Nanometer-Scale Water-Soluble Macrocycles from Nanometer-Sized Amino Acids

Abstract

This paper introduces the unnatural amino acids m-Abc(2K) and o-Abc(2K) as nanometer-sized building blocks for the creation of water-soluble macrocycles with well-defined shapes. m-Abc(2K) and o-Abc(2K) are homologues of the nanometer-sized amino acid Abc(2K), which we recently introduced for the synthesis of water-soluble molecular rods of precise length (J. Am. Chem. Soc. 2007, 129, 7272). Abc(2K) is linear (180 degrees), m-Abc(2K) creates a 120 degree angle, and o-Abc(2K) creates a 60 degree angle. m-Abc(2K) and o-Abc(2K) are derivatives of 3'-amino-(1,1'-biphenyl)-4-carboxylic acid and 2'-amino-(1,1'-biphenyl)-4-carboxylic acid, with two propyloxyammonium side chains for water solubility. m-Abc(2K) and o-Abc(2K) are prepared as Fmoc-protected derivatives Fmoc-m-Abc(2K(Boc))-OH (1a) and Fmoc-o-Abc(2K(Boc))-OH (1b). These derivatives can be used alone or in conjunction with Fmoc-Abc(2K(Boc))-OH (1c) as ordinary amino acids in Fmoc-based solid-phase peptide synthesis. Building blocks 1a-c were used to synthesize macrocyclic "triangles" 9a-c, "parallelograms" 10a,b, and hexagonal "rings" 11a-d. The macrocycles range from a trimer to a dodecamer, with ring sizes from 24 to 114 atoms, and are 1-4 nm in size. Molecular modeling studies suggest that all the macrocycles except 10b should have well-defined triangle, parallelogram, and ring shapes if all of the amide linkages are trans and the o-alkoxy substituents are intramolecularly hydrogen bonded to the amide NH groups. The macrocycles have good water solubility and are readily characterized by standard analytical techniques, such as RP-HPLC, ESI-MS, and NMR spectroscopy. (1)H and (13)C NMR studies suggest that the macrocycles adopt conformations with all trans-amide linkages in CD(3)OD, that the "triangles" and "parallelograms" maintain these conformations in D(2)O, and that the "rings" collapse to form conformations with cis-amide linkages in D(2)O.