S. Thompson et al. / Tetrahedron 68 (2012) 4501e4505
4505
the title compound 12 (165 mg, 0.32 mmol, 78%) as a yellow solid:
4.15. Methyl 2-acetamido-4-(2-acetamido-4-(2-acetamido-5-
mp 123; dH (500 MHz, (CD3)2SO) 10.38 (1H, s, NH), 10.11 (1H, s, NH),
9.81 (1H, s, NH), 8.82 (1H, s, AreH), 8.32 (1H, s, AreH), 7.62 (1H, s,
AreH), 7.46 (1H, s, AreH), 3.98 (3H, s, CH3), 3.85 (6H, s, 2ꢂCH3), 2.16
(2H, d, J 7.0, CH2), 2.09 (3H, s, NHCOCH3), 1.98 (1H, sept, J 6.8,
CH(CH3)2), 0.86 (6H, d, J 6.5, CH(CH3)2); dC (125 MHz, CDCl3) 171.6,
168.9, 167.8, 165.1, 147.3, 143.1, 142.1, 136.8, 132.8, 131.7, 125.4, 119.0,
112.0, 111.9, 111.0, 110.6, 57.1, 56.2, 52.4, 47.0, 25.9, 25.4, 22.4; IR
(neat) nmax 3282, 2957, 1682, 1603, 1528, 1462, 1348, 1206, 999, 822,
783; HRMS (ESI) found 525.1602, C23H26N4NaO9 [MþNa]þ requires
525.1592.
methoxy-4-nitrobenzamido)-5-methoxybenzamido)-5-
methoxybenzoate (16)
Based on the procedure for the synthesis of 10, 15 (870 mg,
1.29 mmol) and acetyl chloride (275 mL, 3.87 mmol) afforded the title
compound 16 (470 mg, 0.69 mmol, 54%); dH (500 MHz, (CD3)2SO)
10.31 (1H, s, NH), 10.12 (1H, s, NH), 9.89 (1H, s, NH), 8.45 (1H, s,
AreH), 8.21 (1H, s, AreH), 8.04 (1H, s, AreH), 7.65 (1H, s, AreH), 7.60
(1H, s, AreH), 7.53 (1H, s, AreH), 4.00 (3H, s, CH3), 3.97 (3H, s, CH3),
3.90 (3H, s, CH3), 3.80 (3H, s, CH3), 2.12 (3H, s, NHCOCH3), 2.09 (3H, s,
NHCOCH3), 2.03 (3H, s, NHCOCH3); dC (125 MHz, CDCl3) 169.6,168.9,
167.3,165.3,160.9,152.0,149.5,147.9,147.4,142.6,140.5,135.6,133.3,
131.5, 130.4, 129.3, 120.6, 118.7, 118.5, 117.0, 116.4, 113.6, 112.8, 104.9,
57.0, 55.9, 55.9, 53.2, 25.1, 24.4, 23.1; HRMS (ESI) found 703.1961,
C31H32N6NaO12 [MþNa]þ requires 703.1970.
4.12. Methyl 2-acetamido-5-methoxy-4-(5-methoxy-4-nitro-
2-(2-phenylacetamido)benzamido)benzoate (13)
Based on the procedure for the synthesis of 10, 9 (184 mg,
0.42 mmol) and phenylacetyl chloride (170 mL, 1.26 mmol) afforded
the title compound 13 (209 mg, 0.38 mmol, 90%) as a yellow solid:
mp 235; dH (500 MHz, (CD3)2SO, CDCl3) 10.39 (1H, s, NH),10.29 (1H,
s, NH), 9.82 (1H, s, NH), 8.81 (1H, s, AreH), 8.31 (1H, s, AreH), 7.61
(1H, s, AreH), 7.45 (1H, s, AreH), 7.26e7.14 (5H, m, AreH), 3.97 (3H,
s, CH3), 3.88 (3H, s, CH3), 3.86 (3H, s, CH3), 3.65 (2H, s, CH2), 2.10
(3H, s, NHCOCH3); dC (125 MHz, (CD3)2SO, CDCl3) 170.5, 169.1, 167.6,
164.7, 148.0, 144.0, 141.0, 135.5, 133.7, 131.4, 130.7, 129.0, 128.6,
128.0, 127.1, 119.5, 113.0, 112.5, 111.4, 111.2, 77.3, 77.0, 76.7, 56.7, 55.8,
52.2, 24.7; IR (neat) nmax 3329, 2954, 1687, 1601, 1528, 1415, 1349,
1237, 1029, 895, 786, 730; HRMS (ESI) found 573.1605,
C27H26N4NaO9 [MþNa]þ requires 573.1592.
Acknowledgements
We thank Dr. Martin D. Smith (Oxford) for helpful discussions
and The University of Oxford for funding (S.T.).
References and notes
1. Jones, S.; Thornton, J. M. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 13e20.
2. Cunningham, B. C.; Wells, J. A. Science 1989, 244, 1081e1085; Bogan, A. A.;
Thorn, K. S. J. Mol. Biol. 1998, 280, 1e9.
3. Peptidic scaffolds including those based on alpha amino acids: Appella, D. H.;
Christianson, L. A.; Karle, I. L.; Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 1996,
118, 13071e13072; Kritzer, J. A.; Stephens, O. M.; Guarracino, D. A.; Reznik, S. K.;
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Isaad, A.; Rovero, P.; Papini, A. M.; Chorev, M.; D’Ursi, A. M. Eur. J. Org. Chem.
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Wells, J. A.; McClendon, C. L. Nature 2007, 450, 1001e1009; (d) Fletcher, S.;
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A. D. J.R. Soc. Interface 2006, 3, 215e233.
4.13. Methyl 2-acetamido-4-(2-acetamido-4-amino-5-
methoxybenzamido)-5-methoxybenzoate (14)
Based on the procedure for the synthesis of 5, 10 (1.07 g,
2.26 mmol) afforded the title compound 14 (949 mg, 2.14 mmol,
95%) as a yellow solid: mp 269; dH (400 MHz, (CD3)2SO) 10.82 (1H,
s, NH), 10.40 (1H, s, NH), 9.47 (1H, s, NH), 8.74 (1H, s, AreH), 7.44
(1H, s, AreH), 7.36 (1H, s, AreH), 7.29 (1H, s, AreH), 5.65 (2H, br,
NH2), 3.85 (3H, s, CH3), 3.84 (3H, s, CH3), 3.81 (3H, s, CH3), 2.08 (3H,
s, NHCOCH3), 2.01 (3H, s, NHCOCH3); dC (125 MHz, (CD3)2SO) 168.4,
168.1, 167.0, 166.4, 145.7, 142.5, 141.9, 133.9, 133.7, 132.2, 115.8, 113.7,
111.5, 110.5, 109.4, 106.6, 56.0, 55.6, 52.2, 24.4, 24.4; IR (neat) nmax
3348, 2922, 1674, 1602, 1528, 1419, 1352, 1234, 1026, 878, 767;
HRMS (ESI) found 467.1538, C21H24N4NaO7 [MþNa]þ requires
467.1537.
5. Adler, M. J.; Hamilton, A. D. J. Org. Chem. 2011, 76, 7040e7047; Rodriguez, J. M.;
Hamilton, A. D. Tetrahedron Lett. 2006, 47, 7443e7446.
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Becerril, J.; Hamilton, A. D. Angew. Chem., Int. Ed. 2007, 46, 4471e4473; Kim, I.
C.; Hamilton, A. D. Org. Lett. 2006, 8, 1751e1754.
7. Hirano, S.; Kawasaki, M.; Ura, H.; Kato, R.; Raiborg, C.; Stenmark, H.; Wakatsuki,
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9. Runge, S.; Thøgersen, H.; Madsen, K.; Lau, J.; Rudolph, R. J. Biol. Chem. 2008, 283,
11,340e11,347.
4.14. Methyl 2-acetamido-4-(2-acetamido-4-(2-amino-5-
methoxy-4-nitrobenzamido)-5-methoxybenzamido)-5-
methoxybenzoate hydrochloride (15)
10. Hancock, R. E. W.; Rozek, A. FEMS Microbiol. Lett. 2002, 206, 143e149.
11. Saraogi, I.; Hebda, J. A.; Becerril, J.; Estroff, L. A.; Miranker, A. D.; Hamilton, A. D.
Angew. Chem., Int. Ed. 2010, 49, 736e739; Saraogi, I.; Incarvito, C. D.; Hamilton,
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12. CCDC #s (a) compound 10: 850703, (b) compound 12: 850704.
13. Calculated for the terminal carbon atoms corresponding to the i, iþ2, iþ4, iþ6
residues using Chimera University of California, San Francisco (supported by
NIH P41 RR001081): Huang, C. C.; Couch, G. S.; Pettersen, E. F.; Ferrin, T. E.
Pacific Symposium on Biocomputing; 1996; Vol. 1 724.
Based on the procedure for the synthesis of 9, 14 (940 mg,
2.11 mmol) and 7 (481 mg, 1.92 mmol) afforded the title compound
15 (875 mg, 1.30 mmol, 67%); dH (400 MHz, (CD3)2SO) 10.41, (1H, s,
NH), 10.33 (1H, s, NH), 9.91 (1H, s, AreH), 9.65 (1H, s, AreH), 8.92,
(1H, s, AreH), 8.24 (1H, s, AreH), 7.55 (1H, s, AreH), 7.51 (1H, s,
AreH), 7.48 (1H, s, AreH), 7.29 (1H, s, AreH), 6.16 (2H, br, NH2), 3.92
(3H, s, CH3), 3.89 (3H, s, CH3), 3.88 (3H, s, CH3), 3.86 (3H, s, CH3),
2.11 (NHCOCH3), 2.04 (NHCOCH3); dC (100 MHz, (CD3)2SO) 168.9,
168.1,166.9,165.7,165.2, 147.8, 145.3, 145.2, 142.9, 142.0, 141.5,133.7,
131.7, 129.8, 129.7, 123.3, 120.0, 119.9, 115.4, 114.0, 112.1, 111.6, 111.5,
57.2, 56.2, 56.1, 52.3, 24.4, 23.7; HRMS (ESI) found 661.5723,
C29H30N6NaO11 [MþNa]þ requires 661.5713.
14. Iyobe, A.; Uchida, M.; Kamata, K.; Hotei, Y.; Kusama, H.; Harada, H. Chem.
Pharm. Bull. 2001, 49, 822e829.
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F.; Hallett, W. A.; Nilakantan, R.; Shen, R.; Wang, Y.-F.; Greenberger, L. M.; Tsou,
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16. Dewar, J. C. S. J. Chem. Soc. 1944, 618e623.