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

Abstract

How Nature synthesizes enantiomerically pure substances from achiral or racemic resources remains a mystery. Here, 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 within the cage frameworks results in twisted conformations, imparting planar chirality to 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) up to 75%, exclusively composed of achiral building blocks. 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.