European Journal of Organic Chemistry
10.1002/ejoc.201801640
FULL PAPER
distinctive secondary structures of native dipeptides by acylation
at N-terminal of amino acid and peptides.
129.18, 126.96, 122.65, 102.73, 80.57, 70.74, 52.59, 47.49, 28.20, 17.94,
+
[M+H]+ 433.2104,
1
1.87. HRMS (ESI-TOF) m/z: calcd. for C21
H N O
29 4 6
found 433.2082.
f 2 2
APA-Ile-OMe (7b). R = 0.30 (0.3:9.7 MeOH/CH Cl ); yield 72 %; FT-IR (ν,̃
Experimental Section
-
1
cm ), CHCl
3
: 3417, 3310, 2970, 2937, 1723, 1691, 1518, 1442, 1243,
1
7
6
168, 1048, 757. 1H-NMR (400 MHz, CDCl
3
) δ 7.59 (d, J = 7.8 Hz, 2H),
General procedure of alkylation:
.44 (t, J = 7.8 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H),
.12 (s, 1H), 4.68 (d, J = 4.0 Hz, 2H), 4.61 (dd, J = 9.0, 4.9 Hz, 1H), 3.74
O-alkylated (4), N-alkylated (5) and C-alkylated (6) products. To a stirred
solution of 3 (1.0 g, 3.46 mmol) in AcCN (35 mL) was added anhydrous
(s, 3H), 2.19 (s, 3H), 1.93 – 1.79 (m, 1H), 1.49 (s, 9H), 1.32 (m, J = 21.3,
13.0, 9.4 Hz, 1H), 1.08 – 0.95 (m, 1H), 0.94 – 0.82 (m, 6H). 13C-NMR (101
2
K CO
3
(1.43 g, 10.3 mmol) and stirred for 30 min. Then methyl
MHz, CDCl
3
) δ 172.10, 167.06, 154.97, 147.11, 138.13, 129.26, 127.01,
bromoacetate (0.393 mL, 4.15 mmol) was added dropwise and stirred an
additional 3h. The crude reaction mixture was filtered and concentrated to
dryness under vacuum. The residual yellow oil was purified via
122.75, 102.66, 80.76, 70.68, 55.98, 52.29, 37.60, 28.21, 24.92, 15.47,
11.91, 11.50. HRMS (ESI-TOF) m/z: calcd. for C24
497.2371, found 497.2376.
34 4 6
H N O
Na+ [M+Na]+
2 2
chromatography with 0.5-5 % MeOH in CH Cl to yield 0.749 g (59 %) of
O-alkylated (4), 0.229 g (18.4 %) of N-alkylated (5) and 0.072 g (6 %) of
C-alkylated (6).
APA-Phe-OMe (7c). R
f
= 0.35 (0.3:9.7 MeOH/CH
2
Cl
2
); yield 88 %; FT-IR
-1
(
1
ν,
̃
cm ), CHCl
3
: 3412, 3310, 2981, 2932, 2856, 1744, 1723, 1691, 1604,
518, 1442, 1366, 1248, 1162, 1051, 762. 1H-NMR (400 MHz, CDCl
3
) δ
-
1
O-alkylated (4). R
f
= 0.26 (0.1:19.9 MeOH/CH
2
Cl
2
); FT-IR (ν,
̃
cm ), CHCl
3
:
7.51 (d, J = 7.7 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.32 – 7.21 (m, 4H), 7.09
– 7.01 (m, 2H), 6.80 (d, J = 8.0 Hz, 1H), 5.87 (s, 1H), 4.89 (dd, J = 13.8,
6.7 Hz, 1H), 4.62 (s, 2H), 3.72 (s, 3H), 3.08 (ddd, J = 20.8, 13.9, 6.2 Hz,
2H), 2.18 (s, 3H), 1.48 (s, 9H). 13C-NMR (101 MHz, CDCl
166.99, 155.03, 147.10, 138.09, 135.50, 129.16, 129.04, 128.70, 127.31,
126.96, 122.59, 102.39, 80.65, 70.39, 52.71, 52.50, 37.72, 28.23, 11.88.
HRMS (ESI-TOF) m/z: calcd. for C27
509.2438.
3
1
320, 2975, 2932, 1766, 1718, 1604, 1512, 1447, 1378, 1248, 1162, 1081,
048, 762. H-NMR (400 MHz, CDCl ) δ 7.66 (d, J = 7.8 Hz, 2H), 7.41 (dd,
3
1
J = 10.8, 5.1 Hz, 2H), 7.33 – 7.21 (m, 1H), 5.89 (s, 1H), 4.69 (s, 2H), 3.75
3
) δ 171.58,
(
(
s, 3H), 2.18 (s, 3H), 1.49 (s, 9H). 13C-NMR (101 MHz, CDCl
s), 154.96 (s), 147.34 (s), 146.73 (s), 138.40 (s), 128.93 (s), 126.65 (s),
3
) δ 169.03
+
[M+H]+ 509.2395, found
1
22.48 (s), 102.70 (s), 80.54 (s), 68.09 (s), 52.31 (s), 28.23 (s), 12.02 (s).
H N O
33 4 6
+
[M+H]+ : 362.1710, found
HRMS (ESI-TOF) m/z: calcd. for C18
H N O
24 3 5
o
362.1751. mp: 148-149 C.
APA-Gly-Ile-OMe (7d). R
IR (ν ,̃ cm ), CHCl
3
f
= 0.36 (0.3:9.7 MeOH/CH
: 3304, 2970, 2932, 2878, 1664, 1523, 1453, 1378, 1259,
1162, 1054, 757. 1H-NMR (400 MHz, CDCl
) δ 7.57 (d, J = 7.9 Hz, 2H),
2 2
Cl ); yield 88 %; FT-
-
1
-1
N-alkylated (5). R
f
= 0.05 (0.1:19.9 MeOH/CH
2
Cl
2
); FT-IR (ν,
̃
cm ), CHCl
3
:
3
1
6
250, 2976, 2927, 2851, 1744 1707, 1674, 1637, 1593, 1491, 1366, 1248,
3
1
210, 1162, 1043, 757. H-NMR (400 MHz, CDCl
.04 (s, 1H), 4.21 (s, 2H), 3.66 (s, 3H), 2.26 (s, 3H), 1.48 (s, 9H). 13C-NMR
) δ 167.07 (s), 162.64 (s), 153.81 (s), 148.49 (s), 134.45
s), 129.41 (s), 127.31 (s), 124.54 (s), 110.04 (s), 80.46 (s), 52.46 (s),
3
) δ 7.51 – 7.25 (m, 5H),
7.41 (t, J = 7.8 Hz, 2H), 7.34-7.18 (m, 2H), 6.75 (s, 1H), 6.56 (d, J = 17.0
Hz, 1H), 4.69 – 4.56 (m, 3H), 3.99 (s, 2H), 3.72 (s, 3H), 2.17 (s, 3H), 1.89
(ddd, J = 7.4, 6.9, 5.2 Hz, 1H), 1.54 – 1.34 (m, 10H), 1.33-1.05 (m, 1H),
(101 MHz, CDCl
3
0.95 – 0.84 (m, 6H). 13C-NMR (101 MHz, CDCl
(
3
) δ 172.47, 168.62, 168.24,
4
C
8.40 (s), 28.23 (s), 11.60 (s). HRMS (ESI-TOF) m/z: calcd. for
162.65, 155.34, 147.23, 138.13, 129.10, 126.80, 122.49, 102.79, 80.29,
+
+
o
H N O
18 24 3 5
[M+H] : 362.1710, found 362.1694. mp: 180-182 C.
70.67, 56.66, 52.13, 42.02, 37.63, 28.18, 25.05, 15.44, 11.87, 11.48.
+
[M+H]+ 532.2766, found
HRMS (ESI-TOF) m/z: calcd. for C26
H N O
38 5 7
f 2 2
= 0.39 (0.1:19.9 MeOH/CH Cl
); 1H-NMR (400 MHz,
532.2796.
C-alkylated (6). R
CDCl ) δ 7.89 (d, J = 7.9 Hz, 2H), 7.39 (t, J = 7.9 Hz, 2H), 7.18 (t, J = 7.4
Hz, 1H), 6.22 (s, 1H), 3.75 (s, 3H), 2.66 (d, J = 9.1 Hz, 2H), 2.09 (s, 3H),
.36 (s, 9H). 13C-NMR (101 MHz, CDCl
) δ 171.04 (s), 169.11 (s), 159.32
s), 138.03 (s), 128.83 (s), 125.12 (s), 118.80 (s), 63.29 (s), 37.85 (s),
3
APA-Ile-Gly-OMe (7e). R
f
= 0.35 (0.3:9.7 MeOH/CH
: 3412, 3304, 3072, 2981, 2937, 2884, 1750, 1691, 1658,
2
Cl
2
); yield 88 %; FT-
-1
1
(
3
IR (ν,
̃
cm ), CHCl
3
1
1604, 1518, 1447, 1383, 1248, 1210, 1168, 1059, 762. H-NMR (400 MHz,
2
C
9.70 (s), 28.06 (s), 13.37 (s). HRMS (ESI-TOF) m/z: calcd. for
H N O [M+H] : 362.1710, found 362.1732. mp: 118-120 C.
18 24 3 5
CDCl
3
) δ 7.58 (d, J = 7.8 Hz, 2H), 7.43 (t, J = 7.8 Hz, 2H), 7.29 (t, J = 7.4
+
+
o
Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.65 (s, 1H), 6.32 (s, 1H), 4.63 (s, 2H),
4.45 – 4.32 (m, 1H), 4.02 (ddd, J = 50.5, 18.2, 5.2 Hz, 2H), 3.74 (s, 3H),
2
6
.17 (s, 3H), 1.46 (s, 10H), 1.00 (dd, J = 14.2, 7.9 Hz, 1H), 0.95 – 0.78 (m,
General experimental procedure for compounds, 7a-7e:
H). 13C-NMR (101 MHz, CDCl
) δ 171.47, 169.98, 167.53, 155.22, 147.20,
3
1
38.06, 138.06, 129.20, 126.90, 122.56, 102.91, 80.40, 70.54, 57.02,
Compound 4a, corresponding Amine (TFA or HCl salt form) (1.5
equivalent), HOAT (1.5 equivalent) was dissolved in Dry DMF (1.5 M).
After stirring for 10 min, N-methyl morpholine (3 equivalent) was added
52.19, 41.04, 37.12, 28.17, 24.57, 15.27, 11.86, 11.15. HRMS (ESI-TOF)
+
+
37 5 7
m/z: calcd. for C26H N O Na [M+Na] 554.2585, found 554.2567.
o
drop wise and cooled the temperature to 0 C and added EDC.HCl. After
o
2
0 min allowed to warm to rt followed by heating at 60 C for 8h. The crude
reaction mixture was evaporated under reduced pressure. The resultant
crude was purified by column chromatography with MeOH in CH Cl (1-
%).
Acknowledgments
2
2
3
AB is thankful to UGC & NISER for fellowship and also thanks to
Tiwari Ranjay Kumar and Dr. C. S. Purohit for helping in X-ray
studies.
APA-Ala-OMe (7a).R
f
= 0.30 (0.3:9.7 MeOH/CH
: 3315, 2981, 1744, 1691, 1513, 1454, 1254, 1173, 1059, 762.
) δ 7.59 (d, J = 7.7 Hz, 2H), 7.44 (t, J = 7.9 Hz,
2 2
Cl ); yield 72 %; FT-IR (ν,̃
-
1
cm ), CHCl
H-NMR (400 MHz, CDCl
3
1
3
2
4
3
H), 7.31 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.07 (s, 1H), 4.72 –
Keywords: Peptides 1 • Amino Acids 2 • 4-Aminopyrazoles 3 •
Synthetic methods 4 • Conformational analysis 5
.55 (m, 3H), 3.76 (s, 3H), 2.19 (s, 3H), 1.48 (s, 9H), 1.36 (d, J = 7.2 Hz,
H). 13C-NMR (101 MHz, CDCl
3
) δ 173.00, 166.99, 155.00, 147.06, 138.11,
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