(2) An extra IMHB was formed within Cterminal delta residue according to our NMR snapshot (large temperature coefficient in chloroform). Nevertheless, the helicity of the core region is highly preserved and almost identical in both states, providing a scaffold that can predictably orient functional groups for diverse applications in catalysis and molecular recognition, with our immediate interests being on the former. To test this possibility, we installed two L-α-Orn residues featuring in i and i+2 positions. We anticipated that this arrangement of primary amine functional groups on one face of the foldamer helix would provide a bifunctional system capable of accelerating retroaldol reactions through nucleophilic catalysis via a bifunctional imine/enamine mechanism (Scheme 1). As a substrate, we chose methodol (4-hydroxy-4-(6-methoxy-2-naphthyl)-2-butanone) 5, which is frequently used to benchmark artificial aldolases. We therefore synthesized the octameric diamine 6 (Figure ), as well as heptameric diamine 8 accessed via its protected intermediate 7 (Figure ). We reasoned that the conformational freedom of the terminal d-residue of the octamer might lead to some unpredictability with regards to application. Gratifyingly, we also managed to obtain the crystal structure of heptamer 7 and to our delight it showed a hydrogen bond between the NH proton of one carbamate and the carbonyl of the other across the helix pitch (Figure ). This further encouraged our prediction that these functionalities were proximal enough to engage in bifunctional catalysis. With foldamers 6 and 8 in hand, we proceeded to measure their rate acceleration of the retro-aldol reaction in chloroform (Figure ). Foldamer 8 proved to be the best catalyst, with a burstphase rate k1' = 0.25 ± 0.04 h -1 (15 mM methodol, 0.75 mM foldamer) and a steady state rate k2 = 0.029 ± 0.002 h -1 . This observation suggests that hydrolysis of the foldamer-acetone imine intermediate is rate limiting under the conditions of the assay. Experiments whereby we have trapped iminium ion intermediates by reduction with sodium acetoxyborohydride confirmed the presence of imines resulting from the reduction of both condensed starting material and acetone (see SI) and are thus compatible with a nucleophilic mechanism. In comparison, the rate of the reaction in the presence of either 1.5 mM butylamine, α,δ-tripeptide 9 or the tertiary amine triethylamine was considerably lower (Figure ), demonstrating the importance of the juxtaposition of amines for the catalytic activity of Foldamer 8. The extended octameric foldamer 6 with the additional δ-amino acid exhibited a lower activity than the heptamer 8 (k1' = 0.044 ± 0.03 h -1 and k2 = 0.015 ± 0.002 h -1 , Figures ). It is possible that this is due to either the aforementioned inability of this residue to participate in helix formation, or that the additional bulk from this building block inhibits substrate access to the catalytic amines. Under the conditions tested, the rate of retroaldol cleavage using 8 was linearly dependent on the concentration of Methodol (Figure ). These observations demonstrate that the foldamers are conducive to arranging multiple functional groups in a catalytically competent manner.