6638
N.-N. Liu et al. / Tetrahedron 70 (2014) 6630e6640
acetone-d6):
d
175.35, 173.42, 172.55, 172.55, 171.82, 171.43, 156.26,
4.18.1. Compound 4. Purification by HPLC (MeCN/H2O: 43:57) to
156.08, 156.04, 141.60, 140.03, 136.70, 130.19, 129.50, 129.39, 128.73,
127.79, 127.50, 127.06, 123.03, 121.33, 118.78, 118.29, 111.67, 111.34,
111.34, 110.87, 79.11, 55.81, 55.27, 55.19, 55.01, 55.01, 51.67, 50.92,
50.76, 50.59, 34.19, 34.02, 27.85, 27.85, 27.85, 26.06, 16.59, 16.40,
15.90. HRMS (ESI-TOF) m/z calcd for C46H57N7O11Na [MþNa]þ
906.4008, found 906.4005.
give compound 4 (66%) as a colorless, amorphous solid.
Mp 200e201 ꢀC; IR nmax (cmꢂ1): 3425, 3063, 2976, 2935, 1650, 1511,
1456, 1403, 1381, 1322, 1266, 1250, 1165, 1130, 1024, 922, 796, 746,
701. 1H NMR (400 MHz, CDCl3):
d
8.50 (1H, d, J¼8.8 Hz, Tyr6-NH),
8.43 (1H, d, J¼6.4 Hz, Ala4-NH), 7.30 (1H, d, J¼5.2 Hz, Ala2-NH), 7.20
d
d
(1H, dd, J¼8.4, 2.0 Hz, Tyr6 a-H), 7.07e7.05 (2H, m, Tyr5 b-H and
D-
Ala1-NH), 6.95 (2H, d, J¼8.4 Hz, Tyr3d-H), 6.88 (1H, d, J¼8.0 Hz,
Tyr5 3 b-H), 6.82 (1H, d, J¼8.4 Hz, Tyr6 3 a-H), 6.75 (1H, d, J¼2.0 Hz,
4.17.4. Compound 47. Yield 67%. Colorless foam. IR nmax (cmꢂ1):
3493, 3308, 2976, 2937, 2839, 2349, 2320, 2242, 1740, 1660, 1509,
1450, 1367, 1256, 1168, 1053, 1026, 915, 857, 788, 730. 1H NMR
d
3
Tyr6 b-H), 6.63 (2H, d, J¼8.4 Hz, Tyr3 -H), 6. 59 (1H, d, J¼2.4 Hz,
d
Tyr5 a-H), 6.17 (1H, d, J¼7.6 Hz, Tyr3-NH), 5.72 (1H, d, J¼7.2 Hz,
(400 MHz, acetone-d6):
d
7.71 (2H, s), 7.54 (1H, br s), 7.17e7.13 (2H,
Tyr5-NH), 4.63e4.58 (1H, m, Tyr3a-H), 4.56e4.54 (1H, m, Tyr5a-H),
a
m), 7.06 (1H, d, J¼7.6 Hz), 6.83 (2H, d, J¼8.0 Hz), 6.69 (1H, s),
6.27e6.17 (1H, m), 4.81 (1H, br s), 4.45 (1H, t, J¼10.0 Hz), 4.22e4.19
(1H, m), 4.14 (2H, m), 4.05 (1H, t, J¼10.0 Hz), 3.83 (3H, s), 3.80 (3H,
s), 3.64 (3H, s), 3.56 (1H, d, J¼13.6 Hz), 3.43e3.41 (1H, m),
3.02e2.96 (1H, m), 2.88 (1H, d, J¼13.6 Hz), 2.49 (1H, dd, J¼14.0,
4.4 Hz), 2.05e2.02 (3H, m), 1.93e1.91 (1H, m), 1.82e1.77 (2H, m),
1.38 (9H, s), 1.35 (3H, d, J¼7.6 Hz), 1.32 (3H, d, J¼6.8 Hz), 1.18 (3H, d,
4.49e4.39 (2H, m,
D
-Ala1a-H and Tyr6a-H), 4.08e4.02 (1H, m, Ala2
-
H), 3.97 (3H, s, Tyr5-OCH3), 3.87 (3H, s, Tyr6-OCH3), 3.76 (1H, d,
J¼14.0 Hz, Tyr5b-Hb), 3.68e3.65 (1H, m, Ala4a-H), 3.59 (3H, s, Tyr3-
OCH3), 3.31e3.28 (1H, m, Tyr6b-Hb), 2.99 (1H, d, J¼12.8 Hz, Tyr6
-
b
Ha), 2.91 (1H, dd, J¼13.2, 5.2 Hz, Tyr3b-Hb), 2.76 (1H, dd, J¼13.2,
8.8 Hz, Tyr3b-Ha), 2.58 (1H, dd, J¼14.0, 5.6 Hz, Tyr5b-Ha), 1.36 (3H, d,
J¼7.2 Hz, Ala2b-H), 1.25 (3H, d, J¼6.8 Hz,
D
-Ala1b-H), 0.88 (3H, d,
J¼6.8 Hz). 13C NMR (100 MHz, acetone-d6):
d
173.23, 172.97, 172.05,
J¼6.4 Hz, Ala4b-H). 13C NMR (100 MHz, CDCl3):
d
172.56 (Ala2-C]O),
171.81, 171.69, 171.36, 156.12, 156.03, 155.41, 141.29, 140.17, 130.19,
129.52, 128.85, 128.65, 128.05, 127.17, 111.32, 111.15, 78.55, 60.50,
55.70, 55.16, 55.09, 54.89, 51.71, 50.85, 49.90, 48.65, 47.06, 33.80,
33.80, 28.36, 27.70, 27.70, 27.70, 25.07, 17.79, 16.52, 15.78. HRMS
(ESI-TOF) m/z calcd for C40H54N6O11Na [MþNa]þ 817.3742, found
817.3745.
172.54 (Tyr6-C]O),172.38 ( -Ala1-C]O),171.98 (Ala4-C]O), 171.51
D
(Tyr3-C]O), 171.48 (Tyr5-C]O), 158.43 (Tyr3z-C), 156.23 (Tyr5z-C),
156.15 (Tyr6z-C), 140.71 (Tyr6 and Tyr5 a-C), 131.21 (Tyr5 3 a-C),
d
b
d
130.82 (Tyr3d-C), 129.08 (Tyr6 a-C), 128.88 (Tyr6g-C), 128.69 (Tyr5
-
d
db
C), 128.30 (Tyr6 3 b-C), 127.90 (Tyr3g-C), 126.28 (Tyr5g-C), 113.50
3
(Tyr3 -C), 112.09 (Tyr5 3 b-C), 111.60 (Tyr6 3 a-C), 56.96 (Tyr6a-C), 56.45
(Tyr5-OCH3), 56.22 (Tyr6-OCH3), 55.67 (Tyr5a-C), 55.11 (Tyr3-OCH3),
4.17.5. Compound 48. Yield 88%. Colorless foam. IR nmax (cmꢂ1):
3505, 3399, 3310, 2978, 2840, 2349, 2324, 2246, 1736, 1659, 1511,
1450, 1371, 1257, 1168, 1057, 1025, 913, 854, 803, 729. 1H NMR
53.78 (Tyr3a-C), 51.29 (Ala2a-C), 50.40 (Ala4a-C), 47.90 ( -Ala1a-C),
D
38.12 (Tyr3b-C), 33.62 (Tyr6b-C), 33.47 (Tyr5b-C), 17.22 (Ala2b-C),
15.13 (Ala4b-C), 14.54 ( -Ala1b-C). HRMS (ESI-TOF) m/z calcd for
39H46N6O9 [M]þ 742.3326, found 742.3321.
D
(400 MHz, Acetone-d6):
d
7.78 (1H, s), 7.72 (1H, d, J¼8.4 Hz), 7.63
C
(1H, br s), 7.17 (1H, d, J¼7.2 Hz), 7.11 (1H, d, J¼6.8 Hz), 6.97 (2H, br
s), 6.86 (1H, d, J¼7.6 Hz), 6.66 (1H, s), 6.31 (1H, br s), 6.06 (1H, d,
J¼7.2 Hz), 4.77 (1H, br s), 4.44 (1H, m), 4.18 (1H, br s), 4.05 (1H, br
s), 3.96e3.94 (1H, m), 3.88 (3H, s), 3.81 (3H, s), 3.69e3.64 (4H,
m), 3.14e3.08 (1H, m), 2.95 (1H, d, J¼13.2 Hz), 2.51 (1H, d,
J¼9.6 Hz), 1.43 (9H, s), 1.38 (3H, d, J¼6.4 Hz), 1.26 (3H, d,
J¼6.0 Hz), 1.11 (3H, d, J¼6.4 Hz). 13C NMR (100 MHz, acetone-d6):
4.18.2. Compound 5. Purification by HPLC (MeCN/H2O: 43:57) to
give compound
5 (69%) as a colorless, amorphous solid.
Mp 192e193 ꢀC; IR nmax (cmꢂ1): 3423, 2976, 2935, 1650, 1512, 1459,
1381, 1320, 1266, 1248, 1178, 1166, 1139, 1027, 888, 816, 719. 1H NMR
(400 MHz, CDCl3):
d
8.50 (1H, d, J¼8.8 Hz, Tyr6-NH), 8.36 (1H, d,
J¼6.0 Hz, Ala4-NH), 7.29 (1H, d, J¼5.2 Hz, Ala2-NH), 7.20 (1H, dd,
d
3
z
d
174.30, 173.07, 171.74, 171.46, 171.22, 156.26, 156.15, 155.81,
J¼8.4, 2.0 Hz, Tyr6 a-H), 7.10e7.05 (7H, m, Phe3d-H, Phe3 -H, Phe3
-
d
140.89, 139.93, 130.53, 129.31, 129.31, 128.92, 128.02, 126.99,
111.84, 111.45, 78.83, 55.72, 55.23, 55.10, 54.61, 51.66, 51.17, 50.59,
48.59, 34.11, 33.65, 27.80, 27.80, 27.80, 16.88, 16.36, 16.11. HRMS
(ESI-TOF) m/z calcd for C35H47N5O10Na [MþNa]þ 720.3215, found
720.3218.
H,
D
-Ala1-NH and Tyr5 b-H), 6.88 (1H, d, J¼8.0 Hz, Tyr5 3 b-H), 6.83
(1H, d, J¼8.4 Hz, Tyr6 3 a-H), 6.77 (1H, d, J¼2.0 Hz, Tyr6 b-H), 6.60 (1H,
d
d, J¼2.0 Hz, Tyr5 a-H), 6.21 (1H, d, J¼7.2 Hz, Phe3-NH), 5.72 (1H, d,
d
J¼6.8 Hz, Tyr5-NH), 4.67 (1H, dd, J¼8.8, 5.2 Hz, Phe3a-H), 4.55e4.52
(1H, m, Tyr5a-H), 4.49e4.41 (2H, m,
D
-Ala1a-H and Tyr6a-H),
4.09e4.03 (1H, m, Ala2a-H), 3.97 (3H, s, Tyr5-OCH3), 3.87 (3H, s,
Tyr6-OCH3), 3.76 (1H, d, J¼14.4 Hz, Tyr5b-Hb), 3.67 (1H, t, J¼6.4 Hz,
Ala4a-H), 3.32 (1H, d, J¼11.6 Hz, Tyr6b-Hb), 3.07 (1H, d, J¼11.6 Hz,
Tyr6b-Ha), 3.00 (1H, dd, J¼13.2, 5.2 Hz, Phe3b-Hb), 2.81 (1H, dd,
J¼13.2, 8.8 Hz, Phe3b-Ha), 2.58 (1H, dd, J¼14.4, 6.0 Hz, Tyr5b-Ha),
4.18. General synthesis procedures for compounds (4e8)
LiOH$H2O (3.7 mg, 0.084 mmol) was added to a solution of 44,
45, 46, 47 or 48 (0.042 mmol) in THF/MeOH/H2O (3:1:1, 2 mL) at
0 ꢀC. The reaction mixture was stirred at the same temperature for
1 h, then quenched with 15% aqueous citric acid to adjust the pH to
3. The whole was extracted with ethyl acetate (3ꢁ5 mL). The or-
ganic extracts were combined and washed with brine (3 mL), dried
with anhydrous Na2SO4, and concentrated in vacuo to give the acid
product. These acid products were dissolved in TFA/DCM (1:1,1 mL)
at 0 ꢀC. After stirring the solution at 0 ꢀC for 1 h, the volatiles was
removed in vacuo, and the residue was dissolved in anhydrous
dichloromethane (50 mL). To this solution DEPBT (128 mg,
0.42 mmol) and NaHCO3 (35 mg, 0.42 mmol) were added at room
temperature. After stirring the solution for 5 days, the solvent was
removed under vacuum. Dichloromethane (10 mL) and 15% aque-
ous citric acid (5 mL) were added and the whole was extracted with
dichloromethane (2ꢁ10 mL). The combined organic extracts were
washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo to give the
crude products.
1.36 (3H, d, J¼7.2 Hz, Ala2b-H), 1.24 (3H, d, J¼6.8 Hz,
D
-Ala1b-H), 0.82
172.57 (Ala2
(3H, d, J¼6.4 Hz, Ala4b-H). 13C NMR (100 MHz, CDCl3):
d
and Tyr6-C]O), 172.36 ( -Ala1-C]O), 172.00 (Ala4-C]O), 171.50
D
(Phe3-C]O), 171.40 (Tyr5-C]O), 156.23 (Tyr5z-C), 156.13 (Tyr6z-C),
d
d
140.81 (Tyr6 b-C), 140.71 (Tyr5 a-C), 135.99 (Phe3g-C), 131.25
(Tyr5 3 a-C), 129.84 (Phe3d-C), 129.07 (Tyr6 a-C), 128.84 (Tyr6g-C),
d
128.65 (Tyr5 b-C), 128.23 (Tyr6 3 b-C), 128.16 (Phe3 -C), 126.78 (Phe3
-
-
d
3
z
C),126.26 (Tyr5g-C),111.99 (Tyr5 3 b-C),111.61 (Tyr6 3 a-C), 56.93 (Tyr6
a
C), 56.43 (Tyr5-OCH3), 56.21 (Tyr6-OCH3), 55.72 (Tyr5a-C), 53.69
(Phe3a-C), 51.29 (Ala2a-C), 50.41 (Ala4a-C), 47.91 (
(Phe3b-C), 33.67 (Tyr6b-C), 33.50 (Tyr5b-C), 17.19 (Ala2b-C), 15.02
(Ala4b-C), 14.59 -Ala1b-C). HRMS (ESI-TOF) m/z calcd for
38H44N6O8 [M]þ 712.3221, found 712.3240.
D
-Ala1a-C), 39.00
(
D
C
4.18.3. Compound 6. Purification by HPLC (MeCN/H2O: 48:52) to
give compound (61%) as colorless, amorphous solid.
Mp 253e255 ꢀC; IR nmax (cmꢂ1): 3472, 3451, 3432, 2927, 1644, 1513,
6
a