Enantioselective Self‐Assembly of a Homochiral Tetrahedral Cage Comprising Only Achiral Precursors

• Published in: Angewandte Chemie International Edition 2024-04, Vol.63 (15), p.e202400467-n/a
• Main Authors: Chen, Yixin, Cao, Ze, Feng, Tinglong, Zhang, Xiaobo, Li, Zhaoyong, Dong, Xue, Huang, Shaoying, Liu, Yingchun, Cao, Xiaoyu, Sue, Andrew C.‐H., Peng, Chuanhui, Lin, Xufeng, Wang, Linjun, Li, Hao
• Format: Article
• Language: English
• Subjects: Cages; chiral induction; Chirality; Enantiomers; enantioselectivity; Equivalence; imine cage; Precursors; Racemization; Self-assembly; Tetrahedra
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202400467

How Nature synthesizes enantiomerically pure substances from achiral or racemic resources remains a mystery. In this study, we aimed to emulate this natural phenomenon by constructing chiral tetrahedral cages through self‐assembly, achieved by condensing two achiral compounds–a trisamine and a trisaldehyde. The occurrence of intercomponent CH⋅⋅⋅π interactions among the phenyl building blocks within the cage frameworks results in twisted conformations, imparting planar chirality to the tetrahedrons. In instances where the trisaldehyde precursor features electron‐withdrawing ester side chains, we observed that the intermolecular CH⋅⋅⋅π forces are strong enough to prevent racemization. To attain enantioselective self‐assembly, a chiral amine was introduced during the imine formation process. The addition of three equivalents of chiral amino mediator to one equivalent of the achiral trisaldehyde precursor formed a trisimino intermediate. This chiral compound was subsequently combined with the achiral trisamino precursor, leading to an imine exchange reaction that releasing the chiral amino mediator and formation of the tetrahedral cage with an enantiomeric excess (ee) of up to 75 %, exclusively composed of achiral building blocks. This experimental observation aligns with theoretical calculations based on the free energies of related cage structures. Moreover, since the chiral amine was not consumed during the imine exchange cycle, it enabled the enantioselective self‐assembly of the tetrahedral cage for multiple cycles when new batches of the achiral trisaldehyde and trisamino precursors were successively added. To achieve enantioselective self‐assembly, we introduced a chiral amine during the imine formation process. Addition of three equivalents of chiral amino mediator to one equivalent of the achiral trisaldehyde formed a trisimino intermediate. The chiral intermediate was then combined with achiral trisamino precursor. Imine exchange reaction led to release of the chiral amino mediator and formation of the tetrahedral cage with an enantiomeric excess (ee) up to 75 %, which is composed of achiral building precursors exclusively.