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. 2010 Mar 19;75(6):1822-30.
doi: 10.1021/jo902268x.

Nanometer-scale water-soluble macrocycles from nanometer-sized amino acids

Chris M Gothard  1 , James S Nowick
Affiliations

Nanometer-scale water-soluble macrocycles from nanometer-sized amino acids

Chris M Gothard et al. J Org Chem. .

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.

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Figures

FIGURE 1
FIGURE 1
Nanometer-scale macrocyclic peptides prepared from m-Abc2K, o-Abc2K, and Abc2K (R = CH2CH2CH2NH3+ CF3CO2−).
FIGURE 2
FIGURE 2
Characterization data for cyclododecamer ring 11d.
FIGURE 3
FIGURE 3
NMR spectra of cyclohexamer ring 11a in CD3OD and D2O.
FIGURE 4
FIGURE 4
NMR spectra of cyclohexamer triangle 9b in D2O.
FIGURE 5
FIGURE 5
Molecular models of low-energy conformers of macrocycles 9a–c, 10a,b, and 11a–d. The macrocycles were modeled as simplified homologues 9a'–c', 10a',b', and 11a'–d' in which the propyloxyammonium side chains (R = CH2CH2CH2NH3+) were replaced with methoxy groups (R = Me). Overlays represent conformers identified within the lowest 5.00 kJ/mol from 1000 Monte-Carlo conformational search steps.
FIGURE 6
FIGURE 6
Molecular models of cttctt-and tttttt-conformers of macrocycle 11a. The macrocycle was modeled as simplified homologue 11a' in which the propyloxyammonium side chains (R = CH2CH2CH2NH3+) were replaced with methoxy groups (R = Me). Structures represent the lowest energy cttctt-and tttttt-conformers identified from 1000 Monte-Carlo conformational search steps.
SCHEME 1
SCHEME 1
Synthesis of Building Blocks 1a and 1b
SCHEME 2
SCHEME 2
Synthesis of Cyclohexamer Triangle 9b from Building Blocks Fmoc-o-Abc2K(Boc)-OH (1b) and Fmoc-Abc2K(Boc)-OH (1c)
See this image and copyright information in PMC

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