8816 J . Org. Chem., Vol. 61, No. 25, 1996
Smith et al.
(8) 4-[[(1,1-Dim eth yleth oxy)car bon yl]am in o]ben zyl Iso-
th iocya n a te. A solution of 4-[(1,1-dimethylethoxy)carbonyl]-
amino]benzylamine (5.10 g, 21.6 mmol) in THF (130 mL) was
added dropwise over a period of 2 h to a solution of 1,3-
dicyclohexylcarbodiimide (4.54 g, 22.0 mmol) and carbon
disulfide (9.0 mL, 149.6 mmol) in THF (80 mL) at -5 °C. The
reaction mixture was allowed to warm with stirring to room
temperature over 24 h. The THF was removed in vacuo, and
diethyl ether (400 mL) was added. The precipitate was
filtered, and the filtrate was collected and concentrated to a
slightly yellow oil. This oil was further purified by flash
chromatography (hexanes/DCM, 4:1) to yield 5.23 g of a white
CDCl3) δ 172.07, 166.64, 145.45, 135.80, 132.41, 129.24, 128.54,
127.37, 127.30, 127.11, 53.51, 52.41, 45.45, 37.71; HRMS (CI+
m/ z) calcd for C18H21N2O3 (M + H+) 313.1552, obsd 313.1550.
(3) L-P h en yla la n in e, N-[4-[[[[[2-[[(1,1-Dim eth yleth oxy)-
ca r b on yl]a m in o]e t h yl]a m in o]t h ioxom e t h yl]a m in o]-
m eth yl]ben zyoyl]-, Meth yl Ester (7). To a solution of 9
(1.44 g, 3.70 mmol) in DCM (50 mL) was added the isothio-
cyanate 1 (0.84 g, 4.4 mmol). The solution was stirred 4 days
at room temperature. The DCM was evaporated in vacuo. The
solid was purified by flash chromatography (DCM/ethyl ac-
etate, 2:1) to give 1.11 g of a white fluffy solid (79%): mp 68-
72 °C dec; 1H NMR (300 MHz, CDCl3) δ 7.47 (d, 2 H), 7.16 (m,
1 H), 5.43 (br, 1 H), 4.89 (dd, 13.2 Hz, 1 H), 4.60 (br, 2 H),
3.65 (s, 3 H), 3.48 (br 2 H), 3.16 (br, 4 H), 1.32 (s, 9 H); 13C
{1H} NMR (75 MHz, CDCl3) δ 182.59 (br), 171.93, 167.09,
156.76, 141.95 (br), 135.79, 132.31, 129.93, 128.39, 127.36,
127.04, 126.91, 79.48, 53.73, 52.20, 47.42 (br), 44.57 (br), 39.89
(br), 37.38, 28.13; HRMS (CI+ m/ z) calcd for C26H34N4O5S (M
+ H+) 515.2328, obsd 515.2310.
(4) L-P h en yla la n in e, N-[4-[[[[(2-Am in oeth yl)a m in o]-
t h ioxom et h yl]a m in o]m et h yl]b en zyoyl]-, Met h yl E st er
(10). To 7 (0.80 g, 1.6 mmol) in a 25-mL round-bottom flask
was added a solution of TFA (9 mL) and water (3 mL). The
solution was stirred at room temperature for 1 h. TFA and
water were removed in vacuo. To the resulting glassy solid
was added a solution of ammonium hydroxide (pH 12, 1 M
NaCl), and the solution was extracted with DCM (3 × 50 mL).
The organic layers were combined, dried (Na2SO4), and
concentrated under reduced pressure to afford 0.44 g of a white
amorphous solid (68%): mp 95-100 °C dec; 1H NMR (300
MHz, CDCl3) δ 7.48 (d, 2 H), 7.36 (br, 1 H), 7.27 (br, 1 H),
7.13 (m, 7 H), 7.04 (br, 1 H), 4.90 (d, 1 H), 4.64 (br, 2 H), 3.65
(s, 3 H), 3.5-3.2 (br, 2 H), 3.42 (br, 2 H), 3.16 (m, 2 H), 2.99
(br, 2 H); 13C {1H} NMR (75 MHz, CDCl3) δ 183.01 (br), 172.04,
167.32, 142.38 (br), 135.88, 132.15, 128.94, 128.40, 127.26,
127.05, 126.92, 53.85, 52.27, 47.49 (br), 45.64 (br), 40.61 (br),
37.38; HRMS (FAB m/ z) calcd for C21H26N4O3S (M + H+)
415.1804, obsd 415.1825.
1
solid (87%): mp 74 °C; H NMR (250 MHz, CDCl3) δ 7.31-
7.24 (m, 4 H), 4.90 (br, 1 H), 4.68 (s, 2 H), 4.30 (d, 2 H), 1.45
(s, 9 H); 13C {1H} NMR (62.5 MHz, CDCl3) δ 155.83, 139.38,
133.24, 127.91, 127.10, 79.62, 48.38, 44.19, 28.35; HRMS (CI+
m/ z) calcd for C14H19N2O2S (M + H+) 279.1167, obsd 279.1157.
Sp a cer Syn th esis. 4-[[(1,1-Dim eth yleth oxy)ca r bon yl]-
a m in om eth yl]ben zoic Acid (12). Di-tert-butyl dicarbonate
(19.1 g, 87.3 mmol) was added dropwise over a period of 1 h
to 4-(aminomethyl)benzoic acid (12.0 g, 79.4 mmol) in a
solution of sodium hydroxide (3.18 g, 79.5 mmol), water (20
mL), and tert-butyl alcohol (30 mL). The mixture was stirred
18 h. Water (200 mL) was added to the mixture, and it was
extracted with hexanes (3 × 75 mL). The aqueous layer was
cooled with the addition of ice (100 g) and then acidified with
sulfuric acid to pH 2. The cold aqueous layer was quickly
extracted with ethyl acetate (2 × 100 mL). The organic layers
were combined and dried, and the solvent was removed in
vacuo to yield 18.31 g of a white powder (92%): mp 158.5 °C;
1H NMR (300 MHz, methanol-d4) δ 7.96 (d, 2 H), 7.36 (d, 2
H), 4.89 (br, 2 H), 4.28 (br, 2 H), 1.4 (s, 9 H); 13C {1H} NMR
(75 MHz, methanol-d4) δ 169.67, 155.23, 146.65, 130.91,
130.56, 127.97, 80.35, 44.75, 28.74; HRMS (CI+ m/ z) calcd for
C13H18NO4 (M + H+) 252.1236, obsd 252.1240.
Solu tion Syn th esis. (1) L-P h en yla la n in e, N-4-[[[[(1,1-
Dim eth yleth oxy)car bon yl]am in o]m eth yl]ben zoyl]-, Meth -
yl Ester (6). A solution of L-phenylalanine methyl ester
hydrochloride (3.90 g, 18.0 mmol) in water (40 mL) was treated
with a solution of potassium carbonate (5.0 g, 36.2 mmol) in
water (15 mL). This aqueous solution was extracted with ethyl
acetate (3 × 50 mL). The ethyl acetate layers were combined,
dried over anhydrous sodium sulfate, and concentrated to an
oil under reduced pressure. To this residue was added DCM
(50 mL) and 4-[[(1,1-dimethylethoxy)carbonyl]aminomethyl]-
benzoic acid (4.69 g, 18.7 mmol) in DMF (5 mL) followed by
diisopropylcarbodiimide (2.82 mL, 18.0 mmol). The solution
was stirred under Ar for 18 h. To the mixture was added DCM
(50 mL), and the solution was filtered through Celite. The
filtrate was washed with saturated, aqueous sodium bicarbon-
ate solution (2 × 50 mL) and a saturated, aqueous solution of
ammonium chloride solution (2 × 50 mL). The DCM solution
was evaporated in vacuo to give a white solid (5.7 g) which
was purified by flash chromatography (DCM/ethyl acetate, 3:1)
to give 2.72 g of a white solid (52%): mp 129.5-131 °C; 1H
NMR (300 MHz, CDCl3) δ 7.67 (d, 2 H), 7.28 (m, 5 H), 7.11 (d,
2 H), 6.59 (d, 1 H), 5.07 (dd, 1 H), 4.98 (br, 1 H), 4.34 (d, 2 H),
3.71 (s, 3 H), 3.28 (dd, 1 H), 3.21 (dd, 1 H), 1.45 (s, 9 H); 13C
{1H} NMR (75 MHz, CDCl3) δ 172.01, 166.44, 155.86, 143.04,
135.71, 132.67, 129.28, 128.60, 127.36, 127.30, 127.17, 79.74,
53.44, 52.48, 44.16, 37.79, 28.35; HRMS (CI+ m/ z) calcd for
C23H29N2O5 (M + H+) 413.2076, obsd 413.2075. Anal. Calcd
for C23H28N2O5: C, 66.97; H, 6.84; N, 6.79. Found: C, 64.42;
H, 6.79; N, 6.76.
(2) L-P h en yla la n in e, N-[4-(Am in om et h yl)b en zoyl]-,
Meth yl Ester (9). To 6 (1.45 g, 3.52 mmol) in a 50-mL round-
bottom flask was added a solution of TFA (15 mL) and water
(5 mL). The solution was stirred 1 h. The water and TFA
were evaporated in vacuo. To the resulting glassy solid was
added a 75 mL solution of ammonium hydroxide (pH 12, 1 M
NaCl). This was extracted with DCM (3 × 50 mL), dried over
anhydrous sodium sulfate, and concentrated to 0.81 g of a
white amorphous solid (93%): mp 103-105 °C; 1H NMR (300
MHz, CDCl3) δ 7.65 (d, 2 H), 7.27 (m, 5 H), 7.13 (d, 2 H), 6.18
(d, 1 H), 5.03 (dd, 1 H), 3.88 (s, 2 H), 3.75 (s, 3 H), 3.28 (dd, 1
H), 3.20 (dd, 1 H), 2.99 (br, 2 H); 13C {1H} NMR (75 MHz,
(5) L-P h en yla la n in e, N-[4-[[[[[2-[[[[4-[[(1,1-Dim eth yl-
eth oxy)car bon yl]am in ocycloh exyl]am in o]th ioxom eth yl]]-
a m in o]et h yl]a m in o]t h ioxom et h yl]a m in o]m et h yl]b en z-
yoyl]-, Meth yl Ester , tr a n s (8). To a solution of 10 (0.40 g,
0.96 mmol) in DCM (50 mL) was added isothiocyanate 3 (0.27
g, 1.06 mmol). The solution was stirred 7 d at room temper-
ature. The DCM was removed under reduced pressure, and
the residue was purified by flash chromatography (DCM/ethyl
acetate, 1:2) to give 0.33 g of a white solid (50%): mp ) 132-
135 °C; 1H NMR (300 MHz, CDCl3) δ 7.47 (d, 2 H), 7.38 (br, 2
H), 7.16 (m, 7 H), 7.07 (d, 2 H), 7.04 (br, 1 H), 6.8 (br, 1 H),
4.90 (q, 2 H), 4.64 (br, 2 H), 4.51 (d, 1 H), 3.65 (s, 3 H), 3.5-
3.3 (br, 4 H), 3.16 (m, 4 H), 1.87 (br, 3 H), 1.33 (s, 9 H), 1.11
(m, 3 H); 13C {1H} NMR (75 MHz, CDCl3) δ 184-178 (br, 2 C),
171.95, 167.46, 155.24, 142.17 (br), 135.82, 132.15, 128.38,
128.41, 127.40, 127.05, 126.94, 79.09, 53.85, 52.29, 48.68, 47.41
(br), 44-41 (br, 3 C), 37.31, 31.48, 30.94, 28.21; HRMS (FAB
m/ z) calcd for C33
H47N6O5S2 (M + H+) 671.3049, obsd 617.3059.
(6) L-P h en yla la n in e, N-[4-[[[[[[2-[[[(4-Am in ocyclo-
h e xyl)a m in o]t h ioxom e t h yl]]a m in o]e t h yl]a m in o]t h i-
oxom eth yl]am in o]m eth yl]ben zyoyl]-, Meth yl Ester , tr a n s
(11). To 8 (0.15 g, 0.22 mmol) in a 25-mL round-bottom flask
was added a solution of TFA (1.5 mL) and water (0.5 mL). The
solution was stirred at room temperature for 1 h. TFA and
water were removed in vacuo. To the resulting glassy solid
was added a solution of ammonium hydroxide (pH 12, 1 M
NaCl). The aqueous solution was decanted, and the residue
was dissolved in THF, dried (Na2SO4), and concentrated under
reduced pressure to afford 0.13 g of a clear glassy solid (98%):
mp 130 °C dec; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (d, 1 H),
8.05 (br, 1 H), 7.81 (br 1 H), 7.73 (d, 2 H), 7.43 (br, 2 H), 7.32
(d, 2 H), 7.25 (m, 3 H), 7.15 (m, 2 H), 4.65 (m, 5 H), 3.62 (s, 3
H), 3.50 (br, 4 H), 3.12 (dd, 2 H), 2.94 (br, 2 H), 1.89, (br, 3 H),
1.32 (m, 3, H); 13C {1H} NMR (75 MHz, DMSO-d6) δ 184-178
(br, 2 C), 172.10, 166.11, 142.96 (br), 137.63, 132.10, 128.98,
128.14, 127.27, 126.83, 126.38, 54.17, 51.85, 48.41, 46.5 (br),
44-41 (br, 3 C), 36.19, 29.68, 29.00; HRMS (FAB m/ z) calcd
for C28H39N6O3S2 (M + H+) 571.2525, obsd 571.2524.