8
P. Fabbrizzi et al. / Tetrahedron xxx (2014) 1e11
Anal. Calcd For C30H47N7O8S: C, 54.12; H, 7.12; N, 14.73. Found C,
54.21; H, 7.20; N, 14.52.
136.4, 129.5, 127.3, 83.8, 78.6, 61.3, 49.3, 48.2, 47.6, 44.1, 28.3, 27.9,
27.1, 24.9, 23, 21.4, 13.9. MS (ESI): m/z (%) 680.2 (100) [MþHþ]. IR
(CHCl3) 3689 (m), 3621 (m), 3046 (s), 2980 (m), 2942 (m), 2838 (w),
2256 (m), 1726 (m), 1600 (s), 1424 (m), 1366 (m), 1325 (m), 1153 (s),
1025 (s) cmꢂ1. Anal. Calcd for C31H49N7O8S: C, 54.77; H, 7.26; N,
14.42. Found C, 54.72; H, 7.24; N, 14.39.
4.6.8. Methyl N-(3-{4-[3-({[(tert-butoxycarbonyl)amino][(tert-bu-
toxycarbonyl)imino]methyl}amino)propyl]-1H-1,2,3-triazol-1-yl}pro-
pyl)-N-[(4-methylphenyl)sulfonyl]glycinate (12). Obtained from
general procedure E starting from 3 and 28. Purified via FCC using
Biotage Isolera system (TLC to gradient, TLC eluant P. E.eEtOAc 1:2,
Rf¼0.38). 26% Yield, colorless oil. 1H NMR (300 MHz, CDCl3)
4.7. General procedure Fddeprotection
d
7.70e7.62 (m, 3H), 7.58 (d, J¼8.4 Hz, 2H), 4.46 (t, J¼6.9 Hz, 2H),
The protected adduct was suspended in 3 N HCl (10 mL/mmol)
and stirred at 30 ꢀC overnight. The solution was evaporated to
dryness in vacuo to afford the pure product in quantitative yield.
4.00e3.64 (m, 4H), 3.63 (s, 2H), 3.20 (t, J¼6.6 Hz, 2H), 2.77 (t,
J¼7.2 Hz, 2H), 2.41 (s, 3H), 2.20 (t, J¼6.6 Hz, 2H), 2.00e1.55 (m, 2H),
1.49 (s, 18H). 13C NMR (50 MHz, CDCl3)
d 169.3, 154.9, 143.8, 135.8,
129.7, 127.3, 127, 83.8, 52.2, 49.1, 47.1, 46.4, 44.1, 29, 28.3, 27.9, 27.8,
23, 21.5. MS (ESI): m/z (%) 651.9 (100) [Mþ]. IR (CHCl3) 3688 (m),
3615 (m), 3044 (s), 2979 (m), 2939 (m), 2831 (w), 2254 (m), 1721
4.7.1. N-{2-[4-(3-{[Amino(imino)methyl]amino}propyl)-1H-1,2,3-
triazol-1-yl]ethyl}-N-[(4-methylphenyl)sulfonyl]glycine monohydro-
chloride (19). Obtained from general procedure F starting from 10.
(m), 1598 (s), 1422 (m), 1361 (m), 1322 (m), 1156 (s), 1022 (s) cmꢂ1
.
Pale yellow solid. 1H NMR (300 MHz, D2O)
d 7.67 (s, 1H), 7.23 (d,
Anal. Calcd For C29H45N7O8S: C, 53.44; H, 6.96; N, 15.04. Found C,
53.48; H, 6.97; N, 15.02.
J¼8.4 Hz, 2H), 7.21 (d, J¼8.4 Hz, 2H), 4.43 (t, J¼3.4 Hz, 2H), 4.00 (s,
2H), 3.67 (d, J¼3.4 Hz, 2H), 3.04 (d, J¼7.2 Hz, 2H), 2.57 (d, J¼7.2 Hz,
2H), 2.27 (s, 3H), 1.82e1.71 (m, 2H). 13C NMR (100 MHz, D2O)
4.6.9. Methyl N-(3-{4-[3-({[(tert-butoxycarbonyl)amino][(tert-bu-
toxycarbonyl)imino]methyl}amino)propyl]-1H-1,2,3-triazol-1-yl}pro-
pyl)-N-[(4-methylphenyl)sulfonyl]-b-alaninate (13). Obtained from
d 172.4,156.7, 145.3, 134.2,129.9,126.8, 48.7, 40, 30.2, 27.1, 21.1, 20.6.
MS (ESI): m/z (%) 424.1 (100) [Mþ]; 410 (28). IR (KBr) 3396 (br s),
3191 (s), 2964 (m), 2921 (m), 2846 (w), 1744 (m), 1733 (m), 1663 (s),
1647 (s), 1626 (m), 1465 (m), 1448 (m), 1379 (m), 1330 (s), 1293 (m),
1260 (m), 1158 (s), 1088 (m), 1045 (m), 932 (w), 814 (m), 803 (m),
663 (m), 572 (m), 551 (m) cmꢂ1. Anal. Calcd For C17H26ClN7O4S: C,
44.39; H, 5.70; N, 21.32. Found C, 44.30; H, 5.74; N, 21.29.
general procedure E starting from 4 and 28. Purified via FCC using
Biotage Isolera system (TLC to gradient, TLC eluant P. E.eEtOAc 1:2,
Rf¼0.58). 47% Yield, colorless oil. 1H NMR (200 MHz, CDCl3)
d
7.68e7.55 (m, 2H), 7.28 (d, J¼8.2 Hz, 2H), 4.37 (t, J¼6.6 Hz, 2H),
3.94 (t, J¼6.6 Hz, 2H), 3.64 (s, 3H), 3.35 (d, J¼7.2 Hz, 2H), 3.10 (t,
J¼6.6 Hz, 2H), 2.75 (t, J¼7.2 Hz, 2H), 2.59 (t, J¼7.8 Hz, 2H), 2.40 (s,
3H), 2.27e2.12 (m, 2H), 2.03e1.88 (m, 2H), 1.48 (s, 18H). 13C NMR
4.7.2. N-{2-[4-(2-{[Amino(imino)methyl]amino}ethyl)-1H-1,2,3-
triazol-1-yl]ethyl}-N-[(4-methylphenyl)sulfonyl]glycine monohydro-
chloride (18). Obtained from general procedure F starting from 9.
(50 MHz, CDCl3)
d 171.6, 163.8, 160.7, 155, 147.5, 144, 135.4, 129.8,
127.1, 126.9, 83.8, 78.7, 51.8, 47.2, 46.8, 44.9, 44.1, 34.2, 29.5, 28.3,
28.0, 27.9, 22.9, 21.4. MS (ESI): m/z (%) 665.4 (100) [Mþ]. IR (CHCl3)
3686 (m), 3619 (m), 3044 (s), 2982 (m), 2941 (m), 2837 (w), 2255
(m), 1721 (m), 1601 (s), 1424 (m), 1366 (m), 1329 (m), 1151 (s), 1019
(s) cmꢂ1. Anal. Calcd For C30H47N7O8S: C, 54.12; H, 7.12; N, 14.73.
Found C, 54.09; H, 7.11; N, 14.74.
Pale yellow solid. 1H NMR (300 MHz, D2O)
d 7.70 (s, 1H), 7.44 (d,
J¼6.9 Hz, 2H), 7.24 (d, J¼6.9 Hz, 2H), 4.44 (t, J¼5.1 Hz, 2H), 3.98 (s,
3H), 3.75e3.62 (m, 2H), 3.33 (d, J¼6.3 Hz, 2H), 2.79 (d, J¼6.3 Hz,
2H), 2.28 (s, 3H). 13C NMR (100 MHz, D2O)
d 172.4, 156.7, 145.3,
134.2, 129.9, 129.9, 126.8, 125.0, 48.7, 48.5, 48.3, 40.4, 24.1, 20.6. MS
(ESI): m/z (%) 410.2 (100) [Mþ], 303.7 (26). IR (KBr) 3396 (br s), 3191
(s), 2964 (m), 2922 (m), 2846 (w), 1744 (m), 1733 (m), 1663 (s), 1647
(s), 1626 (m), 1465 (m), 1448 (m), 1379 (m), 1330 (s), 1293 (m), 1260
(m), 1158 (s), 1081 (m), 1039 (m), 932 (w), 814 (m), 803 (m), 663
(m), 572 (m), 551 (m) cmꢂ1. Anal. Calcd for C16H24ClN7O4S: C, 43.10;
H, 5.42; N, 21.99. Found C, 43.05; H, 5.48; N, 21.95.
4.6.10. Methyl N-(4-{4-[3-({[(tert-butoxycarbonyl)amino][(tert-bu-
toxycarbonyl)imino]methyl}amino)propyl]-1H-1,2,3-triazol-1-yl}bu-
tyl)-N-[(4-methylphenyl)sulfonyl]-b-alaninate (15). Obtained from
general procedure E starting from 6 and 28. Purified via FCC using
Biotage Isolera system (TLC to gradient, TLC eluant P. E.eEtOAc 1:2,
Rf¼0.29). 51% Yield, colorless oil. 1H NMR (200 MHz, CDCl3)
d
7.66
4.7.3. N-[(4-Methylphenyl)sulfonyl]-N-(2-{4-[3-(pyridinium-2-
(d, J¼8 Hz, 2H), 7.56 (s, 1H), 7.30 (d, J¼8 Hz, 2H), 4.34 (t, J¼6.6 Hz,
2H), 3.95 (t, J¼7.2 Hz, 2H), 3.64 (s, 2H), 3.34 (t, J¼7.2 Hz, 2H), 3.12 (t,
J¼7.2 Hz, 2H), 2.75 (t, J¼7.2 Hz, 2H), 2.41 (s, 3H), 2.06e1.89 (m, 4H),
ylamino)propyl]-1H-1,2,3-triazol-1-yl}ethyl)glycine
(32). Obtained from general procedure F starting from 33. Pale
yellow solid. 1H NMR (200 MHz, D2O)
7.81 (s, 1H), 7.72e7.61 (m,
chloride
d
1.55e1.40 (m, 20H). 13C NMR (50 MHz, CDCl3)
d
171.6, 160.7, 155,
1H), 7.55 (d, J¼7 Hz, 1H), 7.39 (d, J¼7.8 Hz, 2H), 7.21 (d, J¼7.8 Hz,
2H), 6.81 (d, J¼9.2 Hz, 1H), 6.66 (t, J¼7 Hz, 1H), 4.52e4.43 (m, 2H),
4.00 (s, 2H), 3.72e3.65 (m, 2H), 3.22 (t, J¼7 Hz, 2H), 2.70 (t, J¼7 Hz,
147.6, 143.5, 136.1, 129.8, 127.1, 121.1, 83.8, 78.7, 51.8, 49.2, 48.4, 44.3,
44.1, 34.3, 28.4, 28, 27.2, 25.4, 23, 21.5. MS (ESI): m/z (%) 702.4 (100)
[MþNaþ], 680.2 (100) [MþHþ]. IR (CHCl3) 3687 (m), 3621 (m), 3047
(s), 2980 (m), 2943 (m), 2839 (w), 2254 (m),1724 (m),1605 (s),1424
(m), 1365 (m), 1323 (m), 1153 (s), 1021 (s) cmꢂ1. Anal. Calcd For
2H), 2.26 (s, 3H), 2.05e1.96 (m, 2H). 13C NMR (50 MHz, D2O)
d 152.4,
145.3, 143.5, 134.5, 134.1, 129.9, 126.8, 113, 112.4, 49.9, 48.9, 40.5,
26.4, 20.8, 20.7. MS (ESI): m/z (%) 459.2 (100) [Mþ]. IR (KBr) 3415 (br
s), 3191 (s), 2964 (m), 2921 (m), 2846 (w), 1744 (m), 1733 (m), 1662
(s), 1647 (s), 1625 (m), 1465 (m), 1448 (m), 1379 (m), 1330 (s), 1293
(m), 1260 (m), 1157 (s), 1088 (m), 1045 (m), 932 (w), 814 (m), 803
(m), 793 (m), 771 (m), 668 (w), 647 (w), 665 (m), 588 (m) 572 (m),
551 (m) cmꢂ1. Anal. Calcd For C21H27ClN6O4S: C, 50.96; H, 5.50; N,
16.98. Found C, 50.89; H, 5.55; N, 16.94.
C
31H49N7O8S: C, 54.77; H, 7.26; N, 14.42. Found C, 54.82; H, 7.23; N,
14.38.
4.6.11. Ethyl N-(4-{4-[3-({[(tert-butoxycarbonyl)amino][(tert-butox-
ycarbonyl)imino]methyl}amino)propyl]-1H-1,2,3-triazol-1-yl}butyl)-
N-[(4-methylphenyl)sulfonyl]glycinate (14). Obtained from general
procedure E starting from 6 and 28. Purified via FCC using Biotage
Isolera system (TLC to gradient, TLC eluant P. E.eEtOAc 1:2,
4.7.4. N-{2-[4-(3-{[Amino(imino)methyl]amino}propyl)-1H-1,2,3-
triazol-1-yl]ethyl}-N-[(4-fluorophenyl)sulfonyl]glycine monohydro-
chloride (25). Obtained from general procedure F starting from 16.
Rf¼0.47). 73% Yield, colorless oil. 1H NMR (300 MHz, CDCl3)
d 7.64
(d, J¼8.1 Hz, 2H), 7.52 (s, 1H), 7.24 (d, J¼8.1 Hz, 2H), 4.29 (t, J¼6.9 Hz,
2H), 4.30e3.88 (m, 6H), 3.20 (t, J¼6.9 Hz, 2H), 2.71 (t, J¼7.2 Hz, 2H),
2.36 (s, 3H), 1.96e1.88 (m, 4H), 1.53e1.44 (m, 20H), 1.13 (t, J¼7.2 Hz,
Pale yellow solid. 1H NMR (300 MHz, D2O)
d 7.85 (s, 1H), 7.66e7.60
(m, 2H), 7.19e7.11 (m, 2H), 4.51 (t, J¼5.4 Hz, 2H), 4.05 (s, 2H),
3H). 13C NMR (50 MHz, CDCl3)
d 168.7, 163.8, 160.7, 155, 144.3, 143.5,
3.73e3.68 (m, 2H), 3.08 (t, J¼6.9 Hz, 2H), 2.66 (t, J¼7.5 Hz, 2H),