Dual Hydrogen-Bond Donor & Cation-π Catalysis: Enantioselective Cycloadditions of Strained Donor-Acceptor Ring Systems

双氢键供体

• 批准号: 9469101
• 负责人: Adam Trotta
• 金额: $ 5.63万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9469101
• 关键词: Acids; Acrylates; Alkenes; Amino Acids; Anions; Aziridines; Benzaldehyde; Biological; Breathing; Carbazoles; Catalysis; Cations; Charge; Chemicals; Chemistry; Cyclobutanes; Cyclopentane; Disease; Epoxy Compounds; Furans; Goals; Hydrogen Bonding; Imines; Improve Access; Indoles; Methods; Molecular; Naphthalene; Peptides; Periodicity; Phase; Pyrans; Pyrenes; Pyrroles; Reaction; Scheme; Solvents; Substrate Interaction; System; Techniques; Temperature; Terpenes; Thiourea; Time; Transition Elements; Urea; Validation; Work; base; bioactive natural products; biological systems; catalyst; cycloaddition; cyclopropane; drug candidate; enolate; experimental study; functional group; guanidinium; improved; nitrone; oxetane; scaffold; small molecule; tetrahydrofuran; tool

Project Summary. The cycloaddition between a small-ring donor-acceptor compound and a dipolarophile produces stereochemically rich heterocyclic and carbocyclic building blocks that are useful in the construction of bioactive small molecules. Improved access to these building blocks will facilitate the construction of a wide range of useful molecular scaffolds that could act as tool compounds to probe biological systems or as drug candidates to treat disease. Current methods for these cycloadditions employ either Lewis acid or transition metal catalysts to partially stabilize the zwitterionic transition state. This proposal aims to leverage a bifunctional catalyst system that will more effectively stabilize both charge components of the transition state, removing the requirement for strong anion and cation stabilizing groups on the substrate, thereby increasing the substrate scope of this transformation. Specifically, current methods stabilize only one of the two charged functional groups in the zwitterionic transition state of the donor-acceptor ring, relying on substrate functionality to stabilize the opposing charge. In contrast, employing a hydrogen-bond donor (HBD)/cation-π catalyst system will stabilize both charge components using optimized catalyst-substrate interactions. The anionic component will be stabilized through a hydrogen-bond interaction between an HBD donor on the catalyst and an enolate on the substrate, while the cationic component will be stabilized through a cation-π interaction between an aryl ring on the catalyst and the cation of the zwitterionic intermediate. The use of multiple noncovalent interactions with a chiral catalyst should produce a well-defined catalyst-substrate construct, allowing for effective differentiation of enantiotopic transition states leading to enantioenriched products. Successful realization of this strategy will broaden the substrate scope of these reactions, increasing the chemical space accessible using this type of chemistry. Ideally, this method will become a universal tool for diverse carbocyclic and heterocyclic frameworks, simplifying disconnections for biologically relevant molecules. A variety of useful heterocycles and carbocycles can be generated from simple starting materials with the proposed catalyst system, including furans, pyrans, substituted cyclopentane rings, and amino acid derivatives. Many of these products are common structural motifs found in bioactive natural products such as polyketides, terpenes, and nonribosomal peptides, and this method would facilitate access to these useful molecules.

项目摘要。 小环供体 - 受体化合物与偶极性的环载物产生的环加成产生 立体化学上丰富的杂环和碳环状构件，可用于构建 生物活性小分子。改善了对这些构建块的访问将有助于建造宽阔的 有用的分子支架范围可以充当探测生物系统或药物的工具化合物 候选人治疗疾病。这些Cycloaditions员工的当前方法要么刘易斯酸或过渡 金属催化剂可以部分稳定Zwitterionic转变状态。该建议旨在利用 双功能催化剂系统将更有效地稳定过渡态的两个电荷成分， 消除对基材上强阴离子和阳离子稳定组的要求，从而增加 此转换的底物范围。具体而言，当前方法仅稳定两个电荷之一 供体 - 受体环的Zwitterion过渡状态的官能团，依赖于基板 稳定相对指控的功能。相反，采用氢键供体（HBD）/阳离子-π 催化剂系统将使用优化的催化剂 - 基底相互作用稳定两个电荷组件。这 阴离子成分将通过HBD供体之间的氢键相互作用稳定 催化剂和基质上的烯烃，而阳离子成分将通过阳离子-π稳定 催化剂上的芳基环与Zwitterion中级阳离子的阳离子之间的相互作用。使用 与手性催化剂的多次非共价相互作用应产生明确定义的催化剂 - 底物 构造，允许有效地分化对映射的过渡状态，从而导致对映体化 产品。 该策略的成功实现将扩大这些反应的底物范围，并增加 使用这种化学性质可访问的化学空间。理想情况下，此方法将成为通用工具 多样的碳环和杂环框架，简化了与生物学相关的断开连接 分子。可以从简单的起始材料中生成各种有用的杂环和碳循环 提出的催化剂系统，包括Furans，Pyrans，取代环戊烷环和氨基酸 衍生物。这些产品中有许多是在生物活性天然产品中发现的常见结构基序，例如 聚酮化合物，萜烯和非核糖体辣椒，此方法将有助于访问这些有用的 分子。