ENANTIOSELECTIVE AND DIASTEREOSELECTIVE MOLECULAR RECOGNITION OF CYCLIC DIPEPTIDES BY A C-2 MACROLACTAM HOST

Two synthetic, optically active, C-2 symmetric macrolactam hosts 11b a nd 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 soft ware, were designed to complex neutral amides in organic solvents thro ugh complementary intermolecular hydrogen bonding. The hosts, which ar e made up of two short peptide strands alternately interlinked with tw o rigid aromatic spacer units to form a large macrocyclic structure, f eature 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 associati on constants ranging from 70 to 2260 M(-1) (+/-15%). 11b was capable o f moderately high enantioselective and diastereoselective molecular re cognition (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 pref erred guests bearing one or more side chains of the L configuration. I n contrast, the diastereomeric host 11c showed very little enantiosele ctivity (Delta Delta G(enan) = 0.09-0.17 kcal/mol), but did show diast ereoselectivity (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 the se 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 bo nds in the binding cavity of the macrocycle as well as favorable van d er Waals contacts between the hydrocarbon surfaces of the host and gue st. The stereoselective binding observed is most likely due to the sli ght energetic differences in the intermolecular hydrogen bonding patte rns 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 stren gth, and the degree, of the selectivity in binding of the guests by ho sts 11b,c could be improved upon through additional structural modific ations.