804 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 3
Sugimoto et al.
carboxylate (19 mg, 0.10 mmol), a solution of (2Z,4Z)-2,4-
heptadienamide 8 (75 mg, 0.60 mmol) and 2,2′-bipyridine (20 mg,
0.12 mmol) in DMA (0.9 mL), which was dried over MS4A, and
then the resulting mixture was immediately degassed until no
bubbles were found. After being stirred for 30 min at room
temperature with light shielding, a solution of 23 (44 mg, 0.10
mmol) in DMA (0.6 mL), which was dried over MS4A, was added
and the resulting solution was immediately degassed until no
bubbles were found. After being stirred for 1 h at 90 °C with light
shielding, the reaction solution was diluted with ether at room
temperatur, and was quenched with pH 7.0 phosphate buffer at 0
°C. The organic layer was separated, washed with pH 7.0 phosphate
buffer, water and brine, and dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash silica gel column chromatography (hexane/ethyl acetate )
3/1 to 1/3) to afford the roughly purified substance (58.3 mg), which
was purified by the preparative HPLC to afford salicylihalamide
A (1a) (10.1 mg, 0.023 mol, 23%) and salicylihalamide B (1b)
(11.4 mg, 0.026 mmol, 26%) as a colorless wax, respectively. HPLC
conditions: column: COSMOSIL 5C18-MS-II (NACALAI TESQUE,
INC.), 10 mm × 250 mm; detection: λ ) 280 nm; flow rate: 2.0
mL/min; elution with a gradient solvent system: MeOH/H2O ) 7/3,
0-100 min: MeOH/H2O ) 7/3 f MeOH, 100-120 min: MeOH,
120-140 min; The tR of salicylihalamide A (1a) and salicylihala-
mide B (1b) were 64.2 and 81.0 min, respectively.
4-19F-Salicylihalamide A (6a) and B (6b). N,N′-dimethyl
acetamide (DMA) used in this reaction was degassed by freeze-thaw
method over 10 times. Rb2CO3 (139 mg, 0.60 mmol) in a Schlenk
flask was dried by heating with a drier under reduced pressure for
15 min. After cooling to room temperature, copper(I) thiophen-
ecarboxylate (19 mg, 0.10 mmol) was added in glove box. A
solution of (2Z,4Z)-2,4-heptadienamide 8 (75 mg, 0.60 mmol) and
2,2′-bipyridine (20 mg, 0.12 mmol) in DMA (0.7 mL), which was
dried over MS4A, was added and the resulting mixture was
immediately degassed over and over again until no bubbles were
found. After being stirred for 30 min at room temperature with
light shielding, a solution of of 22 (46 mg, 0.10 mmol) in DMA
(0.7 mL), which was dried over MS4A, was added and the resulting
solution was immediately degassed over and over again until no
bubbles were found. After being stirred for 1 h at 90 °C with light
shielding, the reaction mixture was diluted with ether at room
temperature and was quenched with pH 7.0 phosphate buffer at 0
°C. The organic layer was separated, washed with pH 7.0 phosphate
buffer, water and brine, and dried over Na2SO4, filtrered, and
concentrated under reduced pressure. The residue was purified by
flash silica gel column chromatography (3:1 to 1:3 hexane/ethyl
acetate) to afford the roughly purified substance (29 mg), which
was purified by the preparative HPLC to afford 4-19F-salicylihala-
mide A (6a) (7.1 mg, 0.015 mol, 15%) and 4-19F-salicylihalamide
B (6b) (10.1 mg, 0.022 mmol, 22%) as a colorless wax, respectively.
HPLC conditions: column: COSMOSIL 5C18-MSII, 10 mm × 250
mm; detection: 280 nm; flow rate: 2.0 mL/min, eluent: 70:30
MeOH/H2O, 100 min, 70:30 f 100:0, 20 min, 100:0, 30 min. The
retention times (tR) of 6a and 6b were 63.4 and 73.4 min,
19
1a. [R]D ) -32.6 (c 0.169, MeOH); Rf 0.25 (hexane/ethyl
acetate ) 1/1); IR (film) 3285, 2964, 1700, 1653, 1589, 1523, 1464,
1
1293, 1248, 1216, 1123, 1066, 971 cm-1; H NMR (500 MHz,
C6D6) δ 11.5 (1H, br, C3-OH), 7.93 (1H, br dd, J ) 11.4, 11.4 Hz,
H22), 7.12 (1H, dd, J ) 14.3, 10.9 Hz, H18), 6.99-6.94 (2H, m,
H4 and H5), 6.62 (1H, dd, J ) 11.6, 11.6 Hz, H21), 6.50 (1H, br
d, -NH), 6.48 (1H, dd, J ) 6.6, 2.3 Hz, H6), 5.62 (1H, ddddd, J
) 10.8, 7.7, 7.7, 1.3, 1.3 Hz, H23), 5.54(1H, ddd, J ) 10.0, 6.6,
6.6 Hz, H15), 5.28 (1H, ddd, J ) 15.5, 4.3, 4.3 Hz, H9), 5.10 (1H,
br d, J ) 10.9 Hz, H20), 5.05 (1H, br ddd, J ) 14.6, 6.9, 6.9 Hz,
H10), 4.77 (1H, br ddd, J ) 14.3, 7.2, 7.2 Hz, H17), 3.62 (1H, br
dd, J ) 16.5, 5.3 Hz, H8a), 3.44 (1H, dd, J ) 8.3, 2.9 Hz, H13),
3.32 (1H, br d, J ) 16.0 Hz, H8b), 2.17 (1H, ddd, J ) 14.0, 7.2,
7.2 Hz, H16a), 2.12 (1H, ddd, J ) 12.3, 5.7, 5.7 Hz, H11a), 2.05
(1H, ddd, J ) 14.0, 6.9, 6.9 Hz, H16b), 1.97 (2H, tdd, J ) 7.6,
7.6, 1.4 Hz, H24), 1.66 (1H, dd, J ) 15.1, 10.8 Hz, H14a), 1.62
(1H, dd, J ) 13.5, 8.9 Hz, H11b), 1.56-1.45 (1H, m, H12), 1.27
(1H, dd, J ) 14.9, 8.6 Hz, H14b), 0.82 (3H, d, J ) 6.9 Hz, H26),
0.77 (3H, t, J ) 7.7 Hz, H25); 13C NMR (125 MHz, C6D6) δ 171.2,
170.0, 163.0, 162.9, 142.6, 141.7, 136.9, 134.0, 132.7, 127.1, 126.0,
124.9, 123.6, 119.7, 117.1, 114.7, 107.0, 75.3, 70.4, 39.3, 38.6,
37.6, 36.4, 35.5, 20.8, 14.0, 13.9; HRMS (ESI-TOF) m/z calcd for
C26H33NNaO5 (M + Na+) 462.2256, found 462.2253.
28
respectively. 6a: [R]D -50.0 (c 0.213, MeOH); Rf ) 0.34 (1:1
hexane/ethyl acetate); λmax (MeOH) 282 nm (ε ) 26200); IR (film)
3281, 2963, 2931, 1691, 1656, 1611, 1492, 1461, 1288, 1248, 1218,
1138, 1081, 1027, 971, 820, 678 cm-1; 1H NMR (500 MHz, C6D6)
δ 10.5 (1H, br, C3-OH), 7.91 (1H, br dd, J ) 11.5, 11.5 Hz, H22),
7.08 (1H, dd, J ) 14.3, 10.6 Hz, H18), 6.72 (1H, dd, J ) 9.7, 8.3
Hz, H5), 6.61 (1H, ddd, J ) 11.5, 11.5, 0.9 Hz, H21), 6.56 (1H, br
s, -NH), 6.19 (1H, dd, J ) 8.3, 4.6 Hz, H6), 5.63 (1H, ddddd, J
) 10.9, 7.7, 7.7, 1.3, 1.3 Hz, H23), 5.53 (1H, m, H15), 5.23 (1H,
ddd, J ) 15.5, 4.7, 4.7 Hz, H9), 5.10 (1H, br d, J ) 11.5 Hz,
H20), 5.13-5.03 (1H, m, H10), 5.05 (1H, br ddd, J ) 14.6, 6.9,
6.9 Hz, H10), 4.85 (1H, ddd, J ) 14.3, 7.2, 7.2 Hz, H17), 3.68
(1H, br d, J ) 6.0 Hz, H13), 3.37 (2H, m, H8), 2.21 (1H, ddd, J
) 14.3, 7.4, 7.4 Hz, H16a), 2.12 (1H, m, H11a), 2.08 (1H, ddd, J
) 13.6, 6.0, 6.0 Hz, H16b), 1.97 (2H, tdd, J ) 7.6, 7.6, 1.4 Hz,
H24), 1.66 (1H, dd, J ) 15.0, 9.9 Hz, H14a), 1.65-1.53 (2H, m,
H11b and H12), 1.31 (1H, dd, J ) 14.6, 9.2 Hz, H14b), 0.83 (3H,
d, J ) 6.9 Hz, H26), 0.77 (3H, t, J ) 7.6 Hz, H25); 13C NMR (125
MHz, C6D6) δ 169.7 164.2, 160.5, 151.5 (d, 1JCF ) 240 Hz), 141.9,
137.2, 135.8, 130.8, 129.5, 126.0, 124.9, 121.7, 119.7, 117.5, 108.8,
76.0, 71.1, 38.3, 37.6, 36.7, 36.2, 20.8, 14.0, 13.7 (1 of the sp2
carbons were obserded); 19F NMR (470 MHz, C6D6) δ -138.6 (s);
HRMS (ESI-TOF) m/z calculated for C26H33FNO5 (M + H+)
458.2343, found 458.2341. 6b: [R]D28 -71.0 (c 0.301, MeOH); Rf
) 0.34 (hexane/ethyl acetate ) 1/1); λmax (MeOH) 282 nm (ε )
22,100); IR (film) 3357, 2964, 2931, 1707, 1654, 1590, 1491, 1274,
1248, 1207, 1170, 1137, 1032, 973, 678 cm-1; 1H NMR (500 MHz,
C6D6) δ 7.90 (1H, dd, J ) 11.5, 11.4 Hz, H22), 7.71 (1H, br s,
-NH), 7.26 (1H, dd, J ) 9.9 Hz, H18), 6.72 (1H, dd, J ) 9.7, 9.7
Hz, H5), 6.67 (1H, dd, J ) 11.7, 11.7 Hz, H21), 6.17 (1H, dd, J )
8.2, 4.6 Hz, H6), 5.63 (1H, br ddd, J ) 10.9, 7.9, 7.9 Hz, H23),
5.51 (1H, d, J ) 10.9 Hz, H20), 5.36 (1H, m, H15), 5.20-5.08
(2H, m, H9 and H10), 4.65 (1H, ddd, J ) 8.3, 8.3, 8.0 Hz, H17),
3.60 (1H, m, H13), 3.34 (1H, br d, J ) 15.7 Hz, H8a), 3.30 (1H,
br d, J ) 15.7 Hz, H8b), 2.17 (1H, ddd, J ) 14.0, 7.2, 7.2 Hz,
H16a), 2.11-2.01 (1H, m, H11a), 2.06 (1H, br d, J ) 14.5 Hz,
H16b), 1.97 (2H, tdd, J ) 7.6, 7.6, 1.4 Hz, H24), 1.76 (1H, dd, J
) 14.9, 10.0 Hz, H14a), 1.72-1.65 (1H, m, H11b), 1.65-1.55 (1H,
m, H12), 1.30 (1H, dd, J ) 14.9, 8.9 Hz, H14b), 0.85 (3H, d, J )
6.9 Hz, H26), 0.78 (3H, t, J ) 7.7 Hz, H25); 13C NMR (125 MHz,
C6D6) δ 170.0, 164.0, 151.2 (d, 1JCF ) 246 Hz), 142.0, 137.4, 136.7,
131.1, 128.9, 124.9 (d, JCF ) 12 Hz), 122.2 (d, JCF ) 5 Hz), 119.6,
20
1b. [R]D ) -90.4 (c 0.025, MeOH); Rf 0.25 (hexane/ethyl
acetate ) 1/1); IR (film) 3286, 2960, 2924, 1695, 1653, 1587, 1507,
1
1464, 1294, 1247, 1211, 1119, 1032, 966 cm-1; H NMR (500
MHz, C6D6) δ 11.8 (1H, br, C3-OH), 7.97 (1H, br dd, J ) 11.4,
11.4 Hz, H22), 7.57 (1H, br d, J ) 9.2 Hz, -NH), 7.31 (1H, dd, J
) 10.0, 10.0 Hz, H18), 6.98-6.94 (2H, m, H4 and H5), 6.62 (1H,
ddd, J ) 11.4, 11.4, 0.9 Hz, H21), 6.45 (1H, dd,6.3, 2.6 Hz, H6),
5.26-5.12 (2H, m, H15 and H10), 6.48 (1H, dd, J ) 6.6, 2.3 Hz,
H6), 5.62 (1H, ddddd, J ) 10.8, 7.7, 7.7, 1.3, 1.3 Hz, H23), 5.44
(1H, d, J ) 11.5 Hz, H20), 5.25-5.12 (2H, m, H15 and H10),
5.07 (1H, ddd, J ) 15.3, 7.2, 7.2 Hz, H9), 4.48 (1H, ddd, J ) 8.0,
8.0, 8.0 Hz, H17), 3.56 (1H, br dd, J ) 16.5, 5.3 Hz, H8a), 3.24
(1H, br d, J ) 16.9 Hz, H8b), 3.21 (1H, br d, J ) 9.7 Hz, H13),
2.11-1.99 (1H, m, H11a), 2.04 (1H, ddd, J ) 14.0, 7.4, 7.4 Hz,
H16a), 1.94 (2H, tdd, J ) 7.6, 7.6, 1.4 Hz, H24), 1.84 (1H, ddd, J
) 14.3, 7.7, 7.7 Hz, H16b), 1.77-1.68 (1H, m, H11b), 1.72 (1H,
dd, J ) 14.7, 10.7 Hz, H14a), 1.45 (1H, br q, J ) 6.8 Hz, H12),
1.19 (1H, dd, J ) 15.2, 8.6 Hz, H14b), 0.82 (3H, d, J ) 6.9 Hz,
H26), 0.77 (3H, t, J ) 7.4 Hz, H25); 13C NMR (125 MHz, C6D6)
δ 172.0, 162.9, 141.9, 137.3, 134.6, 132.8, 126.8, 125.4, 124.9,
123.7, 119.5, 117.2, 103.2, 76.1, 70.9, 39.4, 38.4, 38.0, 36.2, 31.4,
20.8, 14.0, 13.8; HRMS (ESI-TOF) m/z calcd for C26H33NNaO5
(M + Na+) 462.2256, found 462.2245.