The Journal of Organic Chemistry
the reaction mixture was filtered, and washed with CH2Cl2
three times. The filtrate was concentrated to give the crude
product.
Page 6 of 7
1.78-1.70 (4H, overlapped), 1.70-1.60 (6H, overlapped), 1.35
(3H, d, J = 6.5), 1.29 (9H, s), 0.95 (3H, d, J = 6.0), 0.90 (3H,
d, J = 6.5), 0.83 (3H, d, J = 7.0), 0.51 (3H, d, J =7.0); 13C
NMR (125 MHz, CDCl3) ppm: 179.1, 177.2, 175.2, 171.1,
170.6, 170.5, 169.5, 164.7, 154.1, 138.3, 132.8, 129.4, 126.2,
124.6, 78.5, 74.2, 60.7, 55.7, 55.1, 54.7, 49.9, 45.1, 43.0, 40.3,
39.8, 39.7, 37.1, 36.7, 36.3, 30.8, 30.0, 29.8, 28.8, 28.54,
28.48, 28.44, 24.7, 23.5, 23.3, 22.7, 22.4, 19.4, 16.6, 16.4,
14.7; HR-ESI-MS calcd for C34H52N5O8 [M+H]+: 658.3816,
found: 658.3803.
1
2
3
4
5
6
7
8
To a stirred solution of MNBA (125.5 mg, 0.365 mmol) and
DMAP (79.3 mg, 0.65 mmol) in dry CH2Cl2 (8.7 mL) at 50 oC
under N2 was added a solution of the above crude (0.061
mmol) in dry THF (17.8 mL) using syringe pump over a 6 h.
After the addition was completed, the reaction mixture was
stirred for 30 min at the same temperature. The reaction was
quenched with sat. NH4Cl aq., and the layers were separated.
The aqueous layer was extracted two times with ethyl acetate
and the combined organic layers were washed with brine,
dried over Na2SO4, and evaporated. The residue was purified
by silica gel flash column chromatography (ethyl acetate/n-
hexane = 50:50) to afford 16.7 mg (31% from resin 14) of 20
9
N-((6R,9R,12S,15S,16R,Z)-3-ethylidene-6-(4-
hydroxybenzyl)-12-isobutyl-9-isopropyl-16-methyl-
2,5,8,11,14-pentaoxo-1-oxa-4,7,10,13-
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
tetraazacyclohexadecan-15-yl)acetamide (18). To a stirred
solution of compound 21 (8.5 mg, 0.013 mmol) in CH2Cl2
(0.30 mL) was added TFA (0.30 mL) at 0 oC. After stirring for
30 min at room temperature, the volatile substances were
evaporated and the remained TFA was removed by co-
evaporation with toluene to give the crude product. The
residue was purified by reversed-phase HPLC (column:
PEGASIL ODS SP-100 20 × 250 mm, Senshu Scientific Co.,
LTD., Tokyo, Japan, eluent A: MeCN, eluent B: H2O, A/B =
40/60, flow rate: 6.0 mL/min, detection: UV 220 nm) to give
18 (tR = 22.0 min, 5.8 mg, 75%) as a white solid; []D20 +2.30
(c 0.10, MeOH); IR (ATR) max cm-1: 1715, 1697, 1681, 1665,
1645, 1636, 1541, 1456; 1H NMR (500 MHz, CD3OD) ppm:
7.84 (1H, d, J = 7.0), 7.18 (2H, d, J = 8.5), 6.79 (1H, ddd, J =
7.5, 7.5, 7.0), 6.69 (2H, d, J = 8.5), 5.16 (1H, m), 4.57 (1H, d,
J = 3.5), 4.50 (1H, m), 4.29 (1H, t, J = 6.0), 3.80 (1H, d, J =
4.0), 3.37 (1H, m), 3.11 (1H, t, J = 13.3), 2.07 (1H, m), 2.01
(3H, s), 1.73 (3H, d, J = 6.5), 1.63 (1H, m), 1.53 (1H, m), 1.46
(3H, d, J = 6.5), 1.00 (3H, d, J = 6.5), 0.93 (3H, d, J = 6.5),
0.80 (3H, d, J = 7.5), 0.59 (3H, d, J = 7.5); 13C NMR (125
MHz, CD3OD) ppm: 178.7, 174.2, 174.0, 172.1, 171.3,
165.4, 157.3, 138.0, 131.1, 129.9, 127.6, 116.4, 74.9, 62.5,
58.1, 57.3, 54.6, 40.9, 36.4, 30.0, 25.8, 22.9, 22.4, 19.3, 17.1,
16.4, 14.7; HR-ESI-MS calcd for C30H44N5O8 [M+H]+:
602.3190, found: 602.3196.
20
as a white solid; []D +31.5 (c 0.14, CHCl3); IR (ATR) max
cm-1: 1748, 1716, 1697, 1683, 1670, 1647, 1634, 1235, 1163,
771; 1H NMR (500 MHz, CDCl3) ppm: 7.37 (2H, d, J = 6.5),
7.33 (1H, d J = 8.5), 7.28-7.23 (3H, overlapped), 7.21 (1H, d,
J = 6.0), 7.17 (2H, d, J = 8.5), 6.89 (2H, d, J = 8.0), 6.19 (2H,
d, J = 9.0), 5.75 (1H, br-s), 5.21 (1H, m), 4.91 (1H, m), 4.75
(2H, m), 4.60 (2H, s), 4.16 (1H, m), 4.00 (1H, m), 3.94 (1H,
m), 3.69 (1H, dd, 14.5, 3.5), 2.85 (1H, t, J = 13.5), 2.24 (1H,
m), 2.10 (3H, s), 1.55 (2H, m), 1.45 (1H, m), 1.33 (2H, d, J =
6.5), 1.30 (9H, s), 1.23 (2H, d, J = 6.0), 0.97 (3H, d, J = 6.0),
0.93 (3H, d, J = 6.0), 0.80 (3H, d, J = 6.5), 0.47 (3H, d, J =
6.5); 13C NMR (125 MHz, CDCl3) ppm: 173.3, 171.4, 170.9,
170.0, 168.8, 138.8, 132.7, 129.4, 127.9, 127.6, 127.1, 124.3,
72.8, 72.2, 71.4, 60.1, 55.7, 55.2, 54.2, 53.8, 40.0, 36.1, 28.7,
28.1, 24.6, 23.2, 22.5, 22.3, 19.4, 16.5, 16.3; HR-ESI-MS
calcd for C41H60N5O9 [M+H]+: 766.4391, found: 766.4372.
N-((6R,9R,12S,15S,16R,Z)-6-(4-(tert-butoxy)benzyl)-3-
ethylidene-12-isobutyl-9-isopropyl-16-methyl-2,5,8,11,14-
pentaoxo-1-oxa-4,7,10,13-tetraazacyclohexadecan-15-
yl)acetamide (21). To a stirred solution of compound 20 (15.3
mg, 0.020 mmol) in MeOH (1.0 mL) was added Pd(OH)2/C
(10%, 1.5 mg) and the mixture was stirred at room
temperature under H2 atmosphere for 2 h. The mixture was
filtered through Celite and the filtrate was concentrated under
reduced pressure to give a crude product that was subjected to
the next reaction without further purification.
(2S,4S)-N-((6R,9R,12S,15S,16R)-3-ethyl-6-(4-
hydroxybenzyl)-12-isobutyl-9-isopropyl-16-methyl-
2,5,8,11,14-pentaoxo-1-oxa-4,7,10,13-
To a stirred solution of the above crude product in dry CH2Cl2
tetraazacyclohexadecan-15-yl)-2,4-dimethylheptanamide (19).
To a stirred solution of tumescenamide C (1, 11.5 mg, 0.016
mmol) in MeOH (1.0 mL) was added Pd(OH)2/C (10%, 1.2
mg) and the mixture was stirred at room temperature under H2
atmosphere for 16 h. The mixture was filtered through Celite
and the filtrate was concentrated under reduced pressure to
give a crude product. The residue was purified by reversed-
phase HPLC (column: PEGASIL ODS SP-100 20 × 250 mm,
Senshu Scientific Co., LTD., Tokyo, Japan, eluent A: MeCN,
eluent B: H2O, A/B = 53/47, flow rate: 6.0 mL/min, detection:
UV 220 nm) to give 19 (tR = 47.2 min, 6.2 mg, 54%) as a
white solid; []D20 +21.5 (c 0.14, MeOH); IR (ATR) max cm-1:
1715, 1698, 1684, 1653, 1647, 1635, 1558, 1542, 1522, 1507,
(1.0 mL) were added NEt3 (42.5 L, 0.312 mmol), and MsCl
(19.2 L, 0.253 mmol) at 0 C under N2 atmosphere. After
o
stirring for 1 h at room temperature, DBU (41.7 L, 0.285
mmol) was added to the mixture at 0 oC and the whole mixture
was stirred at room temperature for 16 h. The reaction was
quenched with H2O and the layers were separated. The
aqueous layer was extracted two times with ethyl acetate and
the combined organic layers were washed with brine, dried
over Na2SO4, and evaporated. The residue was purified by
silica gel flash column chromatography (ethyl acetate/n-
hexane = 50:50) to afford 15.4 mg (79% in 2 steps) of
depsipeptide 21 as a white solid; []D20 +17.5 (c 0.33, CHCl3);
IR (ATR) max cm-1: 1715, 1648, 1681, 1669, 1653, 1637,
1624, 1557, 1541, 1507, 1317, 1260, 1157, 772; 1H NMR (500
MHz, CDCl3) ppm: 7.98 (1H, s), 7.62 (1H, s), 7.48 (1H, d, J
= 8.5), 7.21 (2H, d, J = 8.0), 6.90 (2H, d, J = 8.5), 6.82 (1H, q,
J = 7.2), 6.36 (2H, m), 6.03 (1H, t, J = 6.5), 5.17 (1H, m), 4.85
(1H, dd, J = 8.0, 3.0), 4.80 (1H, m), 4.04 (1H, m), 3.96 (1H,
m), 3.62 (1H, m), 3.48 (2H, q, J = 5.5), 3.33 (2H, m), 3.19
(1H, m), 3.07 (2H, q, J = 5.5), 2.92 (3H, s), 2.54-2.44 (4H,
overlapped), 2.40 (1H, m), 2.05 (3H, s), 1.79 (3H, d, J = 7.0),
1
669; H NMR (500 MHz, CD3OD) ppm: 7.76 (1H, d, J =
9.0), 7.71 (1H, d, J = 8.5), 7.53 (1H, d, J = 10.0), 7.14 (2H, d,
J = 8.5), 6.68 (2H, d, J = 8.5), 5.35 (1H, m), 4.67 (1H, m),
4.59 (1H, m), 4.48 (1H, m), 4.27 (1H, t, J = 7.5), 3.82 (1H, d,
J = 4.5), 3.40 (1H, m), 3.03 (1H, dd, J = 13.5, 13.0), 2.65 (1H,
m), 2.07 (1H, m), 1.97 (1H, m), 1.70-1.60 (3H, overlapped),
1.53 (2H, m), 1.31 (3H, d, J = 6.5), 1.24-1.10 (2H,
overlapped), 1.11 (3H, d, J = 7.0), 1.04 (1H, m), 0.99 (3H, d, J
= 7.5), 0.95 (3H, d, J = 7.5), 0.90 (3H, t, J = 7.0), 0.82-0.76
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