The Journal of Organic Chemistry
Page 8 of 14
55.4, 48.6, 47.2, 37.3, 23.9, 15.7, 14.1, 11.2; HRMS-ESI (m/z):
(benzyloxy)glycine 4 (700 mg, 3.14 mmol, 1.0 eq.), HATU
[M+H]+ calcd for C32H37N2O6, 545.2646; found, 545.2631 (- 2.8
ppm).
(1.79 g, 4.71 mmol, 1.5 eq.) and HOAt (641 mg, 4.71 mmol,
1.5 eq.) were solubilized in DMF (8.0 mL) under argon. DIPEA
(609 mg, 4.71 mmol, 1.5 eq.) was added to the mixture which
was preactivated 5 min at RT. H-Ile-OtBu (1.40 g, 6.28 mmol,
2.0 eq.) was then added and stirred 15 h at RT. The reaction
progress was monitored by TLC. CH2Cl2 (10 mL) was added
and the mixture was washed successively with a citric acid
solution (15 mL, 5% w/w), then saturated NaHCO3 solution (15
mL) and saturated brine (15 mL). The organic layer was dried
over Na2SO4, filtrated, and the solvent evaporated under
reduced pressure to afford the crude product 11c in a pure form
as a yellow oily solid (841.5 mg, 2.1 mmol, 68% yield). Rf = 0.4
[α]18
1
2
3
4
5
6
7
8
General procedure B, for the coupling of 4 with t-butyl -
amino ester residues: Carboxylic acid 4 (1.0 mmol, 1.0 eq.)
and the H-AA-OtBu (1.2 mmol, 1.2 eq.) were solubilized in
CH2Cl2 (5.0 mL) under argon and cooled down to 0 °C. EDCi
(1.2 mmol, 1.2 eq.) and HOBt (1.2 mmol, 1.2 eq.) were added
to the mixture. DIPEA (2.0 mmol, 2.0 eq.) was added to the
mixture which was stirred 15 h at RT. The reaction progress
was monitored by TLC. CH2Cl2 (5.0 mL) was added and the
mixture was washed successively with a citric acid solution (10
mL, 5% w/w), then saturated NaHCO3 solution (10 mL) and
saturated brine (10 mL). The organic layer was dried over
Na2SO4, filtrated, and the solvent evaporated under reduced
pressure to afford the crude product 11a-b which was purified
by chromatography.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(hexanes/EtOAc 1:1 v/v);
-21.7 (c 1.00, MeOH); IR (dry
D
film) max: 3358, 3276, 2962, 2932, 2873, 1735, 1720, 1689,
1650, 1556, 1536, 1448, 1412, 1391, 1365, 1287, 1257, 1151,
1133, 1079, 1028, 1009, 973, 948, 809, 737, 697 cm-1; 1H NMR
(400 MHz, CDCl3, ): 7.38 (s, 5H), 6.66 (d, J = 8.1 Hz, 1H),
4.92 (s, 2H), 4.47 (dd, J = 8.5, 4.5 Hz, 1H), 4.34 (d, J = 16.5
Hz, 1H), 4.23 (d, J = 16.5 Hz, 1H), 2.14 (s, 3H), 1.87 (m, 1H),
1.58 (m, 1H), 1.45 (s, 9H), 1.15 (m, 1H), 0.92 (t, J = 7.4 Hz,
3H), 0.89 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3,
): 173.8, 170.5, 167.4, 134.1, 129.4 (2C),129.1, 128.8 (2C),
82.1, 77.2, 56.9, 52.0, 38.1, 28.1 (3C), 25.3, 20.3, 15.3, 11.7;
HRMS-ESI (m/z): [M+Na]+ calcd for C21H32N2O5Na,
415.2203; found, 415.2204 (+ 0.2 ppm).
Ac-N(OBn)-Gly-N(Me)-Tert-Butyl-Glycinate (11a) was
prepared according to the general
procedure B, using N-acetyl-N-
(benzyloxy)glycine 4 (100 mg, 0.45
mmol, 1.0 eq.) and H-Sar-OtBu
(98 mg, 0.54 mmol, 1.2 eq.). The
crude product was purified by
chromatography (Ether/EtOAc 1:1
OBn O
N
OtBu
Ac
N
O
11a
C18H26N2O5
MW 350.18 g.mol-1
v/v) to afford 11a in a pure form as an uncolored oil (106 mg,
0.30 mmol, 67% yield). Rf = 0.2 (hexanes/EtOAc 1:1 v/v);
IR (dry film) max: 2980, 2937, 2865, 1737, 1658, 1454, 1367,
1227, 1154, 1119, 1055, 1032, 1013, 846, 747, 700 cm-1;
Product 11a was characterized as a mixture of cis-trans
rotamers in a ratio 2:5 by 1H – 13C HSQC: 1H NMR (400 MHz,
CDCl3, ) trans rotamer: 7.39 (m, 5H), 4.93 (s, 2H), 4.41 (s,
2H), 4.04 (s, 2H), 2.99 (s, 3H), 2.16 (s, 3H), 1.45 (s, 9H); cis
rotamer: 7.39 (m, 5H), 4.93 (s, 2H), 4.33 (s, 2H), 3.91 (s, 2H),
2.98 (s, 3H), 2.14 (s, 3H), 1.48 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3, ) trans rotamer: 175.1, 168.0, 167.2, 134.9,
129.5 (2C),128.9, 128.7 (2C), 82.0, 77.3, 50.3, 50.0, 35.6, 28.1,
20.4; cis rotamer: 175.1, 167.7, 167.4, 134.8, 129.5 (2C),128.9,
128.7 (2C), 82.9, 77.2, 52.1, 49.8, 35.4, 28.0 (3C), 20.4;
HRMS-ESI (m/z): [M+H]+ calcd for C18H27N2O5, 351.1914;
found, 351.1911 (- 0.9 ppm).
Fmoc-N(OBn)-Gly-Tert-Butyl-Isoleucinate (11d). N-Fmoc-
N-(benzyloxy)glycine 5 (500 mg,
1.24 mmol, 1.0 eq.) and EEDQ
OBn O
(460 mg, 1.86 mmol, 1.5 eq.)
N
OtBu
Fmoc
N
were solubilized in CH2Cl2 (3.0
mL) under argon. The mixture
was preactivated 5 min at RT. H-
Ile-OtBu (832 mg, 3.72 mmol,
3.0 eq.) was then added and
H
O
11d
C34H40N2O6
MW 572.29 g.mol-1
stirred 5 h at RT. The reaction progress was monitored by TLC.
CH2Cl2 (3.0 mL) was added and the mixture was washed
successively with a citric acid solution (10 mL, 5% w/w), then
saturated NaHCO3 solution (10 mL) and saturated brine (10
mL). The organic layer was dried over Na2SO4, filtrated, and
the solvent evaporated under reduced pressure to afford the
crude product 11d in a pure form as a yellow oily solid (618
mg, 1.08 mmol, 87% yield). Rf = 0.3 (hexanes/EtOAc 4:1 v/v);
Ac-N(OBn)-Gly-Tert-Butyl-Glycinate (11b) was prepared
according to the general procedure
OBn O
[α]1D8
-10.1 (c 1.00, MeOH); IR (dry film) max: 3343, 3067,
B,
using
N-acetyl-N-
N
OtBu
2965, 2936, 2880, 1725, 1685, 1523, 1451, 1414, 1392, 1368,
1340, 1249, 1216, 1143, 1092, 984, 912, 846, 757, 738, 698,
621 cm-1; 1H NMR (400 MHz, CDCl3, ): 7.75 (d, J = 7.5 Hz,
1H), 7.62 (m, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.32 (m, 7H), 6.55
(d, J = 8.4 Hz, 1H), 4.85 (s, 2H), 4.59 (dd, J = 6.6, 2.8 Hz, 2H),
4.48 (dd, J = 8.5, 4.5 Hz, 1H), 4.28 (t, J = 6.6 Hz, 1H), 4.14 (d,
J = 17.2 Hz, 1H), 4.03 (d, J = 17.2 Hz, 1H), 1.84 (m, 1H), 1.42
(s, 9H), 1.40 (m, 1H), 1.11 (m, 1H), 0.86 (m, 6H); 13C{1H}
NMR (100 MHz, CDCl3, ): 170.5, 167.4, 157.5, 143.5 (2C),
141.4 (2C) 134.9, 129.4 (2C),128.7, 128.5 (2C), 127.8 (2C),
127.2 (2C), 125.1 (2C), 120.0 (2C), 82.1, 77.2, 68.3, 56.8, 54.3,
47.1, 38.2, 28.0 (3C), 25.3, 15.3, 11.7; HRMS-ESI (m/z):
[M+Na]+ calcd for C34H40N2O6Na, 595.2779; found, 595.2763
(- 2.7 ppm).
Ac
N
H
(benzyloxy)glycine 4 (500 mg, 2.24
mmol, 1.0 eq.) and H-Gly-OtBu
(376 mg, 2.69 mmol, 1.2 eq.). The
crude product was purified by
chromatography (Hexanes/EtOAc
O
11b
C17H24N2O5
MW 336.17 g.mol-1
1:1 v/v) to afford 11b in a pure form as a yellowish oil (604 mg,
1.80 mmol, 67% yield). Rf = 0.3 (hexanes/EtOAc 1:1 v/v); IR
(dry film) max: 3288, 2980, 2941, 2865, 1736, 1685, 1620,
1545, 1454, 1404, 1364, 1223, 1154, 1055, 1033, 1016, 961,
853, 753, 697, 641 cm-1; 1H NMR (400 MHz, CDCl3, ): 7.39
(s, 5H), 6.61 (br, 1H), 4.93 (s, 2H), 4.30 (s, 2H), 3.93 (d, J = 5.1
Hz, 2H), 2.14 (s, 3H), 1.46 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3, ): 173.8, 168.5, 167.8, 134.1, 129.5 (2C),129.2, 128.8
(2C), 82.4, 77.4, 51.9, 42.0, 28.0 (3C), 20.3; HRMS-ESI (m/z):
[M+H]+ Calcd for C17H25N2O5, 337.1758; found, 337.1754 (-
1.2 ppm).
General procedure C, for the coupling of 6a or 6b with
11a-c: t-Butyl protected dipeptide 11a-c (1.0 mmol, 1.0 eq.)
was solubilized in dichloromethane (5.0 mL) and cooled down
to 0 °C. Trifluoroacetic acid (5.0 mL) was added dropwise, the
Ac-N(OBn)-Gly-Tert-Butyl-
Isoleucinate (11c). N-acetyl-N-
OBn O
N
OtBu
Ac
N
H
O
ACS Paragon Plus Environment
11c
C21H32N2O5
MW 392.23 g.mol-1