Notes
R]25
-10.3 (c 1.0, MeCN); HPLC t
J . Org. Chem., Vol. 64, No. 23, 1999 8705
[
3
D
R
10.63 min (linear gradient,
CN) δ 1.26-1.47
3.81-3.85 (m, 1H), 7.16-7.34 (m, 10H); 13C NMR (50 MHz, CD
-
3
1
0-100% B, 20 min); H NMR (200 MHz, CD
3
OD) δ 158.8, 158.6, 141.3, 140.1, 130.8, 130.2, 129.8, 127.7, 123.9,
120.7, 80.4, 54.6, 44.8, 40.3, 29.1, 28.8; MS (MALDI-TOF) m/z
(
3
1
m, 6H), 1.41 (s, 9H), 2.73 (s, 4H), 3.05-3.30 (m, 4H), 3.57-
+
+
+
.66 (m, 1H), 5.14 (s, 2H), 5.24 (br d, J ) 8 Hz, 1H), 5.73 (br t,
H), 6.52 (br t, 1H), 7.18-7.47 (m, 4H); 13C NMR (50 MHz, CD
408 [M + K] , 392 [M + Na] , 370 [M + 1] . Anal. Calcd for
3
-
21 27 3 3
C H N O
: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.19; H,
CN) δ 171.7, 157.0, 153.1, 130.5, 130.4, 128.2, 118.3, 79.6, 64.1,
5
m/z 579.9 [M + K] , 563.5 [M + Na] . Anal. Calcd for C24
ClN : C, 53.28; H, 6.15; N, 10.36. Found: C, 53.37; H, 6.12;
N, 10.33.
7.32; N, 11.47.
u
1.5, 46.6, 41.3, 32.4, 30.3, 28.7, 26.3, 23.6; MS (MALDI-TOF)
Boc-F CH -P r o-NH , 7d . Carbamate 4d (1.16 g, 3 mmol) was
2
2
+
+
H
33
-
reacted with HCl‚H-Pro-NH2 (540 mg, 3.6 mmol) according to
4
O
8
the general procedure. Flash chromatography (CHCl /MeOH
3
2
5
10:1) yielded 7d (1.16 g, 88%): white solid; mp 96-98 °C; [R]
D
O-Su ccin im idyl-(2-n itr oph en yl)car bam ate (6). 2-Nitroben-
zoic acid (1.17 g, 7 mmol) was transformed according to the
general procedure for the preparation of 4. The solvent was
removed in vacuo, and recrystallization from EtOAc yielded 6
-20.4 (c 1.02, MeOH); HPLC t 10.02 min (linear gradient, 20-
R
80% B, 20 min); 1H NMR (200 MHz, CD OD) δ 1.36 (s, 9H),
3
1.88-2.17 (m, 4H), 2.59-2.83 (m, 2H), 2.96 (dd, J ) 9.4, 13.6
Hz, 1H), 3.21-3.50 (m, 3H), 3.89-3.99 (m, 1H), 4.29 (dd, J )
3.2, 8.1 Hz, 1H), 7.11-7.29 (m, 5H); 13C NMR (100 MHz, CDCl )
(
9
1.39 g, 71%): light yellow crystals; mp 166-167 °C; HPLC t
R
3
.45 min (linear gradient, 20-80% B, 20 min); 1H NMR (200
δ 175.4, 157.8, 156.6, 137.4, 129.2, 128.6, 126.6, 79.6, 60.1, 51.6,
46.3, 45.7, 39.0, 28.8, 28.4, 24.7; MS (MALDI-TOF) m/z 429
MHz, CDCl ) δ 2.89 (s, 4H), 7.26 (dt, 1H), 7.69 (dt, 1H), 8.26
3
13
+
+
+
(dd, 1H), 8.40 (dd, 1H), 10.40 (br s); C NMR (50 MHz, CDCl
3
)
[M + K] , 413 [M + Na] , 391 [M + 1] . Anal. Calcd for
δ 169.2, 148.5, 136.2, 133.1, 126.2, 124.1, 120.8, 25.6; MS
C
H
30
N O : C, 61.52; H, 7.74. Found: C, 61.78; H, 7.77.
Boc-A CH -A CH -i-P r , 8. Compound 7b (650 mg, 2.5 mmol)
2 2
2
0
4
u
4
+
+
u
(
MALDI-TOF) m/z 318 [M + K] , 302 [M + Na] . Anal. Calcd
for C12 : C, 47.32; H, 3.25; N, 15.05. Found: C, 47.45;
H
10
N
2
O
6
was dissolved in TFA (0.25M) at 0 °C. After stirring at room
temperature for 30 min and concentration under reduced
pressure, the crude trifluoroacetate salt was dried in vacuo over
KOH and used without further purification. Carbamate 4b was
then reacted with a solution of the trifluoroacetate salt in DMF
according to the general procedure. Recrystallization from EtOH/
H, 3.26; N, 15.07.
Ur ea F or m a tion : Gen er a l P r oced u r e. To a stirred solu-
tion of the amine (1.3 mmol) in 5 mL of DMF were successively
added O-succinimidyl carbamate 4 (1 mmol) and Hunig’s base
(
1 mmol). After 10-30 min, the mixture was diluted with
saturated NaHCO and extracted with EtOAc. The organic layer
was washed with 1 N KHSO , brine, saturated NaHCO and
brine, dried (MgSO ), and evaporated. Flash chromatography
3
hexane yielded 8 (630 mg, 70%): white solid; mp 184-185 °C,
[R]25 +9.3 (c 0.88, MeOH); HPLC t 8.52 min (linear gradient,
4
3
D
R
1
4
20-80% B, 20 min);
H NMR (200 MHz, CD OD) δ 1.05-1.12
3
and/or recrystallization afforded pure urea 7.
Meth yl (2S)-2-{[2-(ter t-Bu toxyca r bon yla m in o)eth yl]u r e-
id o}-4-m eth ylp en ta n oa te (Boc-G CH
(m, 12H), 1.42 (s, 9H), 2.92-3.24 (m, 4H), 3.56-3.84 (m, 2H);
13C NMR (100 MHz, CD OD) δ 160.9, 160.7, 158.2, 80.0, 48.2,
3
u
2
-Leu -OMe, 7a ). Car-
47.8, 46.8, 46.4, 42.9, 28.5, 23.6, 23.5, 19.1, 18.6. Anal. Calcd
for C16H33N O : C, 53.46; H, 9.25; N, 19.48. Found: C, 53.62;
bamate 4a (602 mg, 2 mmol) was reacted with HCl‚H-Leu-OMe
436 mg, 2.4 mmol) according to the general procedure. Recrys-
tallization from EtOAc/diisopropyl ether yielded 7a (520 mg,
8%): colorless needles; mp 86-89 °C; [R]25
-10.8 (c 1.02,
MeOH); HPLC t 11.39 min (linear gradient, 20-80% B, 20 min);
H NMR (200 MHz, CDCl ) δ 0.90 (d, J ) 6.4 Hz, 3H), 0.91 (d,
5
4
(
H, 9.29; N, 19.43.
u
u
u
Boc-A CH
2 2 2
-A CH -A CH -i-P r , 9. Compound 8 (440 mg,
7
D
1
.22 mmol) was dissolved in TFA (0.25 M) at 0 °C. After stirring
at room temperature for 30 min and concentration under reduced
pressure, the crude trifluoroacetate salt that precipitated upon
R
1
3
J ) 6.2 Hz, 3H), 1.41 (s, 9H), 1.45-1.75 (m, 3H), 3.16-3.32 (m,
2
addition of Et O was collected by filtration, dried in vacuo over
4
6
H), 3.69 (s, 3H), 4.36-4.47 (m, 1H), 5.34 (br t, J ) 5.2, 1H),
KOH, and used without further purification. To a solution of
the trifluoroacetate salt in DMF were successively added 4b and
Hunig’s base (637 µL, 3.66 mmol). The reaction mixture was
.14 (d, J ) 8.2, 1H), 6.76 (br t, J ) 5.0, 1H); 13C NMR (50 MHz,
3
CDCl ) δ 175.3, 158.5, 156.7, 79.4, 52.1, 51.7, 41.8, 41.3, 40.3,
2
+
8.4, 24.8, 22.9, 21.9; MS (MALDI-TOF) m/z 370 [M + K] , 354
stirred for 20 min, and saturated NaHCO
3
was added. The
+
+
[
M + Na] , 332 [M + 1] . Anal. Calcd for C15
C, 52.94; H, 8.82; N, 12.35. Found: C, 52.92; H, 8.68; N, 12.27.
2S)-1-[2-(ter t-Bu toxyca r bon yla m in o)p r op yl]-3-(1-m eth -
H
29
N
3
O
5
‚0.5H
2
O:
precipitate that formed was filtered, washed with saturated
NaHCO
3
, water, and Et
(350 mg, 62%): white solid; mp 210-211 °C, [R]
.00, MeOH); HPLC t
2
O, and dried in vacuo over P
2
O
D
5
to yield
+63.6 (c
(
25
9
u
yleth yl)u r ea (Boc-A CH
.86 mmol) was reacted with i-PrNH
to the general procedure to yield 7b (701 mg, 95%): white solid;
2
-i-P r , 7b). Carbamate 4b (901 mg,
1
R
8.53 min (linear gradient, 20-80% B, 20
OD) δ 1.03-1.12 (m, 15H), 1.44
s, 9H), 2.55-2.85 (m, 3H), 3.21-3.39 (m, 3H), 3.61-3.95 (m,
2
2
(511 µL, 6 mmol) according
1
min); H NMR (200 MHz, CD
3
(
2
5
mp 101 °C; [R]
D
-7.4 (c 0.89, MeOH); HPLC t
R
8.71 min (linear
CN) δ
.03 (d, J ) 6.6 Hz, 3H), 1.07 (d, J ) 6.5 Hz, 6H), 1.40 (s, 9H),
.02-3.08 (m, 2H), 3.47-3.60 (m, 1H), 3.65-3.81 (m, 1H), 4.92
13
4
8
1
4
2
H); C NMR (100 MHz, CD
0.3, 48.2, 47.6, 47.5, 47.2, 47.1, 46.8, 43.0, 29.0, 23.8, 23.7, 19.5,
3
OD) δ 161.2, 161.1, 160.9, 158.7,
1
gradient, 20-80% B, 20 min); H NMR (200 MHz, CD
3
1
3
+
+
9.0, 18.7; MS (MALDI-TOF) m/z 499 [M + K] , 483 [M + Na] ,
+
61 [M + 1] . Anal. Calcd for C20
41 7 5
H N O : C, 52.27; H, 8.99; N,
1
3
(br d, 1H); 5.1 (br t, 1H), 5.66 (br, 1H); C NMR (50 MHz, CD
3
-
1.33. Found: C, 52.23; H, 9.00; N, 20.93.
CN) δ 158.4, 156.4, 79.4, 47.7, 46.2, 42.2, 28.5, 23.4, 23.3, 18.6;
+
+
MS (MALDI-TOF) m/z 298 [M + K] , 282 [M + Na] . Anal. Calcd
for C12 : C, 55.57; H, 9.72; N, 16.20. Found: C, 55.56;
H, 9.82; N, 16.16.
2S)-1-[2-(ter t-Bu toxyca r bon yla m in o)-3-p h en ylp r op yl]-
Ack n ow led gm en t. The authors greatly acknowl-
25 3 3
H N O
edge Prof. Dr. Seebach for critically reading the manu-
script. This work was supported in part from the Centre
National de la Recherche Scientifique (Programme
“physique et Chimie du Vivant”).
(
u
3
1
-p h en ylu r ea (Boc-F CH
2
-P h , 7c). Carbamate 4d (500 mg,
(119 mg, 1.28 mmol)
.28 mmol) was reacted with PhNH
2
according to the general procedure. Recrystallization from CH
Cl /hexane yielded 7c (412 mg, 87%): white solid; mp 154 °C;
R]25
+10.3 (c 1.03, MeOH); HPLC t 15.23 min (linear gradient,
OD) δ 1.35 (s, 9H),
2
-
2
Su p p or tin g In for m a tion Ava ila ble: Crystal data for
compound 6. This material is available free of charge via the
Internet at http://pubs.acs.org.
[
D
R
1
2
2
3
0-80% B, 20 min); H NMR (200 MHz, CD
3
.70 (dd, J ) 8.0, 13.7 Hz, 1H), 2.80 (dd, J ) 7.8, 13.7 Hz, 1H),
.16 (dd, J ) 8.6, 13.6 Hz, 1H), 3.33 (dd, J ) 4.6, 17.1 Hz, 1H),
J O990092E