提案的中心假设是使用氢键供体催化。小的分子手性硫脲是制备高度对映体富集分子的通用策略，它避免了潜在有毒的过渡金属和路易斯酸，并且不需要能够与手性催化剂共价相互作用的底物功能。通过利用氢键和其他非共价相互作用来影响酶的活性位点，以实现高效和选择性的转化，而不需要更大的酶结构。具体来说，这一假设将在第一个高度酶的开发中得到检验。这些反应涉及直链烯醇（或烯基胺）和醛的酸催化缩合，然后环化碳氧鎓/亚胺鎓中间体，是一种用于制备生物普遍存在的氧的高度通用的合成策略。和含氮脂肪族杂环，但尚未使用传统的不对称方法成功实现对映选择性。将通过探索具有能够参与的功能的手性硫脲催化剂来采用合作催化方法 在与氧碳鎓/亚胺鎓中间体的阳离子-π相互作用中，与布朗斯台德酸助催化剂一起，其共轭碱有效地与硫脲结合，产生紧密结合的手性离子对，对环化的立体化学结果产生显着的控制。 Prins 和 aza-Prins 变体的成功对映选择性方法，该提案旨在 1) 应用对映选择性 Prins 型环化到生物活性分子的合成，2）研究反应机理和模型催化剂-底物相互作用，以阐明对映诱导的起源。特别是，该研究的合成人工智能将集中于引入药效团部分并最大化通用性和结构。对映选择性转化的多样性。这些具体目标的成功实现将代表着重大的实践和概念进步，解决了一个重要的合成问题，并有助于氢键供体催化剂的实用性和基本理解。此外，这种合成方法将允许有效地制备和修饰具有生物活性的脂肪族杂环分子，以开发多种富含sp3的化合物库，从而研究和改进现有疗法并发现治疗人类疾病的新疗法。