Concise Report
Enantioselective Synthesis of C‒B Axial Chirality via Isothiourea-Catalyzed Acylative Kinetic Resolution
Tong-Tong Wang, Zuo-Pu Hu, Jiali Lin, Haisong Xu, and Xin Li*
C–B axially chiral compounds constitute a significant class of stereogenic molecules with growing importance in advanced materials science and pharmaceutical chemistry, particularly as chiral ligands, functional building blocks, and bioactive scaffolds. However, the catalytic asymmetric construction of such stereogenic axes remains a formidable synthetic challenge, primarily due to the elongated C(sp2)-B bond length and its correspondingly low rotational energy barrier, which often leads to configurational instability. To date, asymmetric catalytic synthesis of C – B axially chiral compounds has predominantly employed metal catalysis, whereas organic catalytic strategies remain scarce. In this work, we disclose a highly efficient organocatalytic kinetic resolution (KR) strategy for the selective synthesis of enantioenriched C–B axially chiral compounds. Our method employs a readily accessible tetraimidazole catalyst and utilizes isobutyric anhydride as reactive substrates. This protocol affords the desired axially chiral boranes in high yields and excellent enantioselectivities (with selectivity factor up to 121). The practical utility of this methodology was demonstrated through successful gram-scale synthesis and a series of downstream functional group transformations, highlighting its potential for synthetic applications. The racemization experiments established that the rotational barriers of the axially chiral compound was 41.7 kcal/mol, a value that confirms sufficient thermodynamic stability for the isolation, characterization, and further application of these compounds at ambient conditions. Mechanistic investigations, including a set of control experiments, revealed a critical dual role of the iodine atom present in the reaction: it not only provides steric bulk to impede the rotation around the C–B bond but also plays an important role in governing the stereochemical outcome of the reaction. In addition, the origin of enantioselectivity was elucidated through density functional theory (DFT) calculations.
Atropisomers | C‒B axis | Asymmetric catalysis | Kinetic resolution | Isothiourea catalysis | Anhydride | Organic boron | 1,2-Azaborine
手性异硫脲催化的动力学酰基化反应构建C-B轴手性化合物
近年来，硼因缺电子特性与B-C（硼-碳）共价键的多样性，在生物医学研究和光电子材料应用中受到了极大的关注。利用B-N（硼-氮）键替代苯环中的C=C（碳=碳）键，可构建苯的等电子异构体，该策略能够有效调控芳香化合物的物理与化学性质，为新型功能材料的设计及生物医学应用拓展了广阔空间。迄今为止，已报道的手性有机硼化合物多为硼原子与手性碳原子直接相连的结构。相比之下，基于C–B轴手性的有机硼化合物的不对称催化合成研究仍相对有限，且现有方法主要依赖金属催化，通过有机不对称催化构建的相关工作仅有两例（J. Am. Chem. Soc., 2021, 143, 12924; Angew. Chem. Int. Ed., 2025, e202501991.）。近年来，南开大学李鑫团队在有机不对称催化构建轴手性化合物方面做出了系统性贡献（J. Am. Chem. Soc., 2018, 140, 12836; ACS Catal., 2020, 10, 2324; Chem. Sci., 2022, 13, 141; ACS Catal., 2024, 14, 1183; ACS Catal., 2024, 14, 6667.）。
最近，该团队设计合成了一系列3-碘-1,2-苯并氮杂硼烷类化合物，使用异硫脲催化的酰基化反应对该化合物进行动力学拆分，实现了C-B轴手性化合物的不对称催化构建，选择性因子高达121；反应条件温和，操作简便。后期的放大实验以及衍生化实验证明了该方法的实用性。C-B轴手性化合物中裸露的羟基可用于连接吲哚美辛、布洛芬等药物分子，实现对其结构的功能化修饰；消旋化实验表明，C-B轴手性化合物侧边的碘原子可限制C-B轴的自由旋转，测得旋转能垒为41.7 kcal/mol；控制实验以及DFT计算表明，异硫脲催化剂与底物之间的卤素键以及C-HΠ两种相互作用共同决定了该反应的立体选择性。该工作为C-B轴手性化合物的不对称催化构建提供了新思路。
上述研究结果作为Report发表于Chin. J. Chem. (2026, 44, 1539-1545, DOI: 10.1002/cjoc.70495)。该项工作得到了国家自然科学基金委和物质绿色创造与制造海河实验室的资助。
认识本文的作者们
Left to Right: Tong-Tong Wang, Zuo-Pu Hu, Jiali Lin, Haisong Xu, Xin Li
李鑫教授简介
南开大学 元素有机化学全国重点实验室
物质绿色创造与制造海河实验室
李鑫：南开大学化学学院教授，博士生导师。主要研究方向包括物理有机化学导向的有机催化、新型手性质子酸催化剂设计及应用、非碳中心手性化合物的不对称催化合成等。在J. Am. Chem. Soc.、Angew. Chem. Int. Ed.、Nat. Commun.、CCS. Chem等刊物上发表论文100余篇，获2024年天津市自然科学二等奖（第一完成人）。
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