清华大学林进顺团队报道了双环[1.1.0]丁烷的催化分子间不对称[2π+2σ]环加成反应——富烯并高度取代双环[2.1.1]己烷的实用合成。相关研究成果发表在2024年12月3日出版的《美国化学会杂志》。

sp3杂化碳的高百分比和手性碳中心的存在可能会导致分子复杂性的增加，从而提高候选药物临床成功的可能性。三维（3D）桥接基序最近在药物化学中引起了极大的兴趣。双环[2.1.1]己烷（BCHs）是新兴的3D苯生物异构体，但手性、高度取代的BCHs的合成尚未得到充分探索。

该文中，研究人员公开了路易斯酸催化双环[1.1.0]丁烷，与香豆素、2-吡喃或苯并二氢吡喃的不对称分子间[2π+2σ]环加成反应，以获得各种富含对映体的1,2,3,4-四取代BCHs，这些BCHs带有邻近的叔季立构中心。

成功的关键是引入手性双恶唑啉配体，以有效抑制副反应，抑制显著的外消旋副反应，并微调反应的反应性和区域、对映体和非对映体选择性。由此产生的BCHs在合成手性BCHex Sonidegib和BCHex-BMS-202中，作为苯生物等位体具有巨大的潜力，分别模仿抗癌药物Sonidegip和PD-1/PD-L1抑制剂BMS-202。

该结果强调了生物等量替代对物理化学性质的积极影响，同时保持了与含芳基替代物相当的抗肿瘤活性。

附：英文原文

Title: Catalytic Intermolecular Asymmetric [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes: Practical Synthesis of Enantioenriched Highly Substituted Bicyclo[2.1.1]hexanes

Author: Ying-Jie Li, Zhi-Long Wu, Qiang-Shuai Gu, Tingting Fan, Ming-Hao Duan, Lihong Wu, Yu-Tao Wang, Ji-Peng Wu, Fang-Lei Fu, Fan Sang, Ai-Ting Peng, Yuyang Jiang, Xin-Yuan Liu, Jin-Shun Lin

Issue&Volume: December 3, 2024

Abstract: The high percentage of sp3-hybridized carbons and the presence of chiral carbon centers could contribute to increased molecular complexity, enhancing the likelihood of clinical success of drug candidates. Three-dimensional (3D) bridged motifs have recently garnered significant interest in medicinal chemistry. Bicyclo[2.1.1]hexanes (BCHs) are emerging 3D benzene bioisosteres, but the synthesis of chiral, highly substituted BCHs has been underexplored. Herein, we disclose the Lewis acid-catalyzed asymmetric intermolecular [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes with coumarins, 2-pyrone, or chromenes to access diverse enantioenriched 1,2,3,4-tetrasubstituted BCHs bearing vicinal tertiary-quaternary stereocenters. The key to success is the introduction of chiral bisoxazoline ligands to effectively suppress the side reactions, inhibit significant racemic background reactions, and fine-tune the reactivity and regio-, enantio-, and diastereoselectivities of the reactions. The resulting BCHs hold significant potential as benzene bioisosteres in the synthesis of chiral BCHex-Sonidegib and BCHex-BMS-202, mimicking the anticancer drug Sonidegib and the PD-1/PD-L1 inhibitor BMS-202, respectively. The outcome highlights the positive impact of bioisosteric replacement on physicochemical properties, while maintaining comparable antitumor activity to their aryl-containing counterparts.

DOI: 10.1021/jacs.4c10968

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c10968