Dipeptide-derived lariat ethers as enantioselective carriers of Z-amino acid and dipeptide carboxylates

Lariat ethers bearing N-pivot dipeptide arms have been designed and synthesized as models of natural amino acid and Na+ cation carriers, the "symporters". Two types of dipeptide derived lariats have been prepared: those having amino terminal dipeptide arms (ATD-lariats, 6, 7, 10, 11, 16-18) and those having carboxylic group terminal dipeptide arms (CTD-lariats, 12, 19). ATD-lariats were synthesized by N-acylation of am-15-crown-5, aza-ltkrown-6, and 4,13-diaza-18-crown-6 with Z-GlyOH or Z-PhgOH (Phg = D-alpha-phenylglycine) in the presence of DCC or Ph3P/CCl4/Et3N condensation agents, subsequent hydrogenolytic removal of Z-protecting groups, and the introduction of a second Z-amino acid unit using the same condensation reagents. CTD-lariats 12 and 19 were obtained by N-alkylations of aza-18-crown-6 and 4,13-diam-18-crown-6 with methyl N-(chloro-acetyl)-D-alpha-phenylglycinate (acetonitrile, Na2CO3, NaI). The binding affinities of ATD-lariats toward Na+ and K+ assessed in anh. MeOH and compared with those previously determined for CTD-lariats were found to be approximately 100-fold lower than those of CTD-lariats. Transport studies with 10, 16, 12, and 19 and a series of Z-amino acid and dipeptide K+-carboxylate guests showed that CTD-lariats 12 and 19 are efficient carriers with chiral and constitutional recognition properties. H-1-NMR studies of 19-Z-PheO(-)K(+) complex revealed formation of intra-complex hydrogen bonds between lariat pendant arms and hound substrate.