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

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journal contribution
posted on 19.03.2010, 00:00 by Chris M. Gothard, James S. Nowick
This paper introduces the unnatural amino acids m-Abc2K and o-Abc2K as nanometer-sized building blocks for the creation of water-soluble macrocycles with well-defined shapes. m-Abc2K and o-Abc2K are homologues of the nanometer-sized amino acid Abc2K, which we recently introduced for the synthesis of water-soluble molecular rods of precise length (J. Am. Chem. Soc. 2007, 129, 7272). Abc2K is linear (180°), m-Abc2K creates a 120° angle, and o-Abc2K creates a 60° angle. m-Abc2K and o-Abc2K 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-Abc2K and o-Abc2K are prepared as Fmoc-protected derivatives Fmoc-m-Abc2K(Boc)-OH (1a) and Fmoc-o-Abc2K(Boc)-OH (1b). These derivatives can be used alone or in conjunction with Fmoc-Abc2K(Boc)-OH (1c) as ordinary amino acids in Fmoc-based solid-phase peptide synthesis. Building blocks 1ac were used to synthesize macrocyclic “triangles” 9ac, “parallelograms” 10a,b, and hexagonal “rings” 11ad. 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. 1H and 13C NMR studies suggest that the macrocycles adopt conformations with all trans-amide linkages in CD3OD, that the “triangles” and “parallelograms” maintain these conformations in D2O, and that the “rings” collapse to form conformations with cis-amide linkages in D2O.