X. Wang et al. / Tetrahedron 73 (2017) 2255e2266
2265
4.10e3.92 (m,1H), 3.73e3.64 (m,1H), 3.60e3.52 (m,1H), 3.46e3.38
(m, 1H), 3.34e3.15 (m, 10H), 2.83 (dd, J ¼ 24.8, 11.5 Hz, 1H),
2.39e2.33 (m, 2H), 2.23e1.94 (m, 4H), 1.84e1.59 (m, 3H), 1.58e1.37
(m, 2H), 1.37e1.15 (m, 4H), 1.09 (dd, J ¼ 11.1, 6.8 Hz, 3H), 1.02 (d,
J ¼ 6.4 Hz, 1H), 0.98e0.66 (m, 18H); 13C NMR (100 MHz, CD3OD)
28.2, 27.1, 26.5, 25.9, 25.5, 24.5, 23.8, 20.1, 19.5, 18.8, 18.5, 16.4, 16.0,
15.6, 15.1, 14.5, 11.0, 11.0; HRMS (ESI; m/z) [MþNa]þ calcd for
C42H63N5O8Na 788.4569, found 788.4570.
5.41. N-H-Leu-Val-Dil-Dap-Phe-OH (19e)
d
177.1, 176.6, 175.1, 174.9, 172.1, 171.9, 169.3, 138.8, 138.7, 130.2,
129.9, 129.7, 129.5, 127.8, 127.7, 86.9, 83.1, 79.8, 79.2, 62.1, 61.5, 60.8,
60.6, 59.3, 59.2, 58.5, 58.3, 57.8, 56.9, 56.7, 54.6, 53.7, 45.3, 38.0,
36.7, 35.8, 33.8, 33.5, 33.0, 28.1, 27.1, 26.5, 25.9, 25.4, 24.5, 23.8, 19.9,
19.3, 19.2, 19.0, 18.9, 17.9, 16.8, 16.3, 16.0, 15.6, 15.2, 15.1, 14.5, 14.3,
11.5, 10.9, 10.9; HRMS (ESI; m/z) [MþH]þ calcd for C38H64N5O8
718.4749, found 718.4743.
Compound 19e was synthesized from 18e according the same
procedure described for 19a, a white solid (21 mg, 93% over 2
25
steps); [
a
]
ꢁ25.7ꢀ (c 0.23, MeOH); 1H NMR (400 MHz, CD3OD)
D
d
7.21e7.02 (m, 5H), 4.67 (d, J ¼ 8.2 Hz, 1H), 4.54 (d, J ¼ 8.9 Hz, 1H),
4.10e3.92 (m, 1H), 3.91e3.80 (m, 1H), 3.76 (d, J ¼ 9.3 Hz, 1H),
3.59e3.55 (m, 1H), 3.48e3.38 (m, 1H), 3.34e3.15 (m, 11H), 3.11 (s,
2H), 3.02 (s, 1H), 2.89e2.76 (m, 1H), 2.48e2.28 (m, 2H), 2.24e1.90
(m, 3H),1.84e1.64 (m, 3H),1.63e1.47 (m, 4H),1.20 (t, J ¼ 7.0 Hz, 3H),
1.09 (dd, J ¼ 13.9, 6.7 Hz, 3H), 1.03e0.72 (m, 20H); 13C NMR
5.38. N-H-Ser-Val-Dil-Dap-Phe-OH (19b)
Compound 19b was synthesized from 18b according the same
(100 MHz, CD3OD) d 177.0, 176.5, 175.1, 174.8, 172.1, 171.9, 170.5,
procedure described for 19a, a white solid (20 mg, 87% over 2
138.9, 131.1, 130.9, 130.81, 130.2, 129.9, 129.7, 129.5, 127.8, 127.7,
126.3, 93.7, 86.9, 83.3, 79.7, 79.2, 62.1, 61.5, 60.8, 60.6, 58.6, 58.4,
57.8, 56.9, 56.7, 52.7, 52.6, 45.3, 43.5, 42.0, 38.1, 38.0, 36.8, 36.6, 33.8,
33.5, 33.1, 33.0, 31.8, 31.7, 30.8, 30.8, 30.6, 30.5, 30.3, 30.3, 28.1, 26.9,
26.5, 25.9, 25.4, 25.3, 24.5, 23.8, 23.2, 23.2, 23.1, 22.2, 22.1, 19.9, 19.3,
19.1, 18.9, 16.4, 16.0, 15.6, 15.1, 14.5, 11.6, 10.9, 10.9; HRMS (ESI; m/z)
[MþH]þ calcd for C39H66N5O8 732.4906, found 732.4902.
25
steps); [
a
]
ꢁ24.0ꢀ (c 0.2, MeOH); 1H NMR (400 MHz, CD3OD)
D
d
7.34e7.09 (m, 5H), 4.81e4.66 (m, 2H), 4.17e3.86 (m, 3H),
3.78e3.62 (m, 2H), 3.60e3.39 (m, 2H), 3.36e3.28 (m, 8H), 3.21 (s,
1H), 3.18e3.05 (m, 2H), 2.95 (dd, J ¼ 25.3, 14.9 Hz, 1H), 2.57e2.09
(m, 4H), 1.96e1.78 (m, 3H), 1.73e1.38 (m, 3H), 1.32 (d, J ¼ 17.0 Hz,
3H), 1.20 (d, J ¼ 8.7 Hz, 3H), 1.13e0.84 (m, 13H); 13C NMR (100 MHz,
CD3OD)
d 177.5, 176.6, 174.8, 174.6, 172.1, 168.1, 138.8, 138.5, 131.1,
130.9,130.8,130.2,129.9,129.7,129.5,127.8, 127.8, 126.3,104.9, 86.9,
82.9, 79.9, 79.2, 64.2, 62.1, 61.9, 61.8, 61.7, 61.0, 60.7, 58.6, 58.3, 57.0,
56.9, 56.0, 54.6, 53.6, 45.3, 38.0, 37.9, 36.7, 33.9, 33.6, 33.1, 32.9, 31.7,
31.5, 30.8, 30.8, 30.6, 30.5, 30.3, 30.3, 28.1, 26.9, 26.5, 26.0, 25.9,
25.3, 24.5, 23.8, 20.1, 19.9, 19.5, 18.8, 18.5, 16.6, 16.5, 16.0, 15.6, 15.4,
14.5, 11.7, 10.9; HRMS (ESI; m/z) [MþNa]þ calcd for C36H59N5O9Na
728.4205, found 728.4194.
5.42. N-H-Asn-Val-Dil-Dap-Phe-OH (19f)
Compound 19f was synthesized from 18f according the same
procedure described for 19a, a white solid (16 mg, 82% over 2
25
steps); [
d
a
]
ꢁ22.8ꢀ (c 0.17, MeOH); 1H NMR (400 MHz, CD3OD)
D
7.21e6.99 (m, 5H), 4.67 (d, J ¼ 6.5 Hz, 1H), 4.53 (d, J ¼ 7.9 Hz, 1H),
4.17 (td, J ¼ 9.4, 3.8 Hz, 1H), 4.01 (d, J ¼ 34.0 Hz, 1H), 3.63e3.51 (m,
1H), 3.46e3.37 (m,1H), 3.33e3.29 (m,1H), 3.23 (d, J ¼ 15.3 Hz,10H),
3.11 (s, 2H), 3.01 (s, 1H), 2.88e2.71 (m, 2H), 2.63e2.52 (m, 1H), 2.38
(d, J ¼ 6.1 Hz, 2H), 2.23e2.07 (m, 2H), 1.93 (d, J ¼ 5.3 Hz, 1H),
1.83e1.62 (m, 3H), 1.60e1.42 (m, 2H), 1.36e1.30 (m, 1H), 1.20 (d,
J ¼ 7.2 Hz, 3H), 1.08 (dd, J ¼ 17.1, 6.6 Hz, 3H), 1.01 (d, J ¼ 6.5 Hz, 2H),
0.97e0.86 (m, 8H), 0.79 (dd, J ¼ 13.7, 6.8 Hz, 4H); 13C NMR
5.39. N-H-Ala-Val-Dil-Dap-Phe-OH (19c)
Compound 19c was synthesized from 18c according the same
procedure described for 19a, a white solid (24 mg, 94% over 2
25
steps); [
d
a
]
ꢁ25.0ꢀ (c 0.12, MeOH); 1H NMR (400 MHz, CD3OD)
D
7.33e7.13 (m, 5H), 4.77 (d, J ¼ 7.2 Hz, 1H), 4.66 (dd, J ¼ 17.4, 8.2 Hz,
(100 MHz, CD3OD) d 176.5, 175.1, 173.6, 172.1, 169.5, 169.4, 138.9,
1H), 4.18e3.96 (m, 2H), 3.67 (s, 1H), 3.59e3.40 (m, 2H), 3.34 (d,
J ¼ 14.7 Hz, 8H), 3.23 (s, 2H), 3.14 (s, 1H), 3.02e2.83 (m, 1H),
2.67e2.39 (m, 2H), 2.38e2.00 (m, 4H), 1.95e1.72 (m, 3H), 1.71e1.50
(m, 3H), 1.50e1.43 (m, 3H), 1.31 (s, 3H), 1.24e1.15 (m, 3H), 1.14e0.84
130.9, 130.8, 130.2, 129.9, 129.7, 129.5, 127.8, 127.7, 126.3, 86.9, 83.4,
79.8, 79.3, 64.3, 62.06, 61.5, 60.8, 60.7, 58.6, 58.4, 57.0, 56.9, 51.0,
51.0, 45.3, 38.1, 38.0, 36.8, 36.5, 36.1, 33.8, 33.6, 33.1, 32.9, 31.6, 31.4,
30.9, 30.6, 30.5, 30.3, 30.2, 28.1, 26.9, 26.5, 25.9, 25.5, 24.5, 23.8,
20.1, 19.5, 18.7, 18.4, 16.5, 16.1, 15.6, 15.0, 14.5, 11.0; HRMS (ESI; m/z)
[MþNa]þ calcd for C37H60N6O9Na 755.4314, found 755.4290.
(m, 14H); 13C NMR (100 MHz, CD3OD)
d 176.6, 174.9, 172.1, 170.8,
138.8, 138.7, 131.1, 130.9, 130.8, 130.2, 129.9, 129.7, 129.5, 128.6,
127.8, 127.73, 126.3, 117.5, 86.9, 83.1, 79.8, 79.2, 64.2, 62.1, 61.5, 60.9,
60.6, 58.6, 58.34, 57.7, 56.9, 56.7, 45.3, 38.0, 36.8, 36.6, 33.8, 33.5,
33.1, 33.0, 31.7, 31.5, 30.8, 30.8, 30.6, 30.5, 30.5, 30.3, 30.3, 28.1, 26.9,
26.9, 26.5, 25.9, 25.4, 24.5, 23.8, 22.1, 20.0, 19.4, 19.0, 18.7, 17.8, 17.7,
16.7, 16.4, 16.0, 15.6, 15.2, 14.5, 10.8, 10.7; HRMS (ESI; m/z) [MþH]þ
calcd for C36H60N5O8 690.4436, found 690.4411.
5.43. N-H-Asp-Val-Dil-Dap-Phe-OH (19g)
LiOH$H2O (3 mg, 0.07 mmol) was added to a solution of 18g
(33 mg, 0.035 mmol) in MeOH (2 mL) and water (1 mL) at room
temperature. After stirring at room temperature for 10 h, the re-
action mixture was concentrated in vacuo and the obtained residue
was redissolved in water (5 mL). The mixture was acidified to
pH ¼ 4e5 by addition of 1 N HCl and a white precipitate was
formed. The solid was collected and dried to afford the free acid
species as a white solid. The obtained solid was dissolved in MeOH
(2.5 mL), 10% palladium on carbon (4 mg) was added to the solu-
tion, followed by stirring at room temperature for 5 h under
hydrogen atmosphere. The reaction mixture was filtered, concen-
5.40. N-H-Phe-Val-Dil-Dap-Phe-OH (19d)
Compound 19d was synthesized from 18d according the same
procedure described for 19a, a white solid (28 mg, 83% over 2
25
steps); [
d
a]
ꢁ22.5ꢀ (c 0.31, MeOH); 1H NMR (400 MHz, CD3OD)
D
7.45e6.96 (m, 10H), 4.72e4.52 (m, 2H), 4.13e3.91 (m, 2H), 3.54 (d,
J ¼ 18.5 Hz, 2H), 3.40 (d, J ¼ 14.5 Hz, 1H), 3.34e3.00 (m, 13H),
2.88e2.73 (m, 2H), 2.40 (d, J ¼ 14.4 Hz, 1H), 2.28e1.89 (m, 3H),
1.87e1.62 (m, 3H), 1.58e1.38 (m, 2H), 1.21 (d, J ¼ 16.7 Hz, 3H),
trated in vacuo to give 19g (22 mg, 87%) as a white solid;
25
[
d
a
]
ꢁ35.8ꢀ (c 0.43, MeOH); 1H NMR (400 MHz, CD3OD)
D
1.15e0.69 (m,16H); 13C NMR (100 MHz, CD3OD)
d
176.6,174.8,172.1,
7.27e7.17 (m, 5H), 4.80 (d, J ¼ 5.6 Hz, 1H), 4.75e4.64 (m, 1H),
169.6, 138.8, 138.7, 135.5, 130.9, 130.8, 130.6, 130.6, 130.2, 130.1,
129.9, 129.7, 129.5, 128.9, 127.9, 127.7, 97.3, 86.9, 83.3, 79.3, 62.1,
61.5, 60.7, 60.7, 58.6, 58.4, 57.9, 56.9, 56.7, 55.4, 54.6, 53.7, 45.3, 38.6,
38.0, 36.8, 33.9, 33.6, 33.1, 33.0, 31.8, 31.6, 30.8, 30.6, 30.5, 30.3, 30.3,
4.26e4.01 (m, 2H), 3.89e3.79 (m, 1H), 3.73e3.51 (m, 2H),
3.46e3.25 (m, 9H), 3.19 (s, 2H), 3.11 (s, 1H), 3.02e2.71 (m, 3H),
2.67e2.43 (m, 2H), 2.38e2.07 (m, 2H), 1.99e1.71 (m, 3H), 1.66e1.60
(m, 1H), 1.58e1.39 (m, 3H), 1.30 (s, 2H), 1.19 (dd, J ¼ 17.1, 6.3 Hz, 3H),