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S. Salvadori et al. / Bioorg. Med. Chem. 16 (2008) 3032–3038
(0.05 g, 0.33 mmol) and WSC (0.06 g, 0.33 mmol) were
added. The reaction mixture was stirred for 3 h at 0 ꢁC
and 24 h at room temperature. After DMF was evapo-
rated, the residue was dissolved in EtOAc and washed
with citric acid (10% in H2O), NaHCO3 (5% in H2O),
and brine. The organic phase was dried (Na2SO4) and
evaporated to dryness. The residue was precipitated
5.2.8. Boc-Dmt-Tic-NH-CH2-Bta. This compound was
obtained by condensation of Boc-Dmt-Tic-OH with
H2N-CH2-Bta via WSC/HOBt as reported for Boc-
Dmt-Tic-NH-CH2-Boa: yield 0.14 g (83%); Rf(B) 0.71;
20
HPLC K0 5.89; mp 143–145 ꢁC; ½aꢂ ꢁ 19:3; m/z 616
D
1
(M+H)+; H NMR (DMSO-d6)d 1.40 (s, 9H), 2.35 (s,
6H), 2.92–3.17 (m, 4H), 4.41–4.92 (m, 6H), 6.29 (s,
2H), 6.96–8.23 (m, 8H).
from Et2O/Pe (1:9, v/v): yield 0.15 g (82%); Rf(B) 0.75;
20
HPLC K0 6.02; mp 140–142 ꢁC; ½aꢂ ꢁ 20:8; m/z 600
D
1
(M+H)+; H NMR (DMSO-d6)d 1.40 (s, 9H), 2.35 (s,
6H), 2.92–3.17 (m, 4H), 4.41–4.92 (m, 6H), 6.29 (s,
2H), 6.96–7.26 (m, 8H).
5.2.9. TFA Æ H-Dmt-Tic-NH-CH2-Bta (2). Boc-Dmt-Tic-
NH-CH2-Bta was treated with TFA as reported for
TFA Æ H-Dmt-Tic-NH-CH2-Boa: yield 0.1 g (93%);
Rf(A) 0.34; HPLC K0 4.22; mp 155–157 ꢁC;
20
D
1
5.2.4. TFA Æ H-Dmt-Tic-NH-CH2-Boa (1). Boc-Dmt-
Tic-NH-CH2-Boa (0.12 g, 0.2 mmol) was treated with
TFA (1 mL) for 0.5 h at room temperature. Et2O/Pe
(1:1, v/v) were added to the solution until the product
½aꢂ ꢁ 18:7; m/z 516 (M+H)+; H NMR (DMSO-d6)d
2.35 (s, 6H), 2.92–3.17 (m, 4H), 3.95–4.92 (m, 6H),
6.29 (s, 2H), 6.96–8.23 (m, 8H). Anal. Calcd for
C31H31F3N4O5S: C, 59.23; H, 4.97; N, 8.91. Found: C,
59.52; H, 5.13; N, 8.71.
precipitated: yield 0.12 g (97%); Rf(A) 0.36; HPLC K0
20
4.36; mp 150–152 ꢁC; ½aꢂ ꢁ 21:5; m/z 500 (M+H)+;
D
1H NMR (DMSO-d6)d 2.35 (s, 6H), 2.92–3.17 (m,
4H), 3.95–4.92 (m, 6H), 6.29 (s, 2H), 6.96–7.26 (m,
8H). Anal. Calcd for C31H31F3N4O6: C, 60.78; H,
5.10; N, 9.15. Found: C, 60.62; H, 5.03; N, 8.98.
5.2.10. Boc-Dmt-Tic-NH-CH2-Indl. This compound was
obtained by condensation of Boc-Dmt-Tic-OH with
H2N-CH2-Indl15 via WSC/HOBt as reported for Boc-
Dmt-Tic-NH-CH2-Boa: yield 0.11 g (84%); Rf(B) 0.67;
20
HPLC K0 5.78; mp 147–149 ꢁC; ½aꢂ ꢁ 20:8; m/z 598
D
1
5.2.5. N-(benzyloxycarbonyl)-glycineo-mercaptoanilide,
disulfide derivative. A solution of Z-Gly-OH (1.57 g,
7.5 mmol) and TEA (1.05 mL, 7.5 mmol) in dry THF
(25 mL) was treated at ꢁ20 ꢁC with isobutyl chlorofor-
mate (0.98 mL, 7.5 mmol). After 30 min at ꢁ20 ꢁC, a
solution of o-aminophenyl disulfide (0.93 g; 3.75 mmol)
in THF (25 mL) was added. The reaction mixture was
stirred while slowly warming to room temperature
(4 h). The solvent was evaporated at reduced pressure,
and the residue was slurried in EtOH. The solid was fil-
tered, washed with EtOH, and dried in vacuo: yield
1.77 g (75%); Rf(B) 0.82; HPLC K0 6.54; mp 160–
(M+H)+; H NMR (DMSO-d6)d 1.40 (s, 9 H), 2.35 (s,
6H), 2.92–3.17 (m, 4H), 4.41–4.92 (m, 6H), 6.13–6.29
(m, 3H), 6.96–7.08 (m, 8H).
5.2.11. TFA Æ H-Dmt-Tic-NH-CH2-Indl (3). Boc-Dmt-
Tic-NH-CH2-Indl was treated with TFA as reported
for TFA Æ H-Dmt-Tic-NH-CH2-Boa: yield 0.09 g
(91%); Rf(A) 0.30; HPLC K0 4.16; mp 149–151 ꢁC;
20
D
1
½aꢂ ꢁ 18:1; m/z 498 (M+H)+; H NMR (DMSO-d6)d
2.35 (s, 6 H), 2.92–3.17 (m, 4H), 3.95–4.92 (m, 6H),
6.13–6.29 (m, 3H), 6.96–7.08 (m, 8H). Anal. Calcd for
C32H33F3N4O5: C, 62.94; H, 5.45; N, 9.18. Found: C,
63.15; H, 5.59; N, 9.29.
1
162 ꢁC; m/z 632 (M+H)+; H NMR (DMSO-d6)d 3.87–
3.92 (d, 2H), 5.34 (s, 2H), 7.19–7.48 (m, 9H).
5.2.12. Boc-Dmt-Tic-NH-CH2-Indn. This compound
was obtained by condensation of Boc-Dmt-Tic-OH with
H2N-CH2-Indn16 via WSC/HOBt as reported for Boc-
5.2.6. Benzyl (benzo[d]thiazol-2-yl)methylcarbamate (Z-
NH-CH2-Bta). The above disulfide derivative (1.5 g,
2.38 mmol) in glacial acetic acid (200 mL) was warmed
to 50 ꢁC. Zn powder (4 g, 60 mmol) was added slowly
while most of the disulfide dissolved. The Zn was fil-
tered, the solution was concentrated to dryness. The res-
idue was dissolved in dioxane (200 mL), and the pH was
adjusted to 10 with TEA. The solution was stirred under
N2 at room temperature overnight. After solvent evapo-
ration, the residue was purified by column chromatogra-
phy as reported above for Z-NH-CH2-Boa: yield 1 g
(71%); Rf(B) 0.71; HPLC K0 6.12; mp 93–95 ꢁC; m/z
299 (M+H)+; 1H NMR (DMSO-d6)d 4.18–4.23 (d,
2H), 5.34 (s, 2H), 7.19–8.23 (m, 9H).
Dmt-Tic-NH-CH2-Boa: yield 0.14 g (87%); Rf(B) 0.74;
20
HPLC K0 6.21; mp 139–141 ꢁC; ½aꢂ ꢁ 21:4; m/z 599
D
1
(M+H)+; H NMR (DMSO-d6)d 1.40 (s, 9H), 2.35 (s,
6H), 2.66–3.17 (m, 11H), 4.41–4.92 (m, 4H), 6.29 (s,
2H), 6.96–7.20 (m, 8H).
5.2.13. TFA Æ H-Dmt-Tic-NH-CH2-Indn (4). Boc-Dmt-
Tic-NH-CH2-Indn was treated with TFA as reported
for TFA Æ H-Dmt-Tic-NH-CH2-Boa: yield 0.10 g
(90%); Rf(A) 0.35; HPLC K0 4.44; mp 140–142 ꢁC;
20
D
1
½aꢂ ꢁ 19:8; m/z 499 (M+H)+; H NMR (DMSO-d6)d
2.35 (s, 6H), 2.66–3.95 (m, 12H), 4.41–4.92 (m, 3H),
6.29 (s, 2H), 6.96–7.20 (m, 8H). Anal. Calcd for
C33H36F3N3O5: C, 64.80; H, 5.93; N, 6.87. Found: C,
64.67; H, 5.76; N, 6.73.
5.2.7. H2N-CH2-Bta. Z-NH-CH2-Bta (0.8 g, 2.68 mmol)
was treated with 4 N HBr/AcOH (30 mL) for 1.5 h at
room temperature. The mixture was concentrated in va-
cuo and purified by column chromatography as re-
ported for H2N-CH2-Boa. The purified intermediate
was deprotonated with 5% NaHCO3 as reported for
H2N-CH2-Boa: yield 0.39 g (88%); Rf(B) 0.32; HPLC
5.2.14. tert-butyl (4-phenyl-1H-imidazol-2-yl)methylcar-
bamate (Boc-NH-CH2-ImidPh). A solution of Boc-Gly-
OH (2.87 g, 16.4 mmol) and cesium carbonate (2.7 g,
8.3 mmol) in EtOH (50 mL) was shaken for 30 min at
room temperature and then evaporated under reduced
pressure. To the resulting salt in DMF (60 mL) was
1
K0 3.19; mp 125–127 ꢁC; m/z 165 (M+H)+; H NMR
(DMSO-d6)d 3.87–3.93 (d, 2 H), 7.55–8.23 (m, 4 H).