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

项目摘要。 小环给体-受体化合物与亲偶极体之间的环加成反应 立体化学富含杂环和碳环的构造物，在建造 生物活性小分子。改善对这些积木的访问将有助于建造广泛的 一系列有用的分子支架，可用作探测生物系统的工具化合物或用作药物 治疗疾病的候选人。目前用于这些环加成反应的方法要么使用Lewis酸，要么使用过渡 部分稳定两性离子过渡态的金属催化剂。这项提案旨在利用 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， 消除了对衬底上的强阴离子和阳离子稳定基团的要求，从而增加了 这一转变的底物范围。具体地说，目前的方法只稳定两个电荷中的一个 施主-受体环的两性离子过渡态的官能团对底物的依赖 稳定对方电荷的功能。相反，使用氢键给体(HBD)/阳离子-π 催化剂系统将使用优化的催化剂-底物相互作用来稳定两种电荷成分。这个 阴离子组分将通过HBD施主之间的氢键相互作用稳定在 催化剂和底物上的烯醇，而阳离子成分将通过阳离子-π稳定 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。对.的使用 与手性催化剂的多重非共价相互作用应产生明确定义的催化剂底物 构建，允许有效地区分导致对映体富集化的对映体过渡态 产品。 这一策略的成功实现将扩大这些反应的底物范围，增加 可利用这种类型的化学物质进入的化学空间。理想情况下，此方法将成为 不同的碳环和杂环骨架，简化了与生物相关的断开 分子。从简单的起始原料可以生成各种有用的杂环和碳环 与所提出的催化剂体系，包括呋喃、吡喃、取代环戊烷环和氨基酸 衍生品。其中许多产品是生物活性天然产品中常见的结构基序，如 多酮、萜类和非核糖体肽，这种方法将有助于获得这些有用的 分子。

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.