Parallel Synthesis of Peptide-Like Macrocycles Containing Imidazole-4,5-dicarboxylic Acid
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis
2.2. Characterization
3. Experimental
3.1. General
3.2. LC-MS Analysis
3.3. NMR Spectroscopy
3.4. X-ray Crystallography
3.5. Molecular Modeling
3.6. Synthetic Procedures
4. Conclusions
Supplementary Materials
Acknowledgments
References and Notes
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Sample Availability: Contact the authors. |
R1 = Me | ||||
R2 = H | R2 = (S)-CH3 | R2 = (R)-CH3 | R2 = (S)-CH2CH(CH3)2 | |
R3 = H | 9{1,1,1}; 7% | 9{1,2,1}; — | 9{1,3,1}; — | 9{1,4,1}; — |
R3 = (S)-CH3 | 9{1,1,2}; 7% | 9{1,2,2}; 32% | 9{1,3,2}; 22% | 9{1,4,2}; 14% |
R3 = (R)-CH3 | 9{1,1,3}; 17% | 9{1,2,3}; — | 9{1,3,3}; — | 9{1,4,3}; 37% |
R3 = (S)-CH2CH(CH3)2 | 9{1,1,4}; 37% | 9{1,2,4}; 12% | 9{1,3,4}; 11% | 9{1,4,4}; ‡ |
R1 = Et | ||||
R2 = H | R2 = (S)-CH3 | R2 = (R)-CH3 | R2 = (S)-CH2CH(CH3)2 | |
R3 = H | 9{2,1,1}; — | 9{2,2,1}; — | 9{2,3,1}; 3% | 9{2,4,1}; 8% |
R3 = (S)-CH3 | 9{2,1,2}; 9% | 9{2,2,2}; 7% | 9{2,3,2}; 10% | 9{2,4,2}; 11% |
R3 = (R)-CH3 | 9{2,1,3}; 8% | 9{2,2,3}; 8% | 9{2,3,3}; 9% | 9{2,4,3}; — |
R3 = (S)-CH2CH(CH3)2 | 9{2,1,4}; ‡ | 9{2,2,4}; ‡ | 9{2,3,4}; ‡ | 9{2,4,4}; — |
cmpd | MW (g/mol) | cLogP | cmpd | MW (g/mol) | cLogP | |
---|---|---|---|---|---|---|
9{1,1,1} | 322.32 | −1.70 | 9{2,1,1} | 350.37 | −0.64 | |
9{1,1,2} | 336.35 | −1.36 | 9{2,1,2} | 364.40 | −0.12 | |
9{1,1,3} | 336.35 | −1.36 | 9{2,1,3} | 364.40 | −0.12 | |
9{1,1,4} | 378.43 | 0.10 | 9{2,1,4} | 406.40 | 1.33 | |
9{1,2,1} | 336.35 | −1.36 | 9{2,2,1} | 364.40 | −0.12 | |
9{1,2,2} | 350.37 | −0.84 | 9{2,2,2} | 378.43 | 0.40 | |
9{1,2,3} | 350.37 | −0.84 | 9{2,2,3} | 378.43 | 0.40 | |
9{1,2,4} | 392.45 | 0.62 | 9{2,2,4} | 420.51 | 1.85 | |
9{1,3,1} | 336.35 | −1.36 | 9{2,3,1} | 364.40 | −0.12 | |
9{1,3,2} | 350.37 | −0.84 | 9{2,3,2} | 378.43 | 0.40 | |
9{1,3,3} | 350.37 | −0.84 | 9{2,3,3} | 378.43 | 0.40 | |
9{1,3,4} | 392.45 | 1.85 | 9{2,3,4} | 420.51 | 1.85 | |
9{1,4,1} | 378.43 | 0.10 | 9{2,4,1} | 406.48 | 1.33 | |
9{1,4,2} | 392.45 | 0.62 | 9{2,4,2} | 420.51 | 1.85 | |
9{1,4,3} | 434.53 | 0.62 | 9{2,4,3} | 420.51 | 1.85 | |
9{1,4,4} | 434.53 | 2.08 | 9{2,4,4} | 462.59 | 3.31 |
Crystal data | 9{2,4,1} | 9{2,4,3} | 9{2,1,3} |
---|---|---|---|
formula | C19H30N6O4 + 0.16O | C20H32N6O4 | C16H24N6O4 + H2O |
weight (g mol−1) | 409.03 | 420.51 | 382.43 |
crystal size (mm) | 0.45 × 0.38 × 0.28 | 0.45 × 0.13 × 0.07 | 0.35 × 0.07 × 0.05 |
crystal system | monoclinic | monoclinic | orthorhombic |
space group | P21 | P21 | P212121 |
a (Å) | 13.7441(2) | 14.0826(7) | 8.6170(1) |
b (Å) | 14.4322(2) | 13.9531(7) | 17.9394(3) |
c (Å) | 21.3948(3) | 22.4144(12) | 24.4406(4) |
β (°) | 94.192(1) | 96.766(3) | - |
cell volume (Å3) | 4,232.5(1) | 4,373.7(4) | 3,778.1(1) |
Z | 8 | 8 | 8 |
temp (K) | 100(2) | 100(2) | 100(2) |
S | 1.017 | 1.093 | 0.994 |
Compound | ||||||
---|---|---|---|---|---|---|
Torsion Angle | 9{2,4,1} ‡ | 9{2,4,3} ‡ | 9{2,1,3} † | Minimized 9{2,4,1} § | ||
1-2-3-4 | 131.2 ± 4.3° | 138.8 ± 6.4° | 134.1 ±4.0° | 109.6° | ||
2-3-4-5 | −60.3 ± 13.8° | −66.3 ± 3.0° | −77.4 ± 0.3° | −82.8° | ||
3-4-5-6 | 164.2 ± 4.5° | 165.5 ± 5.2° | 165.0 ± 1.6° | 156.0° | ||
4-5-6-7 | −108.4 ± 12.5° | −109.0 ± 6.8° | −95.2 ± 1.7° | −93.7° | ||
5-6-7-8 | 106.1 ± 7.6° | 111.1 ± 9.1° | 112.0 ± 5.7° | 129.1° | ||
6-7-8-9 | 175.4 ± 3.2° | 177.1 ± 2.3° | 174.7 ± 1.8° | −176.5° | ||
7-8-9-10 | 102.2 ± 1.7° | 100.8 ± 5.4° | 98.5 ± 3.9° | 95.5° | ||
8-9-10-11 | −75.6 ± 4.2° | −77.0 ± 4.2° | −71.9 ± 0.9° | −89.4° | ||
9-10-11-12 | 96.3 ± 0.9° | 99.4 ± 2.9° | 103.6 ± 3.1° | 90.5° | ||
10-11-12-13 | 176.1 ± 1.0° | 175.4 ± 3.0° | 173.3 ± 0.2° | −175.0° | ||
11-12-13-14 | 147.2 ± 3.9° | 145.9 ± 3.1° | 137.3 ± 1.6° | 149.8° | ||
12-13-14-1 | −2.2 ± 1.2° | −3.8 ± 1.9° | −1.1 ± 4.1° | −2.6° | ||
13-14-1-2 | 15.7 ± 4.5° | 13.6 ± 4.3° | 16.3 ± 0.9° | 39.9° | ||
14-1-2-3 | −167.9 ± 2.1° | −166.9 ± 2.7° | −166.4 ± 0.3° | −163.5° |
Measurement | Molecule in Asymmetric Unit | |||
---|---|---|---|---|
9{2,4,1} | 9{2,4,3} | 9{2,1,3} | Minimized 9{2,4,1} | |
N2…O(=C12) | 2.69 ± 0.02 Å | 2.72 ± 0.02 Å | 2.78 ± 0.01 Å | 2.74 Å |
N2-H…O(=C12) | 166.8 ± 3.5° | 160.9 ± 2.6° | 161.7 ± 5.9° | 151.4° |
C12=O…H(-N2) | 106.2 ± 0.8° | 106.4 ± 1.3° | 103.4 ± 2.1° | 114.4° |
compound | Name |
---|---|
9{1,1,1} | cyclo(N,N′dimethylethylenediamine-glycyl-glycyl-4,5-dicarbonyl)-1H-imidazole |
9{1,1,2} | cyclo(N,N′dimethylethylenediamine-glycyl-S-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{1,1,3} | cyclo(N,N′dimethylethylenediamine-glycyl-R-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{1,1,4} | cyclo(N,N′dimethylethylenediamine-glycyl-S-leucyl-4,5-dicarbonyl)-1H-imidazole |
9{1,2,1} | cyclo(N,N′dimethylethylenediamine-S-alanyl-glycyl-4,5-dicarbonyl)-1H-imidazole |
9{1,2,2} | cyclo(N,N′dimethylethylenediamine-S-alanyl-S-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{1,2,3} | cyclo(N,N′dimethylethylenediamine-S-alanyl-R-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{1,2,4} | cyclo(N,N′dimethylethylenediamine-S-alanyl-S-leucyl-4,5-dicarbonyl)-1H-imidazole |
9{1,3,1} | cyclo(N,N′dimethylethylenediamine-R-alanyl-glycyl-4,5-dicarbonyl)-1H-imidazole |
9{1,3,2} | cyclo(N,N′dimethylethylenediamine-R-alanyl-S-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{1,3,3} | cyclo(N,N′dimethylethylenediamine-R-alanyl-R-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{1,3,4} | cyclo(N,N′dimethylethylenediamine-R-alanyl-S-leucyl-4,5-dicarbonyl)-1H-imidazole |
9{1,4,1} | cyclo(N,N′dimethylethylenediamine-S-leucyl-glycyl-4,5-dicarbonyl)-1H-imidazole |
9{1,4,2} | cyclo(N,N′dimethylethylenediamine-S-leucyl-S-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{1,4,3} | cyclo(N,N′dimethylethylenediamine-S-leucyl-R-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{1,4,4} | cyclo(N,N′dimethylethylenediamine-S-leucyl-S-leucyl-4,5-dicarbonyl)-1H-imidazole |
9{2,1,1} | cyclo(N,N′diethylethylenediamine-glycyl-glycyl-4,5-dicarbonyl)-1H-imidazole |
9{2,1,2} | cyclo(N,N′diethylethylenediamine-glycyl-S-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{2,1,3} | cyclo(N,N′diethylethylenediamine)-glycyl-R-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{2,1,4} | cyclo(N,N′diethylethylenediamine-glycyl-S-leucyl-4,5-dicarbonyl)-1H-imidazole |
9{2,2,1} | cyclo(N,N′diethylethylenediamine-S-alanyl-glycyl-4,5-dicarbonyl)-1H-imidazole |
9{2,2,2} | cyclo(N,N′diethylethylenediamine-S-alanyl-S-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{2,2,3} | cyclo(N,N′diethylethylenediamine-S-alanyl-R-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{2,2,4} | cyclo(N,N′diethylethylenediamine-S-alanyl-S-leucyl-4,5-dicarbonyl)-1H-imidazole |
9{2,3,1} | cyclo(N,N′diethylethylenediamine-R-alanyl-glycyl-4,5-dicarbonyl)-1H-imidazole |
9{2,3,2} | cyclo(N,N′diethylethylenediamine-R-alanyl-S-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{2,3,3} | cyclo(N,N′diethylethylenediamine-R-alanyl-R-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{2,3,4} | cyclo(N,N′diethylethylenediamine-R-alanyl-S-leucyl-4,5-dicarbonyl)-1H-imidazole |
9{2,4,1} | cyclo(N,N′diethylethylenediamine-S-leucyl-glycyl-4,5-dicarbonyl)-1H-imidazole |
9{2,4,2} | cyclo(N,N′diethylethylenediamine-S-leucyl-S-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{2,4,3} | cyclo(N,N′diethylethylenediamine-S-leucyl-R-alanyl-4,5-dicarbonyl)-1H-imidazole |
9{2,4,4} | cyclo(N,N′diethylethylenediamine-S-leucyl-S-leucyl-4,5-dicarbonyl)-1H-imidazole |
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Xu, Z.; Wheeler, K.A.; Baures, P.W. Parallel Synthesis of Peptide-Like Macrocycles Containing Imidazole-4,5-dicarboxylic Acid. Molecules 2012, 17, 5346-5362. https://doi.org/10.3390/molecules17055346
Xu Z, Wheeler KA, Baures PW. Parallel Synthesis of Peptide-Like Macrocycles Containing Imidazole-4,5-dicarboxylic Acid. Molecules. 2012; 17(5):5346-5362. https://doi.org/10.3390/molecules17055346
Chicago/Turabian StyleXu, Zhigang, Kraig A. Wheeler, and Paul W. Baures. 2012. "Parallel Synthesis of Peptide-Like Macrocycles Containing Imidazole-4,5-dicarboxylic Acid" Molecules 17, no. 5: 5346-5362. https://doi.org/10.3390/molecules17055346