September 2015
Synthesis of Optically Active 2-Amino-1,3,4-oxadiazoles and their Hybrid Peptides
1445
Cbz-Cys(sBzl)-ψ[(C2N2O)-NH2] (3d).
White solid (85%);
(CH), 129.1 (CH), 139.3 (C-Ph), 141.0 (C-Cbz), 141.4 (C-
1
mp 138–139°C; H NMR (300 MHz, DMSO-d6) δ 2.35 (d, 2H,
J = 6.8 Hz), 3.62 (s, 2H), 5.1 (t, 1H, J = 5.6 Hz), 5.23 (s, 2H),
5.8 (br, 2H), 7.15–7.23 (m, 10H); 13C NMR (100 MHz, DMSO-
d6) 33.9 (S-CH2), 38.4 (S-CH2-Ph), 54.1 (CH), 66.7 (CH2),
126.8 (CH), 127.0 (CH), 127.3 (CH), 128.1 (CH), 128.2 (CH),
136.1 (C-ph), 140.5 (C-Cbz), 156.7 (C═O), 170.2 (C-5
Oxadiazole), 171.5 (C-2 Oxadiazole); LC-MS Calcd for
C19H20N4O3S m/z: 384.1, found 407.1 (M + Na)+.
Fmoc), 144.5 (C-Fmoc), 156.3 (C═O), 156.8 (C═O), 167.2
(NH–C═O), 170.1 (C-5 Oxadiazole), 172.1 (C-2 Oxadiazole).
ESI-MS Calcd for C36H33N5O6 m/z: 631.24, found 654.2
(M + Na)+.
Boc-Val ψ[(C2N2O)NH-CO-Ala-NH-Cbz (4b). White solid
(78%), 1H NMR (300 MHz, DMSO-d6) δ 1.03 (d, 6H, J = 7.2Hz),
1.36 (s, 9H), 1.53 (d, 3H, J = 6.4 Hz), 3.21–3.25 (m, 1H), 4.54–4.59
(m, 2H), 5.24 (s, 2H), 6.3 (br, 1H), 7.24 (s, 5H), 7.4 (br, 1H),
7.83 (br, 1H); 13C NMR (100 MHz, DMSO-d6) δ 17.4 (2CH3),
17.9 (CH3), 27.9 (3CH3-Boc), 36.1 (CH), 47.3 (CH), 61.7
(CH), 67.8 (CH2-Cbz), 80.5 (C-Boc), 126.9 (CH), 127.4 (CH),
129.6 (CH), 140.3 (C-Cbz), 153.7 (C═O), 157.9 (C═O), 161.2
(NH–C═O), 163.7 (C-5 Oxadiazole), 170.9 (C-2 Oxadiazole);
ESI-MS Calcd for C22H31N5O6 m/z: 461.23, found 485.3
(M+ Na)+.
Boc-Val-ψ[(C2N2O)-NH2] (3e).
White solid (87%); mp
178–179°C; 1H NMR (300 MHz, DMSO-d6) δ 1.05 (d, 6H,
J = 7.2 Hz), 1.37 (s, 9H), 2.72–2.78 (m, 1H), 4.79 (d, 1H,
J = 6.8 Hz), 5.35 (br, 2H), 6.84 (br, 1H); 13C NMR (100 MHz,
DMSO-d6) 16.8 (CH3), 28.3 (3CH3-Boc), 34.1 (CH), 59.7
(CH), 79.2 (C-Boc), 155.8 (C═O), 170.9 (C-5 Oxadiazole),
171.4 (C-2 Oxadiazole); LC-MS Calcd for C11H20N4O3 m/z:
256.2, found 257.2(M + H)+.
Boc-Phe ψ[(C2N2O)NH-CO-Val-NH-Fmoc (4c).
White
Boc-Phe-ψ[(C2N2O)-NH2] (3f).
White solid (90%); mp
solid (81%), 1H NMR (300 MHz, DMSO-d6) δ 1.05 (d, 6H,
J = 7.2 Hz), 1.37 (s, 9H), 2.83–2.87 (m, 3H), 4.41 (t, 1H,
J = 5.4 Hz), 4.53 (d, 1H, J = 4.8 Hz), 4.72 (d, 2H, J = 5.6 Hz),
5.23 (t, 1H, J = 4.8 Hz), 6.4 (br, 1H), 6.83 (br, 1H), 7.15–7.72
(m, 13H); 13C NMR (100 MHz, DMSO-d6) 17.3 (2CH3), 28.1
(3CH3-Boc), 30.8 (CH), 41.4 (CH2), 47.3 (CH-Fmoc), 55.4
(CH), 58.1 (CH), 66.7 (CH2-Fmoc), 78.2 (C-Boc), 126.7 (CH),
127.1 (CH), 127.5 (CH), 127.9 (CH), 128.1 (CH), 128.4 (CH),
138.7 (C-Ph), 140.9 (C-Fmoc), 143.3 (C-Fmoc), 155.8 (C═O),
156.0 (C═O), 168.2 (NH–C═O), 170.7 (C-5 Oxadiazole),
171.8 (C-2 Oxadiazole); ESI-MS Calcd for C35H39N5O6 m/z:
625.29, found 648.3 (M + Na)+.
175–176°C; 1H NMR (300 MHz, DMSO-d6) δ 1.35 (s, 9H),
3.23–3.27 (m, 2H), 3.8 (br, 2H), 4.90–4.95 (m, 1H), 5.84 (s,
2H), 6.3 (br, 1H), 7.14–7.27 (m, 5H); 13C NMR (100 MHz,
DMSO-d6) δ 28.2 (3CH3- Boc), 39.5 (CH2), 48.1 (CH), 78.3
(C-Boc), 127.1 (CH), 128.6 (CH), 129.4 (CH), 135.6 (C-Ph),
156.1 (C═O), 170.1 (C-5 Oxadiazole), 171.5 (C-2 Oxadiazole);
LC-MS Calcd for C15H20N4O3 m/z: 304.2, found 303.5
(M À H)+.
Boc-Leu-ψ[(C2N2O)-NH2] (3g).
White solid (88%); mp
173–175°C; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (d, 6H,
J = 7.2 Hz), 1.35 (s, 9H), 1.79–1.82 (m, 3H), 4.91 (t, 1H,
J = 4.4 Hz), 5.6 (br, 2H), 6.3 (br, 1H). 13C NMR (100 MHz,
DMSO-d6) 21.9 (2CH3), 23.4 (CH), 28.1 (3CH3-Boc), 45.7
(CH2), 49.6 (CH), 78.1 (C-Boc), 155.3 (C═O), 170.3 (C-5
Oxadiazole), 171.6 (C-2 Oxadiazole); HRMS Calcd for
C12H22N4O3 m/z: 270.1692, found 271.1778 (M + H)+.
Cbz-Ala-ψ[(C2N2O)-{NH-CO-NH}]-Val-COOMe (5a). White
solid (79%), 1H NMR (300 MHz, DMSO-d6) δ 1.07 (d, 6H,
J= 7.2 Hz), 1.47 (d, 3H, J=6.8Hz), 3.10–3.16 (m, 1H), 3.53 (s,
3H), 4.28 (d, 1H, J= 5.6 Hz), 4.93–4.97 (m, 1H), 5.27 (s, 2H), 5.7
(br, 1H), 6.3 (br, 1H,), 6.85 (br, 1H), 7.18–7.22 (m, 5H); 13C NMR
(100 MHz, DMSO-d6) 17.8 (2CH3), 22.1 (CH3-Ala), 30.7 (CH),
48.4 (CH), 52.1 (OCH3), 56.4 (CH), 65.3 (CH2-Cbz), 127.3 (CH),
127.8 (CH), 128.5 (CH), 140.8 (C-Ph), 153.9 (C═O urea), 156.1
(C═O), 168.1 (C═O ester), 169.5 (C-5 Oxadiazole), 171.4 (C-2
Oxadiazole); ESI-MS Calcd for C19H25N5O6 m/z: 419.18, found
442.08 (M + Na)+.
Boc-Phe-ψ[(C2N2O)-{NH-CO-NH}]-Gly-COOMe (5b). White
solid (76%), 1H NMR (300 MHz, DMSO-d6) δ 1.36 (s, 9H),
2.95 (t, 2H, J = 5.4 Hz), 3.58 (s, 3H), 4.12 (s, 2H), 5.2 (br, 1H),
5.6 (br, 1H), 6.4 (br, 1H), 7.12–7.21 (m, 5H); 13C NMR
(100 MHz, DMSO-d6) 27.9 (3CH3-Boc), 40.8 (CH2), 43.1(CH2),
52.3 (OCH3), 56.2 (CH), 79.4 (C-Boc), 126.8 (CH), 127.5 (CH),
128.4 (CH), 139.8 (C-Ph), 153.5 (C═O urea), 156.1 (C═O),
169.4 (C═O ester), 169.9 (C-5 Oxadiazole), 170.8 (C-2
Oxadiazole); ESI-MS Calcd for C19H25N5O6 m/z: 419.18, found
442.24 (M + Na)+.
Cbz-Phe-ψ[(C2N2O)-{NH-CO-NH}]-Ala-NH-Fmoc (6a). White
solid (83%);1H NMR (300 MHz, DMSO-d6) δ 1.4 (d, 3H, J=6.4Hz),
3.1 (d, 2H, J= 7.0 Hz), 4.5 (s, 2H), 4.75 (t, 1H, J=5.6Hz),
4.83–4.87 (m, 1H), 5.15 (s, 2H), 5.51–5.56 (m, 1H), 5.91 (br,
1H), 6.20 (br, 1H), 7.12–7.84 (m, 18H), 7.95 (br, 1H), 10.58 (br,
1H); 13C NMR (100 MHz, DMSO-d6) δ 20.8 (CH3), 40.9 (CH2),
46.3 (CH-Fmoc), 55.9 (CH), 58.7 (CH), 66.4 (CH2-Cbz), 68.1
(CH2-Fmoc), 125.9 (CH), 126.3 (CH), 127.4 (CH), 127.8 (CH),
128.5 (CH), 128.9 (CH), 139.5 (C-Ph), 141.7 (C-Fmoc),
143.5 (C-Fmoc), 155.9 (C═O urea), 156.7 (C═O), 157.4 (C═O,
Fmoc), 170.8 (C-5 Oxadiazole), 171.4 (C-2 Oxadiazole); ESI-MS
Calcd for C36H34N6O6 m/z: 646.25, found 669.23 (M + Na)+.
Z-Phe-Ala-ψ[(C2N2O)-NH2] (3h). White solid (91%); mp
180–182°C; 1H NMR (300 MHz, DMSO-d6) δ 1.48 (d, 3H,
J = 6.8 Hz), 3.13 (d, 2H, J = 6.2 Hz), 4.93–4.98 (m, 2H), 5.25 (s,
2H), 5.8 (br, 2H), 6.3 (br, 1H), 7.12–7.21 (m, 10H); 13C NMR
(100 MHz, DMSO-d6) 20.8 (CH3), 37.1 (CH2), 51.7 (CH), 54.2
(CH), 66.6 (CH2-Cbz), 126.4 (CH), 126.9 (CH), 127.4 (CH),
127.6 (CH), 128.3 (CH), 129.1 (CH), 138.7 (C-Ph), 141.4 (C-
Cbz), 156.7 (C═O), 168.9 (O═C–NH), 170.8 (C-5 Oxadiazole),
171.2 (C-2 Oxadiazole); LC-MS Calcd for C21H23N5O4 m/z:
409.18, found 432.18 (M + Na)+.
Boc-Phe-Gly-ψ[(C2N2O)-NH2] (3i). White solid (87%); mp
1
100–101°C; H NMR (300 MHz, DMSO-d6) δ 1.36 (s, 9H), 2.9
(d, 2H, J = 7.2 Hz), 3.9 (br, 2H), 4.3 (s, 2H), 4.71–4.76 (m, 1H),
6.3 (br, 2H), 7.12–7.21 (m, 5H); 13C NMR (100 MHz, DMSO-
d6) δ 27.1 (3CH3-Boc), 35.3 (CH2), 43.4 (CH2-Gly), 54.8 (CH),
76.5 (C-Boc), 127.4 (CH), 128.1 (CH), 129.3 (CH), 136.2 (C-
Ph), 155.5 (C═O), 169.8 (O═C–NH), 170.6 (C-5 Oxadiazole),
171.2 (C-2 Oxadiazole); HRMS Calcd for C17H23N5O4 m/z:
361.1828, found 362.1820 (M + H)+.
Cbz-Ala ψ[(C2N2O)NH-CO-Phe-NH-Fmoc (4a).
White
solid (73%), 1H NMR (300 MHz, DMSO-d6) δ 1.51 (d, 3H,
J = 7.6 Hz), 3.07 (d, 2H, J = 5.8 Hz), 4.48 (t, 1H, J = 5.2 Hz),
4.64 (d, 2H, J = 5.8 Hz), 4.73 (t, 1H, J = 4.8 Hz), 5.10–5.14 (m,
1H), 5.23 (s, 2H), 5.1 (br, 1H), 6.3 (br, 1H), 6.69 (br, 1H),
7.12–7.74 (m, 18H). 13C NMR (100 MHz, DMSO-d6) 21.4
(CH3), 36.1 (CH2), 48.2 (CH), 49.4 (CH-Fmoc), 53.7 (CH),
66.1 (CH2), 67.9 (CH2-Fmoc), 126.1 (CH), 126.4 (CH), 126.9
(CH), 127.2 (CH), 127.8 (CH), 128.3 (CH), 128.6 (CH), 128.8
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet