Zinc‐Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes

• Published in: Angewandte Chemie International Edition Vol. 63; no. 48; pp. e202406548 - n/a
• Main Authors: Wu, Feng, Wu, Wen‐Biao, Xiao, Yuanjiu, Li, Zhenxing, Tang, Lei, He, Heng‐Xian, Yang, Xue‐Chun, Wang, Ji‐Jie, Cai, Yuanlin, Xu, Tong‐Tong, Tao, Jia‐Hao, Wang, Guoqiang, Feng, Jian‐Jun
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 25.11.2024
• Subjects: asymmetric catalysis; atom-economy; bridged rings; Chemistry; Chemistry, Multidisciplinary; cycloadditions; Physical Sciences; Science & Technology; strained molecules; DESIGN; strained molecules; ACID; STRAIN-RELEASE; BIS(OXAZOLINE); cycloadditions; asymmetric catalysis; atom-economy; COMPLEXITY; CHEMISTRY; 2-PI+2-SIGMA CYCLOADDITIONS; BASIS-SETS; CHIRALITY; bridged rings
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202406548

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)‐rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza‐BCHs) by an enantioselective zinc‐catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2‐acyl imidazole group and a diverse array of alkynyl‐ and aryl‐substituted imines. The target aza‐BCHs, which consist of α‐chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94 % and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring‐opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid‐catalyzed cycloadditions of BCBs. A zinc Lewis acid catalyzes asymmetric (3+2) cycloadditions of BCBs with imines to afford aza‐BCHs bearing α‐chiral amine fragments and two quaternary carbon centers in high yields and er values. Expeirmental studies and DFT calculations provide mechanistic insight.