Chirality Makes or Breaks Chemically Driven Self-Assembly.

Nature has consistently selected homochiral building blocks from millions of possible diastereomers across diverse biomolecular structures to drive molecular recognition, catalysis and self-assembly. Despite its central role in biology, chirality's influence on chemically driven reaction networks remains unexplored. Here, we demonstrate that chiral aminoacyl phosphate esters, synthetic analogs of biological acylating intermediates, drive self-assembly and reaction pathways, that are modulated purely by their configuration, without the need for changes in functional groups. Using enantiopure aminoacyl phosphate esters, we show that these left- and right-handed acylating agents generate transient epimeric (thio)-esters from homochiral peptide substrates, leading to supramolecular architectures with distinct lifetimes and self-assembly dynamics. Moreover, chirality regulates downstream reactivity in cascade reactions, where stereochemical control over an intermediate propagates into subsequent transformations. Finally, chiral acylating agents differentiate between two reaction cycles, selectively modulating one pathway while keeping another invariant - a level of control that remains difficult to achieve with conventional chemical strategies. Stereochemical programming enables control over reactivity and self-assembly, offering new opportunities to encode chirality in reaction networks and modulate their function through a single molecular parameter.