Two synthetic, optically active, C-2 symmetric macrolactam hosts 11b and 11c have been synthesized from L-leucine, and other simple starting materials, in an 11-step, convergent synthesis. These new macrocycles, which were conceived with the aid of current molecular modeling software, were designed to complex neutral amides in organic solvents through complementary intermolecular hydrogen bonding. The hosts, which are made up of two short peptide strands alternately interlinked with two rigid aromatic spacer units to form a large macrocyclic structure, feature a binding site that consists of a convergent, ordered array of amide functions. H-1 NMR and solution FT-IR spectroscopy demonstrated that in CDCl3 11b and 11c each bound the five various stereoisomers of the cyclic dipeptides cycle-Gly-Leu and cyclo-Leu-Leu, with association constants ranging from 70 to 2260 M(-1) (+/-15%). 11b was capable of moderately high enantioselective and diastereoselective molecular recognition (Delta Delta(enan) = 0.97-1.23 kcal/mol, Delta Delta G(dia) = 0.28-0.95 kcal/mol) of the various chiral diketopiperazines and preferred guests bearing one or more side chains of the L configuration. In contrast, the diastereomeric host 11c showed very little enantioselectivity (Delta Delta G(enan) = 0.09-0.17 kcal/mol), but did show diastereoselectivity (Delta Delta G(dia) = 0.44-0.54 kcal/mol) and showed a modest preference for guests with side chains of the D configuration. Molecular modeling studies, as well as H-1 NMR data, suggest that these hosts are conformationally flexible and bind to the guests with an induced-fit mechanism. The host-guest complexes are stabilized through the formation of three to four intermolecular amide-amide hydrogen bonds in the binding cavity of the macrocycle as well as favorable van der Waals contacts between the hydrocarbon surfaces of the host and guest. The stereoselective binding observed is most likely due to the slight energetic differences in the intermolecular hydrogen bonding patterns that stabilize the host-guest complexes, which are in turn due to the varying degrees of steric interactions that occur between the side chains of the guest and of the host. It is anticipated that the strength, and the degree, of the selectivity in binding of the guests by hosts 11b,c could be improved upon through additional structural modifications.