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

手性異硫脲催化的動力學?；磻獦嫿–-B軸手性化合物

近年來，硼因缺電子特性與B-C（硼-碳）共價鍵的多樣性，在生物醫學研究和光電子材料應用中受到了極大的關注。利用B-N（硼-氮）鍵替代苯環中的C=C（碳=碳）鍵，可構建苯的等電子異構體，該策略能夠有效調控芳香化合物的物理與化學性質，為新型功能材料的設計及生物醫學應用拓展了廣闊空間。迄今為止，已報道的手性有機硼化合物多為硼原子與手性碳原子直接相連的結構。相比之下，基于C–B軸手性的有機硼化合物的不對稱催化合成研究仍相對有限，且現有方法主要依賴金屬催化，通過有機不對稱催化構建的相關工作僅有兩例（J. Am. Chem. Soc., 2021, 143, 12924; Angew. Chem. Int. Ed., 2025, e202501991.）。近年來，南開大學李鑫團隊在有機不對稱催化構建軸手性化合物方面做出了系統性貢獻（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，該團隊設計合成了一系列3-碘-1,2-苯并氮雜硼烷類化合物，使用異硫脲催化的酰基化反應對該化合物進行動力學拆分，實現了C-B軸手性化合物的不對稱催化構建，選擇性因子高達121；反應條件溫和，操作簡便。后期的放大實驗以及衍生化實驗證明了該方法的實用性。C-B軸手性化合物中裸露的羥基可用于連接吲哚美辛、布洛芬等藥物分子，實現對其結構的功能化修飾；消旋化實驗表明，C-B軸手性化合物側邊的碘原子可限制C-B軸的自由旋轉，測得旋轉能壘為41.7 kcal/mol；控制實驗以及DFT計算表明，異硫脲催化劑與底物之間的鹵素鍵以及C-H???Π兩種相互作用共同決定了該反應的立體選擇性。該工作為C-B軸手性化合物的不對稱催化構建提供了新思路。

上述研究結果作為Report發表于Chin. J. Chem. (2026, 44, 1539-1545, DOI: 10.1002/cjoc.70495)。該項工作得到了國家自然科學基金委和物質綠色創造與制造海河實驗室的資助。

認識本文的作者們

Left to Right: Tong-Tong Wang, Zuo-Pu Hu, Jiali Lin, Haisong Xu, Xin Li

李鑫教授簡介

南開大學 元素有機化學全國重點實驗室

物質綠色創造與制造海河實驗室

李鑫：南開大學化學學院教授，博士生導師。主要研究方向包括物理有機化學導向的有機催化、新型手性質子酸催化劑設計及應用、非碳中心手性化合物的不對稱催化合成等。在J. Am. Chem. Soc.、Angew. Chem. Int. Ed.、Nat. Commun.、CCS. Chem等刊物上發表論文100余篇，獲2024年天津市自然科學二等獎（第一完成人）。