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。 小环给体-受体化合物与亲偶极试剂之间的环加成产生 立体化学上丰富的杂环和碳环结构单元，其可用于构建 生物活性小分子。更好地利用这些建筑材料将有助于建造一个广泛的 一系列有用的分子支架，可以作为工具化合物来探测生物系统或作为药物 治疗疾病的候选人。目前用于这些环加成的方法使用刘易斯酸或过渡金属。 金属催化剂以部分稳定两性离子过渡态。该提案旨在利用 双功能催化剂体系将更有效地稳定过渡态的两种电荷组分， 去除了对基材上的强阴离子和阳离子稳定基团的要求，从而增加了 这种转变的基础范围。具体地，目前的方法仅稳定两种带电的 供体-受体环的两性离子过渡态中的官能团，依赖于底物 稳定相反电荷的功能。相比之下，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-基质相互作用来稳定两种装料组分。的 阴离子组分将通过HBD供体与 催化剂和底物上的烯醇化物，而阳离子组分将通过阳离子-π 催化剂上的芳环与两性离子中间体的阳离子之间的相互作用。使用 与手性催化剂的多重非共价相互作用应产生明确的催化剂-底物 构建体，允许有效区分对映体过渡态，导致对映体富集 产品. 这一策略的成功实现将拓宽这些反应的底物范围， 使用这种类型的化学物质可以到达的化学空间。理想情况下，这种方法将成为一种通用工具， 不同的碳环和杂环框架，简化了生物相关的断开 分子。各种有用的杂环和碳环可以从简单的起始原料生成 使用所提出的催化剂体系，包括呋喃、吡喃、取代的环戊烷环和氨基酸， 衍生物.这些产物中的许多是在生物活性天然产物中发现的常见结构基序， 聚酮化合物，萜烯和非核糖体肽，这种方法将有助于获得这些有用的 分子。