1846 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 10
Brief Articles
28.1, 27.9, 27.7, 25.9; IR (CDCl3) 3690, 3605, 3439, 2983, 1703-
1694 cm-1; LRMS (FAB) m/z 447 (M + H)+.
mmol) in acetonitrile (15 mL). The mixture was stirred for 2
h and then concentrated in vacuo. The crude product was
purified by flash chromatography (1:1 EtOAc:hexanes) to
ω-N-Am in o-L-citr u llin e Tr iflu or oa ceta te (8). Deprotec-
afford 27 (0.0742 g, 71%) as a yellow foam: Rf 0.32 (1:1 EtOAc:
tion of 21 (0.2500 g, 0.560 mmol), identical to deprotection of
1
hexanes); [R]20 +11.0 (c ) 0.300, CH2Cl2); H NMR (CDCl3,
22, yielded 8 (0.1832 g, 78%) as a white solid: [R]20 +10.72
D
D
(c ) 1.79, H2O); 1H NMR (D2O, 200 MHz) δ 3.88 (t, 1H, J ) 5
Hz), 3.07 (t, 2H, J ) 6 Hz), 1.79 (m, 2H), 1.49 (m, 2H); 13C
NMR (D2O, 50 MHz) δ 172.0, 158.2, 52.7, 39.3, 27.2, 24.8; IR
(film, 3M Type 61 Disposable IR-card) 3500-2500, 1748, 1658,
1558, 1428 cm-1; LRMS (FAB) m/z 191 (M + H)+; HRMS calcd
for C6H15N4O3 191.1144, found 191.1146.
200 MHz) δ 5.32 (t, 1H, J ) 5 Hz), 5.09 (d, 1H, J ) 8 Hz), 4.14
(br m, 1H), 3.21 (m, 2H), 2.28 (s, 3H), 1.46-1.81 (br m, 4H),
1.44 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3, 50 MHz) δ 171.6,
155.2, 154.3, 81.8, 79.4, 53.3, 42.3, 29.7, 28.1, 27.7, 26.4, 12.8;
IR (CDCl3) 3598, 3427, 3252-3007, 2980, 2934, 2872, 1738-
1683, 1602, 1504 cm-1; LRMS (FAB) m/z 378 (M + H)+.
ω-N-Hyd r oxy-S-m eth yl-L-isoth iocitr u llin e Tr iflu or o-
a ceta te (11). Deprotection of 27 (0.2602 g, 0.69 mmol),
identical to the deprotection of 22, yielded 11 (0.2160 g, 90%)
as a yellow solid: [R]20D +14.51 (c ) 1.14, H2O); 1H NMR (D2O,
200 MHz) δ 3.90 (t, 1H, J ) 5 Hz), 3.28 (t, 2H, J ) 6 Hz), 2.36
(s, 3H), 1.74 (m, 2H), 1.63 (m, 2H); 13C NMR (D2O, 50 MHz) δ
172.2, 167.0, 53.0, 43.7, 27.5, 24.9, 13.5; IR (film, 3M Type 61
Disposable IR-card) 3629-2339, 1734, 1616 cm-1; LRMS (FAB)
m/z 222 (M+); HRMS calcd for C7H16N3O3S 222.0912, found
222.0913. Anal. (C7H15N3SO3‚2HCl‚0.25H2O) C, H, N.
ω-N-Am in o-S-m eth yl-L-isoth iocitr u llin e Tr iflu or oa c-
eta te (12). Iodomethane (0.2810 g, 1.98 mmol) was added to
a solution of 26 (0.3585 g, 0.99 mmol) in acetonitrile (20 mL).
The mixture was stirred for 2 h and then concentrated in
vacuo. The crude product was purified by flash chromatogra-
phy (EtOAc:1% TEA) to afford 28 as a yellow foam: Rf 0.17
(EtOAc:1% TEA). The compound was dissolved in HCl in
dioxane (4 M, 10 mL; Aldrich) and stirred at 23 °C for 1 h
under an argon atmosphere. The mixture was concentrated
in vacuo, dissolved in 0.1% TFA (10 mL) solution, passed
through a 6-mL Supelco LC-18 solid-phase extractor, and
r-N-ter t-Bu t oxyca r b on yl-δ-N-isot h iocya n a t o-L-or n i-
th in e ter t-Bu tyl Ester (24). A mixture of 18 (0.5018 g, 1.23
mmol) and 10% Pd-C (60 mg) in MeOH (20 mL) was shaken
in a Parr hydrogenator under 60 psi of H2 for 12 h. The mixture
was filtered through Celite to remove the catalyst and the
filtrate concentrated under vacuum to give an oil. This oil was
dissolved in CH2Cl2 (20 mL) and added to a mixture of CaCO3
(0.3443 g, 3.44 mmol), H2O (20 mL), CH2Cl2 (20 mL), and
thiophosgene (0.1977 g, 1.72 mmol). This mixture was vigor-
ously stirred at 23 °C, and after 1 h the organic phase was
separated and the aqueous phase extracted with 3 × 10 mL
of CH2Cl2. The combined organic layers were dried (MgSO4),
filtered, and concentrated. The crude product was purified by
flash chromatography (1:7 EtOAc:pentane) to afford 24 (0.3658
g, 90%) as a yellow oil: Rf 0.40 (1:7 EtOAc:pentane); [R]20
+
D
1
12.44 (c ) 1.35, CH2Cl2); H NMR (CDCl3, 200 MHz) δ 5.09
(d, 1H, J ) 7 Hz), 4.15 (br m, 1H), 3.51 (t, 2H, J ) 6 Hz),
1.65-1.72 (br m, 4H), 1.42 (s, 9H), 1.38 (s, 9H); 13C NMR
(CDCl3, 50 MHz) δ 170.9, 155.0, 130.1, 81.8, 79.3, 52.7, 44.3,
29.6, 27.9, 27.6, 25.6; IR (CDCl3) 3434, 2982, 2249, 1737-1694,
1504, 1495 cm-1; LRMS (EI) m/z 331 (M + H)+.
lyophilized to yield 12 (0.2787 g, 63%) as a yellow solid: [R]20
D
r-N -t er t -Bu t oxyca r b on yl-ω-N -h yd r oxy-L-t h iocit r u l-
lin e ter t-Bu tyl Ester (25). A solution of hydroxylamine
(0.1217 g, 3.69 mmol) in MeOH (20 mL) was added to 24
(0.3658 g, 1.10 mmol). The mixture was stirred for 30 min and
concentrated in vacuo. The crude product was purified by flash
chromatography (1:1 EtOAc:hexanes) to afford 25 (0.3658 g,
+12.60 (c ) 0.70, H2O); 1H NMR (D2O, 200 MHz) δ 3.92 (t,
1H, J ) 6 Hz), 3.28 (t, 2H, J ) 6 Hz), 2.36 (s, 3H), 1.80 (m,
2H), 1.62 (m, 2H); 13C NMR (D2O, 50 MHz) δ 171.4, 169.5,
52.3, 42.8, 26.7, 24.0, 12.6; IR (film, 3M Type 61 Disposable
IR-card) 3600-2300, 1734, 1559 cm-1; LRMS (FAB) m/z 221
(M+); HRMS calcd for C7H17N4O2S 221.1070, found 221.1072.
Anal. (C7H16N4SO2‚2HCl‚1H2O) C, H, N, S.
66%) as a clear, colorless foam: Rf 0.21 (1:1 EtOAc:hexanes);
1
[R]20 -10.0 (c ) 1.20, EtOH); H NMR (CDCl3, 200 MHz) δ
D
8.53 (br s, 1H), 8.20 (br s, 1H), 7.28 (br s, 1H), 5.28 (d, 1H, J
) 7 Hz), 4.10 (br m, 1H), 3.60 (m, 2H), 1.65-1.70 (br m, 4H),
1.42 (s, 9H), 1.39 (s, 9H); 13C NMR (CD3OD, 50 MHz) δ 182.4,
173.5, 158.0, 82.6, 80.4, 55.6, 44.0, 29.9, 28.7, 28.2, 26.9; IR
3-Bu tyl-1-h yd r oxyu r ea (13). To a solution of hydroxyl-
amine (0.9979 g, 30.2 mmol) in MeOH (60 mL) was added butyl
isocyanate (1.00 g, 10.1 mmol) at 0 °C. The mixture was stirred
for 1 h and then concentrated in vacuo. The crude white solid
was purified by flash chromatography (EtOAc) to afford 13
(1.12 g, 84%) as a white solid: mp 127-128 °C; Rf 0.40
(EtOAc); 1H NMR (CD3OD, 200 MHz) δ 3.07 (t, 2H, J ) 7 Hz),
1.43-1.19 (m, 4H), 0.83 (t, 3H, J ) 7 Hz); 13C NMR (CD3OD,
50 MHz) δ 164.4, 40.3, 33.2, 20.9, 14.1; IR (NaCl) 3896-2957,
2927, 2863, 1615, 1563 cm-1; LRMS (FAB) m/z 133 (M + H)+.
Anal. (C5H12N2O2) C, H, N.
4-Bu tyl-3-sem ica r ba zid e (14). Condensation of hydrazine
(0.9679 g, 30.2 mmol) with butyl isocyanate (1.00 g, 10.1 mmol)
as described for 13 yielded 14 (1.12 g, 84%) as a white solid:
mp 50-52 °C; Rf 0.08 (EtOAc); 1H NMR (CD3OD, 200 MHz) δ
3.05 (t, 2H, J ) 7 Hz), 1.41-1.19 (m, 4H), 0.83 (t, 3H, J ) 7
Hz); 13C NMR (CD3OD, 50 MHz) δ 163.1, 40.2, 33.5, 20.9, 14.1;
IR (CDCl3) 3407, 2962, 2933, 2875, 1687-1651, 1548-1532
cm-1; LRMS (FAB) m/z 132 (M + H)+. Anal. (C5H13N3O) C, H,
N.
(CDCl3) 3429-3141, 2980, 2935, 1737-1682, 1504, 1468 cm-1
;
LRMS (FAB) m/z 364 (M + H)+, 386 (M + Na)+.
r-N-ter t-Bu t oxyca r b on yl-ω-N-a m in o-L-t h iocit r u llin e
ter t-Bu tyl Ester (26). A solution of hydrazine (0.1058 g, 3.30
mmol) in MeOH (20 mL) was added to 24 (0.7286 g, 2.20
mmol). The mixture was stirred for 30 min and concentrated
in vacuo. The crude product was purified by flash chromatog-
raphy (1:1 EtOAc:hexanes) to afford 26 (0.5033 g, 63%) as a
clear, yellow foam: Rf 0.35 (3:1 EtOAc:hexanes); [R]20D -10.36
(c ) 3.00, EtOH); 1H NMR (CDCl3, 200 MHz) δ 7.52 (br s, 1H),
7.45 (br m, 1H), 5.09 (d, 1H, J ) 8 Hz), 4.17 (br m, 1H), 3.62
(m, 2H), 1.61-1.73 (br m, 4H), 1.43 (s, 9H), 1.41 (s, 9H); 13C
NMR (CDCl3, 50 MHz) δ 181.5, 171.5, 155.2, 81.7, 79.4, 53.4,
43.1, 29.7, 28.0, 27.7, 25.0; IR (CDCl3) 3435, 3400, 3350, 3206-
3148, 2979, 2934, 1738-1682, 1538, 1504 cm-1; LRMS (FAB)
m/z 385 (M + Na)+.
ω-N-Am in o-L-th iocitr u llin e Tr iflu or oacetate (10). Depro-
tection of 26 (0.5605 g, 1.55 mmol), identical to deprotection
of 22, yielded an oil that was dissolved in methanol and
3-Bu tyl-1-h yd r oxyth iou r ea (15). Condensation of hy-
droxylamine (0.8580 g, 26.0 mmol) with butyl isothiocyanate
(1.00 g, 8.70 mmol) as described for 13 yielded 15 (1.22 g, 95%)
as a white solid: mp 99-101 °C dec; Rf 0.30 (1:1 EtOAc:
hexanes); 1H NMR (CD3OD, 200 MHz) δ 3.47 (t, 2H, J ) 7
Hz), 1.49 (m, 2H), 1.29 (m, 2H), 0.85 (t, 3H, J ) 7 Hz); 13C
NMR (CD3OD, 50 MHz) δ 182.4, 44.4, 32.5, 20.9, 14.2; IR
(CDCl3) 3522, 3449, 3420, 2962, 2935, 2875, 1682, 1594, 1532
cm-1; LRMS (FAB) m/z 149 (M + H)+. Anal. (C5H12N2OS) C,
H, N, S.
4-Bu tyl-3-th iosem ica r ba zid e (16). Condensation of hy-
drazine (0.2785 g, 8.70 mmol) with butyl isothiocyanate (1.00
g, 8.70 mmol) yielded 16 (1.20 g, 94%) as a white solid: mp
70-73 °C; Rf 0.35 (2:1 EtOAc:hexanes); 1H NMR (CD3OD, 200
concentrated to give 10 (0.3230 g, 48%) as a yellow solid: [R]20
D
+11.85 (c ) 2.60, H2O); 1H NMR (D2O, 200 MHz) δ 4.13 (t,
1H, J ) 5 Hz), 3.58 (t, 2H, J ) 6 Hz), 2.01 (m, 2H), 1.79 (m,
2H); 13C NMR (D2O, 50 MHz) δ 182.6, 171.7, 52.5, 43.8, 27.0,
23.6; IR (film, 3M Type 61 Disposable IR-card) 3600-2300,
1734, 1559, 1507 cm-1; LRMS (FAB) m/z 207 (M+); HRMS
calcd for C6H15N4O2S 207.0915, found 207.0915. Anal. (C6H14N4-
SO2‚1.5HCl‚1.7CH3OH) C, H, N, S.
r-N -t er t -Bu t oxyca r b on yl-ω-N -h yd r oxy-S -m e t h yl-L -
isoth iocitr u llin e ter t-Bu tyl Ester (27). Iodomethane (0.0781
g, 0.550 mmol) was added to a solution of 25 (0.100 g, 0.275