Disulfide bridge formation was investigated in helical aromatic oligoamide foldamers.D epending on the position of thiol-bearing side chains,e xclusive intramolecular or intermolecular disulfide bridging may occur.T he two processes are capable of self-sorting,p resumably by dynamic exchange.Q uantitative assessment of helix handedness inversion rates showed that bridging stabilizes the folded structures. Intermolecular disulfide bridging serendipitously yielded aw ell-defined, C 2 -symmetrical, two-helix bundle-like macrocyclic structure in which complete control over relative handedness,t hat is,h elix-helix handedness communication, is mediated remotely by the disulfide bridged side chains in the absence of contacts between helices.M Mc alculations suggest that this phenomenon is specific to ag iven side chain length and requires disulfide functions Macrocyclization is ac ommon approach to restrict the conformations available to an otherwise flexible molecular structure.I th as broad significance in folded structures regardless of their size and complexity.I np roteins,m acrocyclization through disulfide bridges between cysteine residues far apart in the primary sequence stabilizes folded conformations,o ften via ad estabilization of unfolded states, and contributes to resistance against proteolytic degradation.[1] Besides their frequent natural occurrence,p rotein disulfide bridges may also be engineered.[2] In essence, disulfide bridges couple the folding behavior of remote secondary motifs.T hese principles have been exploited at as maller scale in synthetic objects,f or example in the disulfide stabilization of a-helical peptides [3] and the capture of one handedness from a P-M mixture of 3 10 helices. [4] Extensions of this concept include various stapling methods between amino acid side chains with chemical functions other than disulfides. [5] Another important aspect of disulfide bridges is their ability to undergo thiol-disulfide exchange reactions.[6] In proteins,e xchange reactions are critical to correct mismatched bridges when more than two cysteine residues are available.T hiol-disulfide exchange has also emerged as ap owerful method for the dynamic covalent assembly of macrocycles from several dithiol units. [7,8] Thef ormation of aparticular macrocycle then reflects its intrinsic stability and the preorganization of the dithiol precursor for cyclization. Herein we report the first implementation of these principles in abiotic foldamer architectures.Depending on the positions of thiol-bearing side chains on aromatic oligoamide helical foldamers,w eo bserved intra-or intermolecular dynamic disulfide formation with high selectivity,y ielding large, structurally well-defined, macrocycles with ac onsiderable and quantifiable stabilization of the folded conformations. Intermolecular bridging serendipitously produced atwo-helix bundle-like structure with aunique,remote,helix-handedness communication mediated by disulfide-bridged side chains. This macrocycle consistently folds with the two hel...