Ping Yuanyuan, Xu Sheng, Kong Wangqing
The Institute for Advanced Studies (IAS), Wuhan University, Wuhan 430072, People's Republic of China.
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.
Acc Chem Res. 2025 Aug 5;58(15):2477-2495. doi: 10.1021/acs.accounts.5c00355. Epub 2025 Jul 18.
ConspectusOxygen-containing heterocycles are increasingly recognized for their biological significance, especially in the field of drug discovery. Therefore, the enantioselective synthesis of oxygen-containing heterocycles has attracted great attention in the past few decades, and many ingenious synthetic strategies have been developed. Despite remarkable progress, they are often limited in terms of the diversity of target scaffolds, accessibility of starting materials, substrate scope, and stereoselectivity. Simple saturated heterocycles are easily accessible, making them ideal starting points for further transformations. Therefore, approaches to functionalize the existing C(sp)-H bonds in these readily available saturated heterocycles appear to be of great potential, opening up new avenues for the design and development of chiral heterocyclic drug candidates. However, saturated oxygen-containing heterocycles have similar steric hindrance and no additional sites for the installation of directing groups, making the catalytic enantiofacial differentiation of oxygen-containing heterocycles extremely challenging. To date, stereoselective C(sp)-H functionalization of saturated oxygen heterocycles remains an unsolved problem in contemporary organic synthesis.In this Account, we summarize the recent progress made in our laboratory in stereoselective functionalization of nondirected oxygen-containing heterocycles via hydrogen atom transfer (HAT)/nickel dual catalysis. First, we discuss the construction of high-value chiral oxygen heterocycles from simple and readily available oxacycles via enantioselective C(sp)-H arylation and alkenylation reactions, focusing on the effects of the ring, ligands, and photocatalysts on C(sp)-C(sp) bond formation and their respective roles. Experimental and density functional theory calculation studies further elucidate the mechanism of the asymmetric C(sp)-H functionalization reactions and the origin of the enantioselectivity. Second, we describe a novel catalytic system that we designed for the enantioselective C(sp)-H alkylation of saturated heterocycles, providing an efficient strategy for the stereoselective construction of C(sp)-C(sp) bonds. Finally, we disclose a facile and versatile method to synthesize a wide range of -glycosides from readily accessible and bench-stable 1-deoxyglycosides. We further develop a catalyst-controlled, site-divergent carbohydrate functionalization approach that can be used to synthesize various unexplored carbohydrates containing arylated quaternary stereocenters. The synthetic applicability of our developed method has been demonstrated in the stereoselective synthesis of natural products, blockbuster drugs, and versatile synthetic building blocks.
概述
含氧杂环因其生物学意义日益受到认可，尤其是在药物发现领域。因此，含氧杂环的对映选择性合成在过去几十年中备受关注，并且已经开发了许多巧妙的合成策略。尽管取得了显著进展，但它们在目标支架的多样性、起始原料的可及性、底物范围和立体选择性方面往往受到限制。简单的饱和杂环易于获得，使其成为进一步转化的理想起始点。因此，对这些易于获得的饱和杂环中现有的C(sp)-H键进行官能团化的方法似乎具有很大潜力，为手性杂环药物候选物的设计和开发开辟了新途径。然而，饱和含氧杂环具有相似的空间位阻，并且没有用于安装导向基团的额外位点，这使得含氧杂环的催化对映面分化极具挑战性。迄今为止，饱和氧杂环的立体选择性C(sp)-H官能团化仍然是当代有机合成中一个未解决的问题。
在本综述中，我们总结了我们实验室最近在通过氢原子转移（HAT）/镍双催化对无导向含氧杂环进行立体选择性官能团化方面取得的进展。首先，我们讨论了通过对映选择性C(sp)-H芳基化和烯基化反应，从简单易得的氧杂环构建高价值手性氧杂环，重点关注环、配体和光催化剂对C(sp)-C(sp)键形成的影响及其各自的作用。实验和密度泛函理论计算研究进一步阐明了不对称C(sp)-H官能团化反应的机理和对映选择性的起源。其次，我们描述了一种我们设计的用于饱和杂环对映选择性C(sp)-H烷基化的新型催化体系，为立体选择性构建C(sp)-C(sp)键提供了一种有效策略。最后，我们公开了一种从易于获得且稳定的1-脱氧糖苷合成多种 -糖苷的简便通用方法。我们进一步开发了一种催化剂控制的、位点发散的碳水化合物官能团化方法，可用于合成各种含有芳基化季碳立体中心的未探索碳水化合物。我们开发的方法的合成适用性已在天然产物、重磅药物和通用合成砌块的立体选择性合成中得到证明。
